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5. Geometry-dependent functional changes in iPSC-derived cardiomyocytes probed by functional imaging and RNA sequencing

Author

Werley, Christopher A, Chien, Miao-Ping, Gaublomme, Jellert, Shekhar, Karthik, Butty, Vincent, Yi, B Alexander, Kralj, Joel M, Bloxham, William, Boyer, Laurie A, Regev, Aviv, and Cohen, Adam E

Subjects
Medical Physiology, Biomedical and Clinical Sciences, Stem Cell Research, Cardiovascular, Stem Cell Research - Induced Pluripotent Stem Cell - Human, Heart Disease, Genetics, Stem Cell Research - Embryonic - Human, Stem Cell Research - Induced Pluripotent Stem Cell, Underpinning research, 1.1 Normal biological development and functioning, Action Potentials, Calcium, Cell Differentiation, Cells, Cultured, Electrophysiological Phenomena, Gene Expression, Humans, Induced Pluripotent Stem Cells, Myocytes, Cardiac, Sequence Analysis, RNA, Transcription, Genetic, General Science & Technology
Abstract

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) are a promising platform for cardiac studies in vitro, and possibly for tissue repair in humans. However, hiPSC-CM cells tend to retain morphology, metabolism, patterns of gene expression, and electrophysiology similar to that of embryonic cardiomyocytes. We grew hiPSC-CM in patterned islands of different sizes and shapes, and measured the effect of island geometry on action potential waveform and calcium dynamics using optical recordings of voltage and calcium from 970 islands of different sizes. hiPSC-CM in larger islands showed electrical and calcium dynamics indicative of greater functional maturity. We then compared transcriptional signatures of the small and large islands against a developmental time course of cardiac differentiation. Although island size had little effect on expression of most genes whose levels differed between hiPSC-CM and adult primary CM, we identified a subset of genes for which island size drove the majority (58%) of the changes associated with functional maturation. Finally, we patterned hiPSC-CM on islands with a variety of shapes to probe the relative contributions of soluble factors, electrical coupling, and direct cell-cell contacts to the functional maturation. Collectively, our data show that optical electrophysiology is a powerful tool for assaying hiPSC-CM maturation, and that island size powerfully drives activation of a subset of genes involved in cardiac maturation.

Published
2017

9. Metabolic modulation to improve MSC expansion and therapeutic potential for articular cartilage repair

Author

Tee, Ching A., Roxby, Daniel N., Othman, Rashidah, Denslin, Vinitha, Bhat, Kiseer S., Yang, Zheng, Han, Jongyoon, Tucker-Kellogg, Lisa, Boyer, Laurie A., Tee, Ching A., Roxby, Daniel N., Othman, Rashidah, Denslin, Vinitha, Bhat, Kiseer S., Yang, Zheng, Han, Jongyoon, Tucker-Kellogg, Lisa, and Boyer, Laurie A.

Abstract

Background Articular cartilage degeneration can result from injury, age, or arthritis, causing significant joint pain and disability without surgical intervention. Currently, the only FDA cell-based therapy for articular cartilage injury is Autologous Chondrocyte Implantation (ACI); however, this procedure is costly, time-intensive, and requires multiple treatments. Mesenchymal stromal cells (MSCs) are an attractive alternative autologous therapy due to their availability and ability to robustly differentiate into chondrocytes for transplantation with good safety profiles. However, treatment outcomes are variable due to donor-to-donor variability as well as intrapopulation heterogeneity and unstandardized MSC manufacturing protocols. Process improvements that reduce cell heterogeneity while increasing donor cell numbers with improved chondrogenic potential during expansion culture are needed to realize the full potential of MSC therapy. Methods In this study, we investigated the potential of MSC metabolic modulation during expansion to enhance their chondrogenic commitment by varying the nutrient composition, including glucose, pyruvate, glutamine, and ascorbic acid in culture media. We tested the effect of metabolic modulation in short-term (one passage) and long-term (up to seven passages). We measured metabolic state, cell size, population doubling time, and senescence and employed novel tools including micro-magnetic resonance relaxometry (µMRR) relaxation time (T2) to characterize the effects of AA on improved MSC expansion and chondrogenic potential. Results Our data show that the addition of 1 mM L-ascorbic acid-2-phosphate (AA) to cultures for one passage during MSC expansion prior to initiation of differentiation improves chondrogenic differentiation. We further demonstrate that AA treatment reduced the proportion of senescent cells and cell heterogeneity also allowing for long-term expansion that led to a > 300-fold increase in yield of MSCs with enhanced

Published
2024

10. Plasticity of ether lipids promotes ferroptosis susceptibility and evasion

Author

Zou, Yilong, Henry, Whitney S., Ricq, Emily L., Graham, Emily T., Phadnis, Vaishnavi V., Maretich, Pema, Paradkar, Sateja, Boehnke, Natalie, Deik, Amy A., Reinhardt, Ferenc, Eaton, John K., Ferguson, Bryan, Wang, Wenyu, Fairman, Joshua, Keys, Heather R., Dančík, Vlado, Clish, Clary B., Clemons, Paul A., Hammond, Paula T., Boyer, Laurie A., Weinberg, Robert A., and Schreiber, Stuart L.

