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165 results on '"Gifford, Casey A."'

1. A lethal mitonuclear incompatibility in complex I of natural hybrids

Author

Moran, Benjamin M., Payne, Cheyenne Y., Powell, Daniel L., Iverson, Erik N. K., Donny, Alexandra E., Banerjee, Shreya M., Langdon, Quinn K., Gunn, Theresa R., Rodriguez-Soto, Rebecca A., Madero, Angel, Baczenas, John J., Kleczko, Korbin M., Liu, Fang, Matney, Rowan, Singhal, Kratika, Leib, Ryan D., Hernandez-Perez, Osvaldo, Corbett-Detig, Russell, Frydman, Judith, Gifford, Casey, Schartl, Manfred, Havird, Justin C., and Schumer, Molly

Published
2024
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2. Single-cell multimodal analyses reveal epigenomic and transcriptomic basis for birth defects in maternal diabetes

Author

Nishino, Tomohiro, Ranade, Sanjeev S., Pelonero, Angelo, van Soldt, Benjamin J., Ye, Lin, Alexanian, Michael, Koback, Frances, Huang, Yu, Wallace, Langley Grace, Sadagopan, Nandhini, Lam, Adrienne, Zholudeva, Lyandysha V., Li, Feiya, Padmanabhan, Arun, Thomas, Reuben, van Bemmel, Joke G., Gifford, Casey A., Costa, Mauro W., and Srivastava, Deepak

Published
2023
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3. Transcription Factor GATA4 Regulates Cell Type-Specific Splicing Through Direct Interaction With RNA in Human Induced Pluripotent Stem Cell-Derived Cardiac Progenitors.

Author

Zhu, Lili, Gonzalez-Teran, Barbara, Ang, Yen-Sin, Thomas, Reuben, Stone, Nicole, Liu, Lei, Zhou, Ping, Zhu, Chenchen, Ruan, Hongmei, Huang, Yu, Jin, Shibo, Pelonero, Angelo, Koback, Frances, Padmanabhan, Arun, Sadagopan, Nandhini, Hsu, Austin, Costa, Mauro, Gifford, Casey, van Bemmel, Joke, Hüttenhain, Ruth, Conklin, Bruce, Black, Brian, Bruneau, Benoit, Steinmetz, Lars, Krogan, Nevan, Pollard, Katherine, Srivastava, Deepak, Vedantham, Vasanth, and Choudhary, Krishna

Subjects
GATA4 transcription factor, RNA splicing, RNA-binding motifs, induced pluripotent stem cells, myocytes, cardiac, Alternative Splicing, Animals, GATA4 Transcription Factor, Heart, Humans, Induced Pluripotent Stem Cells, Mice, Myocytes, Cardiac, RNA
Abstract

BACKGROUND: GATA4 (GATA-binding protein 4), a zinc finger-containing, DNA-binding transcription factor, is essential for normal cardiac development and homeostasis in mice and humans, and mutations in this gene have been reported in human heart defects. Defects in alternative splicing are associated with many heart diseases, yet relatively little is known about how cell type- or cell state-specific alternative splicing is achieved in the heart. Here, we show that GATA4 regulates cell type-specific splicing through direct interaction with RNA and the spliceosome in human induced pluripotent stem cell-derived cardiac progenitors. METHODS: We leveraged a combination of unbiased approaches including affinity purification of GATA4 and mass spectrometry, enhanced cross-linking with immunoprecipitation, electrophoretic mobility shift assays, in vitro splicing assays, and unbiased transcriptomic analysis to uncover GATA4s novel function as a splicing regulator in human induced pluripotent stem cell-derived cardiac progenitors. RESULTS: We found that GATA4 interacts with many members of the spliceosome complex in human induced pluripotent stem cell-derived cardiac progenitors. Enhanced cross-linking with immunoprecipitation demonstrated that GATA4 also directly binds to a large number of mRNAs through defined RNA motifs in a sequence-specific manner. In vitro splicing assays indicated that GATA4 regulates alternative splicing through direct RNA binding, resulting in functionally distinct protein products. Correspondingly, knockdown of GATA4 in human induced pluripotent stem cell-derived cardiac progenitors resulted in differential alternative splicing of genes involved in cytoskeleton organization and calcium ion import, with functional consequences associated with the protein isoforms. CONCLUSIONS: This study shows that in addition to its well described transcriptional function, GATA4 interacts with members of the spliceosome complex and regulates cell type-specific alternative splicing via sequence-specific interactions with RNA. Several genes that have splicing regulated by GATA4 have functional consequences and many are associated with dilated cardiomyopathy, suggesting a novel role for GATA4 in achieving the necessary cardiac proteome in normal and stress-responsive conditions.

Published
2022

4. Transcription factor protein interactomes reveal genetic determinants in heart disease

Author

Gonzalez-Teran, Barbara, Pittman, Maureen, Felix, Franco, Thomas, Reuben, Richmond-Buccola, Desmond, Hüttenhain, Ruth, Choudhary, Krishna, Moroni, Elisabetta, Costa, Mauro W, Huang, Yu, Padmanabhan, Arun, Alexanian, Michael, Lee, Clara Youngna, Maven, Bonnie EJ, Samse-Knapp, Kaitlen, Morton, Sarah U, McGregor, Michael, Gifford, Casey A, Seidman, JG, Seidman, Christine E, Gelb, Bruce D, Colombo, Giorgio, Conklin, Bruce R, Black, Brian L, Bruneau, Benoit G, Krogan, Nevan J, Pollard, Katherine S, and Srivastava, Deepak

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Biomedical and Clinical Sciences, Genetics, Cardiovascular Medicine and Haematology, Clinical Sciences, Stem Cell Research, Biotechnology, Heart Disease - Coronary Heart Disease, Pediatric, Cardiovascular, Heart Disease, Congenital Structural Anomalies, Stem Cell Research - Embryonic - Human, Aetiology, 2.1 Biological and endogenous factors, Animals, GATA4 Transcription Factor, Heart Defects, Congenital, Mice, Mutation, Nuclear Proteins, Oxidoreductases, Proteomics, T-Box Domain Proteins, Transcription Factors, GATA4, GLYR1, NPAC, TBX5, congenital heart disease, de novo variants, disease variants, genetics, protein interactome networks, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
Abstract

Congenital heart disease (CHD) is present in 1% of live births, yet identification of causal mutations remains challenging. We hypothesized that genetic determinants for CHDs may lie in the protein interactomes of transcription factors whose mutations cause CHDs. Defining the interactomes of two transcription factors haplo-insufficient in CHD, GATA4 and TBX5, within human cardiac progenitors, and integrating the results with nearly 9,000 exomes from proband-parent trios revealed an enrichment of de novo missense variants associated with CHD within the interactomes. Scoring variants of interactome members based on residue, gene, and proband features identified likely CHD-causing genes, including the epigenetic reader GLYR1. GLYR1 and GATA4 widely co-occupied and co-activated cardiac developmental genes, and the identified GLYR1 missense variant disrupted interaction with GATA4, impairing in vitro and in vivo function in mice. This integrative proteomic and genetic approach provides a framework for prioritizing and interrogating genetic variants in heart disease.

Published
2022

5. Abstract 11332: Integration of Protein Interactome Networks with Congenital Heart Disease Variants Reveals Candidate Disease Genes

Author

Teran, Barbara Gonzalez, Pittman, Maureen, Thomas, Reuben, Felix, Franco, Richmond-Buccola, Desmond, Choudhary, Krishna, Moroni, Elisabetta, Giorgio, Colombo, Padmanabhan, Arun, Costa, Mauro, Huang, Yu, Alexanian, Michael, Lee, Clara, Cole, Bonie, Samse-Knapp, Kaitlen, McGregor, Michael, Gifford, Casey, Huttenhain, Ruth, Gelb, Bruce, Conklin, Bruce, Black, Brian L, Bruneau, Benoit, Krogan, Nevan, Pollard, Katherine, and Srivastava, Deepak

Subjects
Biotechnology, Cardiovascular, Stem Cell Research, Stem Cell Research - Embryonic - Human, Heart Disease, Genetics, Congenital Structural Anomalies, Pediatric, Human Genome, 2.1 Biological and endogenous factors, Aetiology, Good Health and Well Being, Cardiorespiratory Medicine and Haematology, Clinical Sciences, Public Health and Health Services, Cardiovascular System & Hematology
Abstract

Congenital heart disease (CHD) is present in 1% of live births, yet despite large-scale genomic sequencing efforts, identification of causal mutations remains a challenge. We hypothesized that genetic determinants for CHDs may lie in the protein interactomes of GATA4 and TBX5, two transcription factors whose mutation cause CHDs. Defining the GATA4 or TBX5 interactomes in human cardiac progenitors via affinity purification-mass spectrometry and integrating the results with genetic data from the Pediatric Cardiac Genomic Consortium revealed an enrichment of de novo variants associated with CHD. A consolidative score that prioritized interactome members based on variant, gene, and proband features identified likely CHD-causing genes, including the epigenetic reader GLYR1. GLYR1 and GATA4 widely co-occupied and co-activated cardiac developmental genes, and the GLYR1 missense variant identified disrupted interaction with GATA4 and impaired transcriptional co-regulation in cardiomyocyte differentiation in vitro and cardiogenesis in vivo. This integrative proteomic and genetic approach provides a framework for prioritizing and interrogating the contribution of genetic variants in disease.