Published
2020
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11. Ketone Body Signaling Mediates Intestinal Stem Cell Homeostasis and Adaptation to Diet

Author

Cheng, Chia-Wei, Biton, Moshe, Haber, Adam L., Gunduz, Nuray, Eng, George, Gaynor, Liam T., Tripathi, Surya, Calibasi-Kocal, Gizem, Rickelt, Steffen, Butty, Vincent L., Moreno-Serrano, Marta, Iqbal, Ameena M., Bauer-Rowe, Khristian E., Imada, Shinya, Ulutas, Mehmet Sefa, Mylonas, Constantine, Whary, Mark T., Levine, Stuart S., Basbinar, Yasemin, Hynes, Richard O., Mino-Kenudson, Mari, Deshpande, Vikram, Boyer, Laurie A., Fox, James G., Terranova, Christopher, Rai, Kunal, Piwnica-Worms, Helen, Mihaylova, Maria M., Regev, Aviv, and Yilmaz, Ömer H.

Published
2019
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14. Dynamic and coordinated epigenetic regulation of developmental transitions in the cardiac lineage.

Author

Wamstad, Joseph A, Alexander, Jeffrey M, Truty, Rebecca M, Shrikumar, Avanti, Li, Fugen, Eilertson, Kirsten E, Ding, Huiming, Wylie, John N, Pico, Alexander R, Capra, John A, Erwin, Genevieve, Kattman, Steven J, Keller, Gordon M, Srivastava, Deepak, Levine, Stuart S, Pollard, Katherine S, Holloway, Alisha K, Boyer, Laurie A, and Bruneau, Benoit G

Subjects
Myocardium, Heart, Chromatin, Animals, Humans, Mice, Transcription Factors, Cell Differentiation, Epigenesis, Genetic, Embryonic Stem Cells, Gene Regulatory Networks, Enhancer Elements, Genetic, Transcriptome, Human Genome, Heart Disease, Pediatric, Cardiovascular, Genetics, Congenital Structural Anomalies, Stem Cell Research, 1.1 Normal biological development and functioning, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

Heart development is exquisitely sensitive to the precise temporal regulation of thousands of genes that govern developmental decisions during differentiation. However, we currently lack a detailed understanding of how chromatin and gene expression patterns are coordinated during developmental transitions in the cardiac lineage. Here, we interrogated the transcriptome and several histone modifications across the genome during defined stages of cardiac differentiation. We find distinct chromatin patterns that are coordinated with stage-specific expression of functionally related genes, including many human disease-associated genes. Moreover, we discover a novel preactivation chromatin pattern at the promoters of genes associated with heart development and cardiac function. We further identify stage-specific distal enhancer elements and find enriched DNA binding motifs within these regions that predict sets of transcription factors that orchestrate cardiac differentiation. Together, these findings form a basis for understanding developmentally regulated chromatin transitions during lineage commitment and the molecular etiology of congenital heart disease.

Published
2012

16. Approche quantitative des interactions soignantes à l'hôpital psychiatrique depuis une perspective interactionniste

Author

Chalancon Benoit, Colón de Carvajal Isabel, Maritaud Louis, Lascar Justine, and Boyer Laurie

Subjects
Social Sciences
Abstract

La réforme du système de santé incite les soignants à être de plus en plus efficaces lors de situations de communication. Les spécificités de la pratique infirmière en santé mentale peuvent s'illustrer par le soin relationnel qui représente un enjeu dans la continuité des soins au vu de la complexité grandissante des prises en charge. Dans un tel contexte, une étude portant sur les compétences d’interaction des infirmiers dans un service psychiatrique pour adultes semble se justifier. L’ancrage théorique et méthodologique de cette recherche relèvent de l’analyse conversationnelle et de l’ethnométhodologie. Le projet CIPSY est ainsi un projet exploratoire qui étudie les compétences d’interaction durant les relèves infirmières, et les multiples façons de transmettre de l’information disponibles dans leur pratique, qu’elles soient écrites ou orales. Cet article présente d’une part la méthode exploratoire utilisée et propose une analyse quantitative du temps passé dans chaque relève enregistrée, comparant en particulier les patients en mesure d’isolement et les patients en chambre simple. D’autre part, nous présentons trois résultats statistiques soulignant les différences de contenu des relèves orales et écrites. Nous décrivons enfin l’ébauche d’une méthode utilisée pour visualiser les données orales d’un même patient à l’aide du logiciel Voyant Tools.