Published
2021

6. Integration of Protein Interactome Networks With Congenital Heart Disease Variants Reveals Candidate Disease Genes

Author

Gonzalez-Teran, Barbara, Pittman, Maureen, Felix, Franco, Richmond-Buccola, Desmond, Thomas, Reuben, Choudhary, Krishna, Moroni, Elisabetta, Colombo, Giorgio, Alexanian, Michael, Cole, Bonnie, Samse-Knapp, Kaitlen, McGregor, Michael, Gifford, Casey A, Huttenhain, Ruth, Gelb, Bruce D, Conklin, Bruce, Black, Brian L, Bruneau, Benoit G, Krogan, Nevan J, Pollard, Katherine S, and Srivastava, Deepak

Published
2021

7. Considerations for reporting variants in novel candidate genes identified during clinical genomic testing

Author

Abouhala, Siwaar, Albert, Jessica, Almalvez, Miguel, Alvarez, Raquel, Amin, Mutaz, Anderson, Peter, Aradhya, Swaroop, Ashley, Euan, Assimes, Themistocles, Auriga, Light, Austin-Tse, Christina, Bamshad, Mike, Barseghyan, Hayk, Baxter, Samantha, Behera, Sairam, Beheshti, Shaghayegh, Bejerano, Gill, Berger, Seth, Bernstein, Jon, Best, Sabrina, Blankenmeister, Benjamin, Blue, Elizabeth, Boerwinkle, Eric, Bonkowski, Emily, Bonner, Devon, Boone, Philip, Bornhorst, Miriam, Brand, Harrison, Buckingham, Kati, Calame, Daniel, Carter, Jennefer, Casadei, Silvia, Chadwick, Lisa, Chavez, Clarisa, Chen, Ziwei, Chinn, Ivan, Chong, Jessica, Coban-Akdemir, Zeynep, Cohen, Andrea J., Conner, Sarah, Conomos, Matthew, Coveler, Karen, Cui, Ya Allen, Currin, Sara, Daber, Robert, Dardas, Zain, Davis, Colleen, Dawood, Moez, de Dios, Ivan, de Esch, Celine, Delaney, Meghan, Delot, Emmanuele, DiTroia, Stephanie, Doddapaneni, Harsha, Du, Haowei, Duan, Ruizhi, Dugan-Perez, Shannon, Duong, Nhat, Duyzend, Michael, Eichler, Evan, Emami, Sara, Fraser, Jamie, Fusaro, Vincent, Galey, Miranda, Ganesh, Vijay, Garcia, Brandon, Garimella, Kiran, Gibbs, Richard, Gifford, Casey, Ginsburg, Amy, Goddard, Page, Gogarten, Stephanie, Gogate, Nikhita, Gordon, William, Gorzynski, John E., Greenleaf, William, Grochowski, Christopher, Groopman, Emily, Sousa, Rodrigo Guarischi, Gudmundsson, Sanna, Gulati, Ashima, Hall, Stacey, Harvey, William, Hawley, Megan, Heavner, Ben, Horike-Pyne, Martha, Hu, Jianhong, Huang, Yongqing, Hwang, James, Jarvik, Gail, Jensen, Tanner, Jhangiani, Shalini, Jimenez-Morales, David, Jin, Christopher, Saad, Ahmed K., Kahn-Kirby, Amanda, Kain, Jessica, Kaur, Parneet, Keehan, Laura, Knoblach, Susan, Ko, Arthur, Kundaje, Anshul, Kundu, Soumya, Lancaster, Samuel M., Larsson, Katie, Lee, Arthur, Lemire, Gabrielle, Lewis, Richard, Li, Wei, Li, Yidan, Liu, Pengfei, LoTempio, Jonathan, Lupski, James (Jim), Ma, Jialan, MacArthur, Daniel, Mahmoud, Medhat, Malani, Nirav, Mangilog, Brian, Marafi, Dana, Marmolejos, Sofia, Marten, Daniel, Martinez, Eva, Marvin, Colby, Marwaha, Shruti, Mastrorosa, Francesco Kumara, Matalon, Dena, May, Susanne, McGee, Sean, Meador, Lauren, Mefford, Heather, Mendez, Hector Rodrigo, Miller, Alexander, Miller, Danny E., Mitani, Tadahiro, Montgomery, Stephen, Moyses, Mariana, Munderloh, Chloe, Muzny, Donna, Nelson, Sarah, Nguyen, Thuy-mi P., Nguyen, Jonathan, Nussbaum, Robert, Nykamp, Keith, O'Callaghan, William, O'Heir, Emily, O'Leary, Melanie, Olsen, Jeren, Osei-Owusu, Ikeoluwa, O'Donnell-Luria, Anne, Padhi, Evin, Pais, Lynn, Pan, Miao, Panchal, Piyush, Patterson, Karynne, Payne, Sheryl, Pehlivan, Davut, Petrowski, Paul, Pham, Alicia, Pitsava, Georgia, Podesta, Astaria`Sara, Ponce, Sarah, Porter, Elizabeth, Posey, Jennifer, Prosser, Jaime, Quertermous, Thomas, Rai, Archana, Ramani, Arun, Rehm, Heidi, Reuter, Chloe, Reuter, Jason, Richardson, Matthew, Rivera-Munoz, Andres, Rubio, Oriane, Sabo, Aniko, Salani, Monica, Samocha, Kaitlin, Sanchis-Juan, Alba, Savage, Sarah, Scott, Evette, Scott, Stuart, Sedlazeck, Fritz, Shah, Gulalai, Shojaie, Ali, Singh, Mugdha, Smith, Kevin, Smith, Josh, Snow, Hana, Snyder, Michael, Socarras, Kayla, Starita, Lea, Stark, Brigitte, Stenton, Sarah, Stergachis, Andrew, Stilp, Adrienne, Sutton, V. Reid, Tai, Jui-Cheng, Talkowski, Michael (Mike), Tise, Christina, Tong, Catherine (Cat), Tsao, Philip, Ungar, Rachel, VanNoy, Grace, Vilain, Eric, Voutos, Isabella, Walker, Kim, Wei, Chia-Lin, Weisburd, Ben, Weiss, Jeff, Wellington, Chris, Weng, Ziming, Westheimer, Emily, Wheeler, Marsha, Wheeler, Matthew, Wiel, Laurens, Wilson, Michael, Wojcik, Monica, Wong, Quenna, Xiao, Changrui, Yadav, Rachita, Yi, Qian, Yuan, Bo, Zhao, Jianhua, Zhen, Jimmy, Zhou, Harry, Chong, Jessica X., Berger, Seth I., Smith, Erica, Calame, Daniel G., Hawley, Megan H., Rivera-Munoz, E. Andres, Bamshad, Michael J., and Rehm, Heidi L.