Published
2022
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17. Emergent mechanical control of vascular morphogenesis

Author

Whisler, Jordan, primary, Shahreza, Somayeh, additional, Schlegelmilch, Karin, additional, Ege, Nil, additional, Javanmardi, Yousef, additional, Malandrino, Andrea, additional, Agrawal, Ayushi, additional, Fantin, Alessandro, additional, Serwinski, Bianca, additional, Azizgolshani, Hesham, additional, Park, Clara, additional, Shone, Victoria, additional, Demuren, Olukunle O., additional, Del Rosario, Amanda, additional, Butty, Vincent L., additional, Holroyd, Natalie, additional, Domart, Marie-Charlotte, additional, Hooper, Steven, additional, Szita, Nicolas, additional, Boyer, Laurie A., additional, Walker-Samuel, Simon, additional, Djordjevic, Boris, additional, Sheridan, Graham K., additional, Collinson, Lucy, additional, Calvo, Fernando, additional, Ruhrberg, Christiana, additional, Sahai, Erik, additional, Kamm, Roger, additional, and Moeendarbary, Emad, additional

Published
2023
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20. Expansion of human bone marrow-derived mesenchymal stromal cells with enhanced immunomodulatory properties

Author

Singapore-MIT Alliance in Research and Technology (SMART), Massachusetts Institute of Technology. Department of Biological Engineering, Massachusetts Institute of Technology. Department of Biology, Neo, Shu H., Her, Zhisheng, Othman, Rashidah, Tee, Ching A., Ong, Li C., Wang, Yuehua, Tan, Irwin, Tan, Jaylen, Yang, Yanmeng, Yang, Zheng, Chen, Qingfeng, Boyer, Laurie A., Singapore-MIT Alliance in Research and Technology (SMART), Massachusetts Institute of Technology. Department of Biological Engineering, Massachusetts Institute of Technology. Department of Biology, Neo, Shu H., Her, Zhisheng, Othman, Rashidah, Tee, Ching A., Ong, Li C., Wang, Yuehua, Tan, Irwin, Tan, Jaylen, Yang, Yanmeng, Yang, Zheng, Chen, Qingfeng, and Boyer, Laurie A.

Abstract

Background Mesenchymal stromal cells (MSCs) have broad potential as a cell therapy including for the treatment of drug-resistant inflammatory conditions with abnormal T cell proliferation such as graft-versus-host disease (GVHD). Clinical success, however, has been complicated by the heterogeneity of culture-expanded MSCs as well as donor variability. Here, we devise culture conditions that promote expansion of MSCs with enhanced immunomodulatory functions both in vitro and in animal models of GVHD. Methods Human bone marrow-derived MSCs were expanded at high-confluency (MSCHC) and low-confluency state (MSCLC). Their immunomodulatory properties were evaluated with in vitro co-culture assays based on suppression of activated T cell proliferation and secretion of pro-inflammatory cytokines from activated T cells. Metabolic state of these cells was determined, while RNA sequencing was performed to explore transcriptome of these MSCs. Ex vivo expanded MSCHC or MSCLC was injected into human peripheral blood mononuclear cells (PBMC)-induced GVHD mouse model to determine their in vivo therapeutic efficacy based on clinical grade scoring, human CD45+ blood count and histopathological examination. Results As compared to MSCLC, MSCHC significantly reduced both the proliferation of anti-CD3/CD28-activated T cells and secretion of pro-inflammatory cytokines upon MSCHC co-culture across several donors even in the absence of cytokine priming. Mechanistically, metabolic analysis of MSCHC prior to co-culture with activated T cells showed increased glycolytic metabolism and lactate secretion compared to MSCLC, consistent with their ability to inhibit T cell proliferation. Transcriptome analysis further revealed differential expression of immunomodulatory genes including TRIM29, BPIFB4, MMP3 and SPP1 in MSCHC as well as enriched pathways including cytokine–cytokine receptor interactions, cell adhesion and PI3K-AKT signalling. Lastly, we demonstrate in a human PBMC-induced GV