Published
2024
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9. A transcriptional switch governs fibroblast activation in heart disease

Author

Alexanian, Michael, Przytycki, Pawel F, Micheletti, Rudi, Padmanabhan, Arun, Ye, Lin, Travers, Joshua G, Gonzalez-Teran, Barbara, Silva, Ana Catarina, Duan, Qiming, Ranade, Sanjeev S, Felix, Franco, Linares-Saldana, Ricardo, Li, Li, Lee, Clara Youngna, Sadagopan, Nandhini, Pelonero, Angelo, Huang, Yu, Andreoletti, Gaia, Jain, Rajan, McKinsey, Timothy A, Rosenfeld, Michael G, Gifford, Casey A, Pollard, Katherine S, Haldar, Saptarsi M, and Srivastava, Deepak

Subjects
Heart Disease, Cardiovascular, Lung, Genetics, Underpinning research, 2.1 Biological and endogenous factors, Aetiology, 1.1 Normal biological development and functioning, Animals, Chromatin, Enhancer Elements, Genetic, Epigenomics, Fibroblasts, Gene Expression Regulation, Heart Diseases, Homeodomain Proteins, Humans, Mice, Proteins, Single-Cell Analysis, Transcription Factors, Transcriptome, Transforming Growth Factor beta, General Science & Technology
Abstract

In diseased organs, stress-activated signalling cascades alter chromatin, thereby triggering maladaptive cell state transitions. Fibroblast activation is a common stress response in tissues that worsens lung, liver, kidney and heart disease, yet its mechanistic basis remains unclear1,2. Pharmacological inhibition of bromodomain and extra-terminal domain (BET) proteins alleviates cardiac dysfunction3-7, providing a tool to interrogate and modulate cardiac cell states as a potential therapeutic approach. Here we use single-cell epigenomic analyses of hearts dynamically exposed to BET inhibitors to reveal a reversible transcriptional switch that underlies the activation of fibroblasts. Resident cardiac fibroblasts demonstrated robust toggling between the quiescent and activated state in a manner directly correlating with BET inhibitor exposure and cardiac function. Single-cell chromatin accessibility revealed previously undescribed DNA elements, the accessibility of which dynamically correlated with cardiac performance. Among the most dynamic elements was an enhancer that regulated the transcription factor MEOX1, which was specifically expressed in activated fibroblasts, occupied putative regulatory elements of a broad fibrotic gene program and was required for TGFβ-induced fibroblast activation. Selective CRISPR inhibition of the single most dynamic cis-element within the enhancer blocked TGFβ-induced Meox1 activation. We identify MEOX1 as a central regulator of fibroblast activation associated with cardiac dysfunction and demonstrate its upregulation after activation of human lung, liver and kidney fibroblasts. The plasticity and specificity of BET-dependent regulation of MEOX1 in tissue fibroblasts provide previously unknown trans- and cis-targets for treating fibrotic disease.

Published
2021

10. Network-based screen in iPSC-derived cells reveals therapeutic candidate for heart valve disease

Author

Theodoris, Christina V, Zhou, Ping, Liu, Lei, Zhang, Yu, Nishino, Tomohiro, Huang, Yu, Kostina, Aleksandra, Ranade, Sanjeev S, Gifford, Casey A, Uspenskiy, Vladimir, Malashicheva, Anna, Ding, Sheng, and Srivastava, Deepak

Subjects
Heart Disease, Biotechnology, Stem Cell Research, Rare Diseases, Stem Cell Research - Induced Pluripotent Stem Cell, Cardiovascular, Stem Cell Research - Induced Pluripotent Stem Cell - Human, Orphan Drug, Genetics, Regenerative Medicine, Aetiology, 5.1 Pharmaceuticals, 2.1 Biological and endogenous factors, Development of treatments and therapeutic interventions, Good Health and Well Being, Algorithms, Animals, Aortic Valve, Aortic Valve Disease, Aortic Valve Stenosis, Calcinosis, Disease Models, Animal, Drug Discovery, Drug Evaluation, Preclinical, Gene Expression Regulation, Gene Regulatory Networks, Haploinsufficiency, Humans, Induced Pluripotent Stem Cells, Machine Learning, Mice, Inbred C57BL, Nitriles, RNA-Seq, Receptor, Notch1, Small Molecule Libraries, Thiazoles, General Science & Technology
Abstract

Mapping the gene-regulatory networks dysregulated in human disease would allow the design of network-correcting therapies that treat the core disease mechanism. However, small molecules are traditionally screened for their effects on one to several outputs at most, biasing discovery and limiting the likelihood of true disease-modifying drug candidates. Here, we developed a machine-learning approach to identify small molecules that broadly correct gene networks dysregulated in a human induced pluripotent stem cell (iPSC) disease model of a common form of heart disease involving the aortic valve (AV). Gene network correction by the most efficacious therapeutic candidate, XCT790, generalized to patient-derived primary AV cells and was sufficient to prevent and treat AV disease in vivo in a mouse model. This strategy, made feasible by human iPSC technology, network analysis, and machine learning, may represent an effective path for drug discovery.

Published
2021

11. Beyond the exome: What’s next in diagnostic testing for Mendelian conditions

Author

Abouhala, Siwaar, Albert, Jessica, Almalvez, Miguel, Alvarez, Raquel, Amin, Mutaz, Anderson, Peter, Aradhya, Swaroop, Ashley, Euan, Assimes, Themistocles, Auriga, Light, Austin-Tse, Christina, Bamshad, Mike, Barseghyan, Hayk, Baxter, Samantha, Behera, Sairam, Beheshti, Shaghayegh, Bejerano, Gill, Berger, Seth, Bernstein, Jon, Best, Sabrina, Blankenmeister, Benjamin, Blue, Elizabeth, Boerwinkle, Eric, Bonkowski, Emily, Bonner, Devon, Boone, Philip, Bornhorst, Miriam, Bozkurt-Yozgatli, Tugce, Brand, Harrison, Buckingham, Kati, Calame, Daniel, Casadei, Silvia, Chadwick, Lisa, Chavez, Clarisa, Chen, Ziwei, Chinn, Ivan, Chong, Jessica, Coban-Akdemir, Zeynep, Cohen, Andrea J., Conner, Sarah, Conomos, Matthew, Coveler, Karen, Cui, Ya Allen, Currin, Sara, Daber, Robert, Dardas, Zain, Davis, Colleen, Dawood, Moez, de Dios, Ivan, de Esch, Celine, Delaney, Meghan, Délot, Emmanuèle, DiTroia, Stephanie, Doddapaneni, Harsha, Du, Haowei, Duan, Ruizhi, Dugan-Perez, Shannon, Duong, Nhat, Duyzend, Michael, Eichler, Evan, Emami, Sara, Fatih, Jawid, Fraser, Jamie, Fusaro, Vincent, Galey, Miranda, Ganesh, Vijay, Garimella, Kiran, Gibbs, Richard, Gifford, Casey, Ginsburg, Amy, Goddard, Pagé, Gogarten, Stephanie, Gogate, Nikhita, Gordon, William, Gorzynski, John E., Greenleaf, William, Grochowski, Christopher, Groopman, Emily, Guarischi Sousa, Rodrigo, Gudmundsson, Sanna, Gulati, Ashima, Guo, Daniel, Hale, Walker, Hall, Stacey, Harvey, William, Hawley, Megan, Heavner, Ben, Herman, Isabella, Horike-Pyne, Martha, Hu, Jianhong, Huang, Yongqing, Hwang, James, Jarvik, Gail, Jensen, Tanner, Jhangiani, Shalini, Jimenez-Morales, David, Jin, Christopher, Saad, Ahmed K., Kahn-Kirby, Amanda, Kain, Jessica, Kaur, Parneet, Keehan, Laura, Knoblach, Susan, Ko, Arthur, Kohler, Jennefer, Kundaje, Anshul, Kundu, Soumya, Lancaster, Samuel M., Larsson, Katie, Lemire, Gabrielle, Lewis, Richard, Li, Wei, Li, Yidan, Liu, Pengfei, LoTempio, Jonathan, Lupski, James, Ma, Jialan, MacArthur, Daniel, Mahmoud, Medhat, Malani, Nirav, Mangilog, Brian, Marafi, Dana, Marmolejos, Sofia, Marten, Daniel, Martinez, Eva, Marvin, Colby, Marwaha, Shruti, Kumara Mastrorosa, Francesco, Matalon, Dena, May, Susanne, McGee, Sean, Meador, Lauren, Mefford, Heather, Rodrigo Mendez, Hector, Miller, Alexander, Miller, Danny E., Mitani, Tadahiro, Montgomery, Stephen, Moussa, Hala Mohamed, Moyses, Mariana, Munderloh, Chloe, Muzny, Donna, Nelson, Sarah, Neu, Matthew B., Nguyen, Jonathan, Nguyen, Thuy-mi P., Nussbaum, Robert, Nykamp, Keith, O'Callaghan, William, O'Heir, Emily, O'Leary, Melanie, Olsen, Jeren, Osei-Owusu, Ikeoluwa, O'Donnell-Luria, Anne, Padhi, Evin, Pais, Lynn, Pan, Miao, Panchal, Piyush, Patterson, Karynne, Payne, Sheryl, Pehlivan, Davut, Petrowski, Paul, Pham, Alicia, Pitsava, Georgia, Podesta, Astaria, Ponce, Sarah, Posey, Jennifer, Prosser, Jaime, Quertermous, Thomas, Rai, Archana, Ramani, Arun, Rehm, Heidi, Reuter, Chloe, Reuter, Jason, Richardson, Matthew, Rivera-Munoz, Andres, Rubio, Oriane, Sabo, Aniko, Salani, Monica, Samocha, Kaitlin, Sanchis-Juan, Alba, Savage, Sarah, Scott, Stuart, Scott, Evette, Sedlazeck, Fritz, Shah, Gulalai, Shojaie, Ali, Singh, Mugdha, Smith, Josh, Smith, Kevin, Snow, Hana, Snyder, Michael, Socarras, Kayla, Starita, Lea, Stark, Brigitte, Stenton, Sarah, Stergachis, Andrew, Stilp, Adrienne, Sundaram, Laksshman, Sutton, V. Reid, Tai, Jui-Cheng, Talkowski, Michael, Tise, Christina, Tong, Catherine, Tsao, Philip, Ungar, Rachel, VanNoy, Grace, Vilain, Eric, Voutos, Isabella, Walker, Kim, Weisburd, Ben, Weiss, Jeff, Wellington, Chris, Weng, Ziming, Westheimer, Emily, Wheeler, Marsha, Wheeler, Matthew, Wiel, Laurens, Wilson, Michael, Wojcik, Monica, Wong, Quenna, Wong, Issac, Xiao, Changrui, Yadav, Rachita, Yi, Qian, Yuan, Bo, Zhao, Jianhua, Zhen, Jimmy, Zhou, Harry, Wojcik, Monica H., Reuter, Chloe M., Duyzend, Michael H., Boone, Philip M., Groopman, Emily E., Délot, Emmanuèle C., Jain, Deepti, Starita, Lea M., Montgomery, Stephen B., Bamshad, Michael J., Chong, Jessica X., Wheeler, Matthew T., Berger, Seth I., and Sedlazeck, Fritz J.

Published
2023
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12. Integration of Protein Interactome Networks with Congenital Heart Disease Variants Reveals Candidate Disease Genes

Author

Teran, Barbara Gonzalez, Pittman, Maureen, Thomas, Reuben, Felix, Franco, Richmond-Buccola, Desmond, Choudhary, Krishna, Moroni, Elisabetta, Giorgio, Colombo, Padmanabhan, Arun, Costa, Mauro, Huang, Yu, Alexanian, Michael, Lee, Clara, Cole, Bonie, Samse-Knapp, Kaitlen, McGregor, Michael, Gifford, Casey, Huttenhain, Ruth, Gelb, Bruce, and Conklin, Bruce

Subjects
Cardiorespiratory Medicine and Haematology, Clinical Sciences, Public Health and Health Services, Cardiovascular System & Hematology
Published
2021

13. Single-cell analysis of cardiogenesis reveals basis for organ-level developmental defects

Author

de Soysa, T Yvanka, Ranade, Sanjeev S, Okawa, Satoshi, Ravichandran, Srikanth, Huang, Yu, Salunga, Hazel T, Schricker, Amelia, del Sol, Antonio, Gifford, Casey A, and Srivastava, Deepak

Subjects
Pediatric, Stem Cell Research, Heart Disease, Stem Cell Research - Nonembryonic - Non-Human, Congenital Structural Anomalies, Cardiovascular, Genetics, 1.1 Normal biological development and functioning, Aetiology, Underpinning research, 2.1 Biological and endogenous factors, Animals, Basic Helix-Loop-Helix Transcription Factors, Cell Differentiation, Cell Movement, Cluster Analysis, Female, Heart, Heart Defects, Congenital, Male, Mice, Sequence Analysis, RNA, Single-Cell Analysis, Tretinoin, General Science & Technology
Abstract

Organogenesis involves integration of diverse cell types; dysregulation of cell-type-specific gene networks results in birth defects, which affect 5% of live births. Congenital heart defects are the most common malformations, and result from disruption of discrete subsets of cardiac progenitor cells1, but the transcriptional changes in individual progenitors that lead to organ-level defects remain unknown. Here we used single-cell RNA sequencing to interrogate early cardiac progenitor cells as they become specified during normal and abnormal cardiogenesis, revealing how dysregulation of specific cellular subpopulations has catastrophic consequences. A network-based computational method for single-cell RNA-sequencing analysis that predicts lineage-specifying transcription factors2,3 identified Hand2 as a specifier of outflow tract cells but not right ventricular cells, despite the failure of right ventricular formation in Hand2-null mice4. Temporal single-cell-transcriptome analysis of Hand2-null embryos revealed failure of outflow tract myocardium specification, whereas right ventricular myocardium was specified but failed to properly differentiate and migrate. Loss of Hand2 also led to dysregulation of retinoic acid signalling and disruption of anterior-posterior patterning of cardiac progenitors. This work reveals transcriptional determinants that specify fate and differentiation in individual cardiac progenitor cells, and exposes mechanisms of disrupted cardiac development at single-cell resolution, providing a framework for investigating congenital heart defects.

Published
2019

15. Context-Specific Transcription Factor Functions Regulate Epigenomic and Transcriptional Dynamics during Cardiac Reprogramming

Author

Stone, Nicole R, Gifford, Casey A, Thomas, Reuben, Pratt, Karishma JB, Samse-Knapp, Kaitlen, Mohamed, Tamer MA, Radzinsky, Ethan M, Schricker, Amelia, Ye, Lin, Yu, Pengzhi, van Bemmel, Joke G, Ivey, Kathryn N, Pollard, Katherine S, and Srivastava, Deepak

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Biological Sciences, Genetics, Heart Disease, Human Genome, Cardiovascular, Animals, Cell Differentiation, Cell Lineage, Cells, Cultured, Cellular Reprogramming, Chromatin Assembly and Disassembly, Epigenesis, Genetic, GATA4 Transcription Factor, MEF2 Transcription Factors, Machine Learning, Mice, Myocytes, Cardiac, Protein Binding, T-Box Domain Proteins, Transcriptional Activation, ATAC-seq, ChIP-seq, cardiac fibroblast, cardiomyocyte, reprogramming, single-cell RNA-seq, transcription factor, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
Abstract

Ectopic expression of combinations of transcription factors (TFs) can drive direct lineage conversion, thereby reprogramming a somatic cell's identity. To determine the molecular mechanisms by which Gata4, Mef2c, and Tbx5 (GMT) induce conversion from a cardiac fibroblast toward an induced cardiomyocyte, we performed comprehensive transcriptomic, DNA-occupancy, and epigenomic interrogation throughout the reprogramming process. Integration of these datasets identified new TFs involved in cardiac reprogramming and revealed context-specific roles for GMT, including the ability of Mef2c and Tbx5 to independently promote chromatin remodeling at previously inaccessible sites. We also find evidence for cooperative facilitation and refinement of each TF's binding profile in a combinatorial setting. A reporter assay employing newly defined regulatory elements confirmed that binding of a single TF can be sufficient for gene activation, suggesting that co-binding events do not necessarily reflect synergy. These results shed light on fundamental mechanisms by which combinations of TFs direct lineage conversion.

Published
2019

16. Oligogenic inheritance of a human heart disease involving a genetic modifier

Author

Gifford, Casey A, Ranade, Sanjeev S, Samarakoon, Ryan, Salunga, Hazel T, de Soysa, T Yvanka, Huang, Yu, Zhou, Ping, Elfenbein, Aryé, Wyman, Stacia K, Bui, Yen Kim, Cordes Metzler, Kimberly R, Ursell, Philip, Ivey, Kathryn N, and Srivastava, Deepak

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Rare Diseases, Cardiovascular, Pediatric, Stem Cell Research - Induced Pluripotent Stem Cell - Human, Stem Cell Research, Heart Disease, Human Genome, Stem Cell Research - Induced Pluripotent Stem Cell, Aetiology, 2.1 Biological and endogenous factors, Animals, CRISPR-Associated Protein 9, Cardiac Myosins, Cardiomyopathies, Clustered Regularly Interspaced Short Palindromic Repeats, Exome, Gene Frequency, Heterozygote, Homeobox Protein Nkx-2.5, Humans, Induced Pluripotent Stem Cells, Mice, Mice, Mutant Strains, Multifactorial Inheritance, Mutation, Missense, Myocytes, Cardiac, Myosin Heavy Chains, Paternal Inheritance, Thyroid Nuclear Factor 1, Transcription Factors, General Science & Technology
Abstract

Complex genetic mechanisms are thought to underlie many human diseases, yet experimental proof of this model has been elusive. Here, we show that a human cardiac anomaly can be caused by a combination of rare, inherited heterozygous mutations. Whole-exome sequencing of a nuclear family revealed that three offspring with childhood-onset cardiomyopathy had inherited three missense single-nucleotide variants in the MKL2, MYH7, and NKX2-5 genes. The MYH7 and MKL2 variants were inherited from the affected, asymptomatic father and the rare NKX2-5 variant (minor allele frequency, 0.0012) from the unaffected mother. We used CRISPR-Cas9 to generate mice encoding the orthologous variants and found that compound heterozygosity for all three variants recapitulated the human disease phenotype. Analysis of murine hearts and human induced pluripotent stem cell-derived cardiomyocytes provided histologic and molecular evidence for the NKX2-5 variant's contribution as a genetic modifier.

Published
2019

19. Genetic analysis and multimodal imaging identify novel mtDNA 12148T>C leading to multisystem dysfunction with tissue-specific heteroplasmy

Author

Belle, Kinsley, primary, Kreymerman, Alexander, additional, Vadgama, Nirmal, additional, Ji, Marco H., additional, Randhawa, Sandeep, additional, Caicedo, Juan, additional, Wong, Megan, additional, Muscat, Stephanie P., additional, Gifford, Casey A., additional, Lee, Richard T., additional, Nasir, Jamal, additional, Young, Jill L., additional, Enns, Gregory, additional, Karakikes, Ioannis, additional, Mercola, Mark, additional, and Wood, Edward H., additional

Published
2023
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20. Differentiation of V2a interneurons from human pluripotent stem cells.

Author

Butts, Jessica, McCreedy, Dylan, Martinez-Vargas, Jorge, Mendoza-Camacho, Frederico, Hookway, Tracy, Gifford, Casey, Taneja, Praveen, Noble-Haeusslein, Linda, and Mcdevitt, Todd

Subjects
V2a interneurons, differentiation, human pluripotent stem cells, single-cell RNAseq, Antigens, Differentiation, Cell Differentiation, Human Embryonic Stem Cells, Humans, Induced Pluripotent Stem Cells, Neurons
Abstract

The spinal cord consists of multiple neuronal cell types that are critical to motor control and arise from distinct progenitor domains in the developing neural tube. Excitatory V2a interneurons in particular are an integral component of central pattern generators that control respiration and locomotion; however, the lack of a robust source of human V2a interneurons limits the ability to molecularly profile these cells and examine their therapeutic potential to treat spinal cord injury (SCI). Here, we report the directed differentiation of CHX10+ V2a interneurons from human pluripotent stem cells (hPSCs). Signaling pathways (retinoic acid, sonic hedgehog, and Notch) that pattern the neural tube were sequentially perturbed to identify an optimized combination of small molecules that yielded ∼25% CHX10+ cells in four hPSC lines. Differentiated cultures expressed much higher levels of V2a phenotypic markers (CHX10 and SOX14) than other neural lineage markers. Over time, CHX10+ cells expressed neuronal markers [neurofilament, NeuN, and vesicular glutamate transporter 2 (VGlut2)], and cultures exhibited increased action potential frequency. Single-cell RNAseq analysis confirmed CHX10+ cells within the differentiated population, which consisted primarily of neurons with some glial and neural progenitor cells. At 2 wk after transplantation into the spinal cord of mice, hPSC-derived V2a cultures survived at the site of injection, coexpressed NeuN and VGlut2, extended neurites >5 mm, and formed putative synapses with host neurons. These results provide a description of V2a interneurons differentiated from hPSCs that may be used to model central nervous system development and serve as a potential cell therapy for SCI.

Published
2017

24. Single cell transcriptomics of human prenatal anterior foregut-derived organs identifies distinct developmental signatures directing commitment and specialization of the thymic epithelial stroma

Author

Mohammed, Abdulvasey, primary, Solomon, Benjamin, additional, Slepicka, Priscila F., additional, Hubka, Kelsea M., additional, Dan Nguyen, Hanh, additional, Chavez, Michael G., additional, Yeh, Christine Y., additional, Winn, Virginia D., additional, Gifford, Casey A., additional, Khatri, Purvesh, additional, Gentles, Andrew, additional, and Weinacht, Katja G., additional

Published
2022
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25. Single Cell Multimodal Analyses Reveal Epigenomic and Transcriptomic Basis for Birth Defects in Maternal Diabetes

Author

Nishino, Tomohiro, primary, Ranade, Sanjeev S., additional, Pelonero, Angelo, additional, van Soldt, Benjamin J., additional, Ye, Lin, additional, Alexanian, Michael, additional, Koback, Frances, additional, Huang, Yu, additional, Sadagopan, Nandhini, additional, Padmanabhan, Arun, additional, Thomas, Reuben, additional, van Bemmel, Joke G., additional, Gifford, Casey A., additional, Costa, Mauro W., additional, and Srivastava, Deepak, additional

Published
2022
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26. Single Cell Epigenetics Reveal Cell-Cell Communication Networks in Normal and Abnormal Cardiac Morphogenesis

Author

Ranade, Sanjeev S., primary, Whalen, Sean, additional, Zlatanova, Ivana, additional, Nishino, Tomohiro, additional, van Soldt, Benjamin, additional, Ye, Lin, additional, Pelonero, Angelo, additional, Wallace, Langley Grace, additional, Huang, Yu, additional, Alexanian, Michael, additional, Padmanabhan, Arun, additional, Gonzalez-Teran, Barbara, additional, Przytycki, Pawel, additional, Costa, Mauro W., additional, Gifford, Casey A., additional, Black, Brian L., additional, Pollard, Katherine S., additional, and Srivastava, Deepak, additional

Published
2022
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27. SARS-CoV-2 Susceptibility and ACE2 Gene Variations Within Diverse Ethnic Backgrounds

Author

Vadgama, Nirmal, primary, Kreymerman, Alexander, additional, Campbell, Jackie, additional, Shamardina, Olga, additional, Brugger, Christiane, additional, Research Consortium, Genomics England, additional, Deaconescu, Alexandra M., additional, Lee, Richard T., additional, Penkett, Christopher J., additional, Gifford, Casey A., additional, Mercola, Mark, additional, Nasir, Jamal, additional, and Karakikes, Ioannis, additional

Published
2022
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30. Dissecting neural differentiation regulatory networks through epigenetic footprinting

Author

Ziller, Michael J., Edri, Reuven, Yaffe, Yakey, Donaghey, Julie, Pop, Ramona, Mallard, William, Issner, Robbyn, Gifford, Casey A., Goren, Alon, Xing, Jeffrey, Gu, Hongcang, Cacchiarelli, Davide, Tsankov, Alexander M., Epstein, Charles, Rinn, John L., Mikkelsen, Tarjei S., Kohlbacher, Oliver, Gnirke, Andreas, Bernstein, Bradley E., Elkabetz, Yechiel, and Meissner, Alexander

Subjects
Neural circuitry -- Research, Genetic research, Stem cells -- Genetic aspects, Neurological research, Cell differentiation -- Research, Epigenetic inheritance -- Research, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Models derived from human pluripotent stem cells that accurately recapitulate neural development in vitro and allow for the generation of specific neuronal subtypes are of major interest to the stem cell and biomedical community. Notch signalling, particularly through the Notch effector HES5, is a major pathway critical for the onset and maintenance of neural progenitor cells in the embryonic and adult nervous system (1-3). Here we report the transcriptional and epigenomic analysis of six consecutive neural progenitor cell stages derived from a HES5::eGFP reporter human embryonic stem cell line (4). Using this system, we aimed to model cell-fate decisions including specification, expansion and patterning during the ontogeny of cortical neural stem and progenitor cells. In order to dissect regulatory mechanisms that orchestrate the stage-specific differentiation process, we developed a computational framework to infer key regulators of each cell-state transition based on the progressive remodelling of the epigenetic landscape and then validated these through a pooled short hairpin RNA screen. We were also able to refine our previous observations on epigenetic priming at transcription factor binding sites and suggest here that they are mediated by combinations of core and stage-specific factors. Taken together, we demonstrate the utility of our system and outline a general framework, not limited to the context of the neural lineage, to dissect regulatory circuits of differentiation., We used the human embryonic stem (ES) cell line WA9 (also known as H9) expressing GFP under the HES5 promoter (4) to isolate defined neural progenitor populations of neuroepithelial (NE), [...]

Published
2015

31. Abstract 11332: Integration of Protein Interactome Networks with Congenital Heart Disease Variants Reveals Candidate Disease Genes

Author

Gonzalez Teran, Barbara, primary, Pittman, Maureen, additional, Thomas, Reuben, additional, Felix, Franco, additional, Richmond-Buccola, Desmond, additional, Choudhary, Krishna, additional, Moroni, Elisabetta, additional, Giorgio, Colombo, additional, Padmanabhan, Arun, additional, Costa, Mauro, additional, Huang, Yu, additional, Alexanian, Michael, additional, Lee, Clara, additional, Cole, Bonie, additional, Samse-Knapp, Kaitlen, additional, McGregor, Michael, additional, Gifford, Casey, additional, Huttenhain, Ruth, additional, Gelb, Bruce, additional, Conklin, Bruce, additional, Black, Brian L, additional, Bruneau, Benoit, additional, Krogan, Nevan, additional, Pollard, Katherine, additional, and Srivastava, Deepak, additional

Published
2021
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32. Integrative analysis of 111 reference human epigenomes

Author

Consortium, Roadmap Epigenomics, Kundaje, Anshul, Meuleman, Wouter, Ernst, Jason, Bilenky, Misha, Yen, Angela, Heravi-Moussavi, Alireza, Kheradpour, Pouya, Zhang, Zhizhuo, Wang, Jianrong, Ziller, Michael J., Whitaker, John W., Ward, Lucas D., Sarkar, Abhishek, Sandstrom, Richard S., Wu, Yi-Chieh, Pfenning, Andreas R., Wang, Xinchen, Claussnitzer, Melina, Liu, Yaping, Harris, Alan R., Epstein, Charles B., Leung, Danny, Hawkins, David R., Hong, Chibo, Mungall, Andrew J., Chuah, Eric, Hansen, Scott R., Bansal, Mukul S., Dixon, Jesse R., Feizi, Soheil, Kim, Ah-Ram, Li, Daofeng, Elliott, GiNell, Neph, Shane J., Polak, Paz, Ray, Pradipta, Siebenthall, Kyle T., Thurman, Robert E., Zhou, Xin, Boyer, Laurie A., De Jager, Philip L., Fisher, Susan J., Li, Wei, McManus, Michael T., Sunyaev, Shamil, Tlsty, Thea D., Wang, Wei, Waterland, Robert A., Costello, Joseph F., Hirst, Martin, Stamatoyannopoulos, John A., Wang, Ting, Amin, Viren, Schultz, Matthew D., Quon, Gerald, Eaton, Matthew L., Pfenning, Andreas, Liu, Melina ClaussnitzerYaping, Coarfa, Cristian, Shoresh, Noam, Gjoneska, Elizabeta, Xie, Wei, Lister, Ryan, Moore, Richard, Tam, Angela, Canfield, Theresa K., Kaul, Rajinder, Sabo, Peter J., Carles, Annaick, Farh, Kai-How, Karlic, Rosa, Kulkarni, Ashwinikumar, Lowdon, Rebecca, Mercer, Tim R., Onuchic, Vitor, Rajagopal, Nisha, Sallari, Richard C., Sinnott-Armstrong, Nicholas A., Stevens, Michael, Wu, Jie, Zhang, Bo, Abdennur, Nezar, Adli, Mazhar, Akerman, Martin, Barrera, Luis, Antosiewicz-Bourget, Jessica, Ballinger, Tracy, Barnes, Michael J., Bates, Daniel, Bell, Robert J. A., Bennett, David A., Bianco, Katherine, Bock, Christoph, Boyle, Patrick, Brinchmann, Jan, Caballero-Campo, Pedro, Camahort, Raymond, Carrasco-Alfonso, Marlene J., Charnecki, Timothy, Chen, Huaming, Chen, Zhao, Cheng, Jeffrey B., Cho, Stephanie, Chu, Andy, Chung, Wen-Yu, Cowan, Chad, Deng, Qixia Athena, Deshpande, Vikram, Diegel, Morgan, Ding, Bo, Durham, Timothy, Echipare, Lorigail, Edsall, Lee, Flowers, David, Genbacev-Krtolica, Olga, Gifford, Casey, Gillespie, Shawn, Giste, Erika, Glass, Ian A., Gnirke, Andreas, Gormley, Matthew, Gu, Hongcang, Gu, Junchen, Hafler, David A., Hangauer, Matthew J., Hariharan, Manoj, Hatan, Meital, Haugen, Eric, He, Yupeng, Heimfeld, Shelly, Herlofsen, Sarah, Hou, Zhonggang, Humbert, Richard, Issner, Robbyn, Jackson, Andrew R., Jia, Haiyang, Jiang, Peng, Johnson, Audra K., Kadlecek, Theresa, Kamoh, Baljit, Kapidzic, Mirhan, Kent, Jim, Kim, Audrey, Kleinewietfeld, Markus, Klugman, Sarit, Krishnan, Jayanth, Kuan, Samantha, Kutyavin, Tanya, Lee, Ah-Young, Lee, Kristen, Li, Jian, Li, Nan, Li, Yan, Ligon, Keith L., Lin, Shin, Lin, Yiing, Liu, Jie, Liu, Yuxuan, Luckey, John C., Ma, Yussanne P., Maire, Cecile, Marson, Alexander, Mattick, John S., Mayo, Michael, McMaster, Michael, Metsky, Hayden, Mikkelsen, Tarjei, Miller, Diane, Miri, Mohammad, Mukame, Eran, Nagarajan, Raman P., Neri, Fidencio, Nery, Joseph, Nguyen, Tung, OʼGeen, Henriette, Paithankar, Sameer, Papayannopoulou, Thalia, Pelizzola, Mattia, Plettner, Patrick, Propson, Nicholas E., Raghuraman, Sriram, Raney, Brian J., Raubitschek, Anthony, Reynolds, Alex P., Richards, Hunter, Riehle, Kevin, Rinaudo, Paolo, Robinson, Joshua F., Rockweiler, Nicole B., Rosen, Evan, Rynes, Eric, Schein, Jacqueline, Sears, Renee, Sejnowski, Terrence, Shafer, Anthony, Shen, Li, Shoemaker, Robert, Sigaroudinia, Mahvash, Slukvin, Igor, Stehling-Sun, Sandra, Stewart, Ron, Subramanian, Sai Lakshmi, Suknuntha, Kran, Swanson, Scott, Tian, Shulan, Tilden, Hannah, Tsai, Linus, Urich, Mark, Vaughn, Ian, Vierstra, Jeff, Vong, Shinny, Wagner, Ulrich, Wang, Hao, Wang, Tao, Wang, Yunfei, Weiss, Arthur, Whitton, Holly, Wildberg, Andre, Witt, Heather, Won, Kyoung-Jae, Xie, Mingchao, Xing, Xiaoyun, Xu, Iris, Xuan, Zhenyu, Ye, Zhen, Yen, Chia-an, Yu, Pengzhi, Zhang, Xian, Zhang, Xiaolan, Zhao, Jianxin, Zhou, Yan, Zhu, Jiang, Zhu, Yun, Ziegler, Steven, Beaudet, Arthur E., Farnham, Peggy J., Haussler, David, Jones, Steven J. M., Marra, Marco A., Thomson, James A., Tsai, Li-Huei, Zhang, Michael Q., Chadwick, Lisa H., Bernstein, Bradley E., Ecker, Joseph R., Meissner, Alexander, Milosavljevic, Aleksandar, Ren, Bing, and Kellis, Manolis

Published
2015
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34. Integration of Protein Interactome Networks with Congenital Heart Disease Variants Reveals Candidate Disease Genes

Author

Gonzalez-Teran, Barbara, primary, Pittman, Maureen, additional, Felix, Franco, additional, Richmond-Buccola, Desmond, additional, Thomas, Reuben, additional, Choudhary, Krishna, additional, Moroni, Elisabetta, additional, Colombo, Giorgio, additional, Alexanian, Michael, additional, Cole, Bonnie, additional, Samse-Knapp, Kaitlen, additional, McGregor, Michael, additional, Gifford, Casey A., additional, Huttenhain, Ruth, additional, Gelb, Bruce D., additional, Conklin, Bruce R., additional, Black, Brian L., additional, Bruneau, Benoit G., additional, Krogan, Nevan J., additional, Pollard, Katherine S., additional, and Srivastava, Deepak, additional

Published
2021
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35. A Transcriptional Switch Governing Fibroblast Plasticity Underlies Reversibility of Chronic Heart Disease

Author

Alexanian, Michael, primary, Przytycki, Pawel F., additional, Micheletti, Rudi, additional, Padmanabhan, Arun, additional, Ye, Lin, additional, Travers, Joshua G., additional, Teran, Barbara Gonzalez, additional, Duan, Qiming, additional, Ranade, Sanjeev S., additional, Felix, Franco, additional, Linares-Saldana, Ricardo, additional, Huang, Yu, additional, Andreoletti, Gaia, additional, Yang, Jin, additional, Ivey, Kathryn N., additional, Jain, Rajan, additional, McKinsey, Timothy A., additional, Rosenfeld, Michael G., additional, Gifford, Casey, additional, Pollard, Katherine S., additional, Haldar, Saptarsi M., additional, and Srivastava, Deepak, additional

Published
2020
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36. Integration of Protein Interactome Networks With Congenital Heart Disease Variants Reveals Candidate Disease Genes

Author

Gonzalez-Teran, Barbara, primary, Pittman, Maureen, additional, Felix, Franco, additional, Richmond-Buccola, Desmond, additional, Thomas, Reuben, additional, Choudhary, Krishna, additional, Moroni, Elisabetta, additional, Colombo, Giorgio, additional, Alexanian, Michael, additional, Cole, Bonnie, additional, Samse-Knapp, Kaitlen, additional, McGregor, Michael, additional, Gifford, Casey A., additional, Huttenhain, Ruth, additional, Gelb, Bruce D., additional, Conklin, Bruce, additional, Black, Brian L., additional, Bruneau, Benoit G., additional, Krogan, Nevan J., additional, Pollard, Katherine S., additional, and Srivastava, Deepak, additional

Published
2020
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37. An improved ScoreCard to assess the differentiation potential of human pluripotent stem cells

Author

Tsankov, Alexander M., Akopian, Veronika, Pop, Ramona, Chetty, Sundari, Gifford, Casey A., Daheron, Laurence, Melton, Douglas A., Tsankova, Nadejda M., and Meissner, Alexander

Subjects
Pluripotent Stem Cells, Mice, Teratoma, Animals, Computational Biology, Humans, Cell Differentiation, Neoplasms, Experimental, Polymerase Chain Reaction, Article, Embryoid Bodies
Abstract

Research on human pluripotent stem cells has been hampered by the lack of a standardized, quantitative, scalable assay of pluripotency. We previously described an assay called ScoreCard that used gene expression signatures to quantify differentiation efficiency. Here we report an improved version of the assay based on qPCR that enables faster, more quantitative assessment of functional pluripotency. We provide an in-depth characterization of the revised signature panel (commercially available as the TaqMan hPSC Scorecard Assay) through embryoid body and directed differentiation experiments as well as a detailed comparison to the teratoma assay. We further show that the improved ScoreCard enables a wider range of applications, such as screening of small molecules, genetic perturbations and assessment of culture conditions. Our approach can be extended beyond stem cell applications to characterize and assess the utility of other cell types and lineages.

Published
2015

38. Unique Transcription Factor Functions Regulate Epigenetic and Transcriptional Dynamics During Cardiac Reprogramming

Author

Stone, Nicole R., primary, Gifford, Casey A., additional, Thomas, Reuben, additional, Pratt, Karishma J. B., additional, Samse-Knapp, Kaitlen, additional, Mohamed, Tamer M. A., additional, Radzinsky, Ethan M., additional, Schricker, Amelia, additional, Yu, Pengzhi, additional, Ivey, Kathryn N., additional, Pollard, Katherine S., additional, and Srivastava, Deepak, additional

Published
2019
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39. Considerations for reporting variants in novel candidate genes identified during clinical genomic testing

Author

Chong, Jessica X., Berger, Seth I., Baxter, Samantha, Smith, Erica, Xiao, Changrui, Calame, Daniel G., Hawley, Megan H., Rivera-Munoz, E. Andres, DiTroia, Stephanie, Abouhala, Siwaar, Albert, Jessica, Almalvez, Miguel, Alvarez, Raquel, Amin, Mutaz, Anderson, Peter, Aradhya, Swaroop, Ashley, Euan, Assimes, Themistocles, Auriga, Light, Austin-Tse, Christina, Bamshad, Mike, Barseghyan, Hayk, Baxter, Samantha, Behera, Sairam, Beheshti, Shaghayegh, Bejerano, Gill, Berger, Seth, Bernstein, Jon, Best, Sabrina, Blankenmeister, Benjamin, Blue, Elizabeth, Boerwinkle, Eric, Bonkowski, Emily, Bonner, Devon, Boone, Philip, Bornhorst, Miriam, Brand, Harrison, Buckingham, Kati, Calame, Daniel, Carter, Jennefer, Casadei, Silvia, Chadwick, Lisa, Chavez, Clarisa, Chen, Ziwei, Chinn, Ivan, Chong, Jessica, Coban-Akdemir, Zeynep, Cohen, Andrea J., Conner, Sarah, Conomos, Matthew, Coveler, Karen, Cui, Ya Allen, Currin, Sara, Daber, Robert, Dardas, Zain, Davis, Colleen, Dawood, Moez, de Dios, Ivan, de Esch, Celine, Delaney, Meghan, Delot, Emmanuele, DiTroia, Stephanie, Doddapaneni, Harsha, Du, Haowei, Duan, Ruizhi, Dugan-Perez, Shannon, Duong, Nhat, Duyzend, Michael, Eichler, Evan, Emami, Sara, Fraser, Jamie, Fusaro, Vincent, Galey, Miranda, Ganesh, Vijay, Garcia, Brandon, Garimella, Kiran, Gibbs, Richard, Gifford, Casey, Ginsburg, Amy, Goddard, Page, Gogarten, Stephanie, Gogate, Nikhita, Gordon, William, Gorzynski, John E., Greenleaf, William, Grochowski, Christopher, Groopman, Emily, Sousa, Rodrigo Guarischi, Gudmundsson, Sanna, Gulati, Ashima, Hall, Stacey, Harvey, William, Hawley, Megan, Heavner, Ben, Horike-Pyne, Martha, Hu, Jianhong, Huang, Yongqing, Hwang, James, Jarvik, Gail, Jensen, Tanner, Jhangiani, Shalini, Jimenez-Morales, David, Jin, Christopher, Saad, Ahmed K., Kahn-Kirby, Amanda, Kain, Jessica, Kaur, Parneet, Keehan, Laura, Knoblach, Susan, Ko, Arthur, Kundaje, Anshul, Kundu, Soumya, Lancaster, Samuel M., Larsson, Katie, Lee, Arthur, Lemire, Gabrielle, Lewis, Richard, Li, Wei, Li, Yidan, Liu, Pengfei, LoTempio, Jonathan, Lupski, James (Jim), Ma, Jialan, MacArthur, Daniel, Mahmoud, Medhat, Malani, Nirav, Mangilog, Brian, Marafi, Dana, Marmolejos, Sofia, Marten, Daniel, Martinez, Eva, Marvin, Colby, Marwaha, Shruti, Mastrorosa, Francesco Kumara, Matalon, Dena, May, Susanne, McGee, Sean, Meador, Lauren, Mefford, Heather, Mendez, Hector Rodrigo, Miller, Alexander, Miller, Danny E., Mitani, Tadahiro, Montgomery, Stephen, Moyses, Mariana, Munderloh, Chloe, Muzny, Donna, Nelson, Sarah, Nguyen, Thuy-mi P., Nguyen, Jonathan, Nussbaum, Robert, Nykamp, Keith, O'Callaghan, William, O'Heir, Emily, O'Leary, Melanie, Olsen, Jeren, Osei-Owusu, Ikeoluwa, O'Donnell-Luria, Anne, Padhi, Evin, Pais, Lynn, Pan, Miao, Panchal, Piyush, Patterson, Karynne, Payne, Sheryl, Pehlivan, Davut, Petrowski, Paul, Pham, Alicia, Pitsava, Georgia, Podesta, Astaria Sara, Ponce, Sarah, Porter, Elizabeth, Posey, Jennifer, Prosser, Jaime, Quertermous, Thomas, Rai, Archana, Ramani, Arun, Rehm, Heidi, Reuter, Chloe, Reuter, Jason, Richardson, Matthew, Rivera-Munoz, Andres, Rubio, Oriane, Sabo, Aniko, Salani, Monica, Samocha, Kaitlin, Sanchis-Juan, Alba, Savage, Sarah, Scott, Evette, Scott, Stuart, Sedlazeck, Fritz, Shah, Gulalai, Shojaie, Ali, Singh, Mugdha, Smith, Kevin, Smith, Josh, Snow, Hana, Snyder, Michael, Socarras, Kayla, Starita, Lea, Stark, Brigitte, Stenton, Sarah, Stergachis, Andrew, Stilp, Adrienne, Sutton, V. Reid, Tai, Jui-Cheng, Talkowski, Michael (Mike), Tise, Christina, Tong, Catherine (Cat), Tsao, Philip, Ungar, Rachel, VanNoy, Grace, Vilain, Eric, Voutos, Isabella, Walker, Kim, Wei, Chia-Lin, Weisburd, Ben, Weiss, Jeff, Wellington, Chris, Weng, Ziming, Westheimer, Emily, Wheeler, Marsha, Wheeler, Matthew, Wiel, Laurens, Wilson, Michael, Wojcik, Monica, Wong, Quenna, Xiao, Changrui, Yadav, Rachita, Yi, Qian, Yuan, Bo, Zhao, Jianhua, Zhen, Jimmy, Zhou, Harry, Bamshad, Michael J., and Rehm, Heidi L.

Abstract

Since the first novel gene discovery for a Mendelian condition was made via exome sequencing (ES), the rapid increase in the number of genes known to underlie Mendelian conditions coupled with the adoption of exome (and more recently, genome) sequencing by diagnostic testing labs has changed the landscape of genomic testing for rare disease. Specifically, many individuals suspected to have a Mendelian condition are now routinely offered clinical ES. This commonly results in a precise genetic diagnosis but frequently overlooks the identification of novel candidate genes. Such candidates are also less likely to be identified in the absence of large-scale gene discovery research programs. Accordingly, clinical laboratories have both the opportunity, and some might argue a responsibility, to contribute to novel gene discovery which should in turn increase the diagnostic yield for many conditions. However, clinical diagnostic laboratories must necessarily balance priorities for throughput, turnaround time, cost efficiency, clinician preferences, and regulatory constraints, and often do not have the infrastructure or resources to effectively participate in either clinical translational or basic genome science research efforts. For these and other reasons, many laboratories have historically refrained from broadly sharing potentially pathogenic variants in novel genes via networks like Matchmaker Exchange, much less reporting such results to ordering providers. Efforts to report such results are further complicated by a lack of guidelines for clinical reporting and interpretation of variants in novel candidate genes. Nevertheless, there are myriad benefits for many stakeholders, including patients/families, clinicians, researchers, if clinical laboratories systematically and routinely identify, share, and report novel candidate genes. To facilitate this change in practice, we developed criteria for triaging, sharing, and reporting novel candidate genes that are most likely to be promptly validated as underlying a Mendelian condition and translated to use in clinical settings.

Published
2024
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41. Oligogenic inheritance of congenital heart disease involving a NKX2-5 modifier

Author

Gifford, Casey A., primary, Ranade, Sanjeev S., additional, Samarakoon, Ryan, additional, Salunga, Hazel T., additional, de Soysa, T. Yvanka, additional, Huang, Yu, additional, Zhou, Ping, additional, Elfenbein, Aryé, additional, Wyman, Stacia K., additional, Bui, Yen Kim, additional, Cordes Metzler, Kimberly R., additional, Ursell, Philip, additional, Ivey, Kathryn N., additional, and Srivastava, Deepak, additional

Published
2018
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42. Transcriptional and Chromatin Dynamics of Muscle Regeneration after Severe Trauma

Author

Aguilar, Carlos A., primary, Pop, Ramona, additional, Shcherbina, Anna, additional, Watts, Alain, additional, Matheny, Ronald W., additional, Cacchiarelli, Davide, additional, Han, Woojin M., additional, Shin, Eunjung, additional, Nakhai, Shadi A., additional, Jang, Young C., additional, Carrigan, Christopher T., additional, Gifford, Casey A., additional, Kottke, Melissa A., additional, Cesana, Marcella, additional, Lee, Jackson, additional, Urso, Maria L., additional, and Meissner, Alexander, additional

Published
2016
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46. Integrative Analyses of Human Reprogramming Reveal Dynamic Nature of Induced Pluripotency

Author

Cacchiarelli, Davide, primary, Trapnell, Cole, additional, Ziller, Michael J., additional, Soumillon, Magali, additional, Cesana, Marcella, additional, Karnik, Rahul, additional, Donaghey, Julie, additional, Smith, Zachary D., additional, Ratanasirintrawoot, Sutheera, additional, Zhang, Xiaolan, additional, Ho Sui, Shannan J., additional, Wu, Zhaoting, additional, Akopian, Veronika, additional, Gifford, Casey A., additional, Doench, John, additional, Rinn, John L., additional, Daley, George Q., additional, Meissner, Alexander, additional, Lander, Eric S., additional, and Mikkelsen, Tarjei S., additional

Published
2015
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47. Targeted disruption of DNMT1, DNMT3A and DNMT3B in human embryonic stem cells

Author

Liao, Jing, primary, Karnik, Rahul, additional, Gu, Hongcang, additional, Ziller, Michael J, additional, Clement, Kendell, additional, Tsankov, Alexander M, additional, Akopian, Veronika, additional, Gifford, Casey A, additional, Donaghey, Julie, additional, Galonska, Christina, additional, Pop, Ramona, additional, Reyon, Deepak, additional, Tsai, Shengdar Q, additional, Mallard, William, additional, Joung, J Keith, additional, Rinn, John L, additional, Gnirke, Andreas, additional, and Meissner, Alexander, additional

Published
2015
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48. Dissecting neural differentiation regulatory networks through epigenetic footprinting

Author

Ziller, Michael J., primary, Edri, Reuven, additional, Yaffe, Yakey, additional, Donaghey, Julie, additional, Pop, Ramona, additional, Mallard, William, additional, Issner, Robbyn, additional, Gifford, Casey A., additional, Goren, Alon, additional, Xing, Jeffrey, additional, Gu, Hongcang, additional, Cacchiarelli, Davide, additional, Tsankov, Alexander M., additional, Epstein, Charles, additional, Rinn, John L., additional, Mikkelsen, Tarjei S., additional, Kohlbacher, Oliver, additional, Gnirke, Andreas, additional, Bernstein, Bradley E., additional, Elkabetz, Yechiel, additional, and Meissner, Alexander, additional

Published
2014
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49. Differentiation of V2a interneurons from human pluripotent stem cells.

Author

Mendoza-Camacho, Frederico N., Hookway, Tracy A., Gifford, Casey A., Butts, Jessica C., McCreedy, Dylan A., McDevitt, Todd C., Noble-Haeusslein, Linda, Alexis Martinez-Vargas, Jorge, and Tanejaf, Praveen

Subjects
INTERNEURONS, PLURIPOTENT stem cells, SPINAL cord injuries, PROGENITOR cells, CELLULAR therapy
Abstract

The spinal cord consists of multiple neuronal cell types that are critical to motor control and arise from distinct progenitor domains in the developing neural tube. Excitatory V2a interneurons in particular are an integral component of central pattern generators that control respiration and locomotion; however, the lack of a robust source of human V2a interneurons limits the ability to molecularly profile these cells and examine their therapeutic potential to treat spinal cord injury (SCI). Here, we report the directed differentiation of CHX10+ V2a interneurons from human pluripotent stem cells (hPSCs). Signaling pathways (retinoic acid, sonic hedgehog, and Notch) that pattern the neural tube were sequentially perturbed to identify an optimized combination of small molecules that yielded ∼25% CHX10+ cells in four hPSC lines. Differentiated cultures expressed much higher levels of V2a phenotypic markers (CHX10 and SOX14) than other neural lineage markers. Over time, CHX10+ cells expressed neuronal markers [neurofilament, NeuN, and vesicular glutamate transporter 2 (VGlut2)], and cultures exhibited increased action potential frequency. Single-cell RNAseq analysis confirmed CHX10+ cells within the differentiated population, which consisted primarily of neurons with some glial and neural progenitor cells. At 2 wk after transplantation into the spinal cord of mice, hPSC-derived V2a cultures survived at the site of injection, coexpressed NeuN and VGlut2, extended neurites >5 mm, and formed putative synapses with host neurons. These results provide a description of V2a interneurons differentiated from hPSCs that may be used to model central nervous system development and serve as a potential cell therapy for SCI. [ABSTRACT FROM AUTHOR]

Published
2017
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50. Transcriptional and Epigenetic Dynamics during Specification of Human Embryonic Stem Cells

Author

Gifford, Casey A., primary, Ziller, Michael J., additional, Gu, Hongcang, additional, Trapnell, Cole, additional, Donaghey, Julie, additional, Tsankov, Alexander, additional, Shalek, Alex K., additional, Kelley, David R., additional, Shishkin, Alexander A., additional, Issner, Robbyn, additional, Zhang, Xiaolan, additional, Coyne, Michael, additional, Fostel, Jennifer L., additional, Holmes, Laurie, additional, Meldrim, Jim, additional, Guttman, Mitchell, additional, Epstein, Charles, additional, Park, Hongkun, additional, Kohlbacher, Oliver, additional, Rinn, John, additional, Gnirke, Andreas, additional, Lander, Eric S., additional, Bernstein, Bradley E., additional, and Meissner, Alexander, additional

Published
2013
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