Published
2023

21. Emergent mechanical control of vascular morphogenesis

Author

Wellcome Trust, Leverhulme Trust, Biotechnology and Biological Sciences Research Council (UK), Cancer Research UK, Francis Crick Institute, Medical Research Council (UK), Whisler, Jordan, Shahreza, Somayeh, Schlegelmilch, Karin, Ege, Nil, Javanmardi, Yousef, Malandrino, Andrea, Agrawal, Ayushi, Fantin, Alessandro, Serwinski, Bianca, Azizgolshani, Hesham, Park, Clara, Shone, Victoria, Demuren, Olukunle O., Del Rosario, Amanda, Butty, Vincent L., Holroyd, Natalie, Domart, Marie-Charlotte, Hooper, Steven, Szita, Nicolás, Boyer, Laurie A., Walker-Samuel, Simon, Djordjevic, Boris, Sheridan, Graham K., Collinson, Lucy, Calvo, Fernando, Ruhrberg, Christiana, Sahai, Erik, Kamm, Roger, Moeendarbary, Emad, Wellcome Trust, Leverhulme Trust, Biotechnology and Biological Sciences Research Council (UK), Cancer Research UK, Francis Crick Institute, Medical Research Council (UK), Whisler, Jordan, Shahreza, Somayeh, Schlegelmilch, Karin, Ege, Nil, Javanmardi, Yousef, Malandrino, Andrea, Agrawal, Ayushi, Fantin, Alessandro, Serwinski, Bianca, Azizgolshani, Hesham, Park, Clara, Shone, Victoria, Demuren, Olukunle O., Del Rosario, Amanda, Butty, Vincent L., Holroyd, Natalie, Domart, Marie-Charlotte, Hooper, Steven, Szita, Nicolás, Boyer, Laurie A., Walker-Samuel, Simon, Djordjevic, Boris, Sheridan, Graham K., Collinson, Lucy, Calvo, Fernando, Ruhrberg, Christiana, Sahai, Erik, Kamm, Roger, and Moeendarbary, Emad

Abstract

Vascularization is driven by morphogen signals and mechanical cues that coordinately regulate cellular force generation, migration, and shape change to sculpt the developing vascular network. However, it remains unclear whether developing vasculature actively regulates its own mechanical properties to achieve effective vascularization. We engineered tissue constructs containing endothelial cells and fibroblasts to investigate the mechanics of vascularization. Tissue stiffness increases during vascular morphogenesis resulting from emergent interactions between endothelial cells, fibroblasts, and ECM and correlates with enhanced vascular function. Contractile cellular forces are key to emergent tissue stiffening and synergize with ECM mechanical properties to modulate the mechanics of vascularization. Emergent tissue stiffening and vascular function rely on mechanotransduction signaling within fibroblasts, mediated by YAP1. Mouse embryos lacking YAP1 in fibroblasts exhibit both reduced tissue stiffness and develop lethal vascular defects. Translating our findings through biology-inspired vascular tissue engineering approaches will have substantial implications in regenerative medicine.

Published
2023

24. HiExM: high-throughput expansion microscopy enables scalable super-resolution imaging

Author

Day, John H., Maretich, Pema, Della Santina, Catherine Marin, Auld, Alexander L., Shin, Tay, Boyden, Edward S., and Boyer, Laurie A.

Subjects
Article
Abstract

Expansion microscopy (ExM) involves the physical, isotropic expansion of specimens enabling nanoscale imaging using a standard confocal microscope. ExM is widely employed to image proteins, nucleic acids, and lipid membranes in single cells at nanoscale; however, current methods are low throughput which limits the number of samples that can be processed simultaneously. We developed High-throughput Expansion Microscopy (HiExM), a robust platform that enables expansion microscopy of cells cultured in a standard 96-well plate. Our method enables consistent ∼4.2x expansion across individual wells and entire plates in parallel. We also demonstrate that samples expanded using HiExM can be imaged and analyzed using standard high-throughput confocal imaging platforms. Our method broadens the application of ExM as a tool for scalable super-resolution imaging of specimens for pharmaceutical and research applications including drug and cell phenotype screening.

Published
2023
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26. RBPMS2 Is a Myocardial-Enriched Splicing Regulator Required for Cardiac Function

Author

Akerberg, Alexander A., primary, Trembley, Michael, additional, Butty, Vincent, additional, Schwertner, Asya, additional, Zhao, Long, additional, Beerens, Manu, additional, Liu, Xujie, additional, Mahamdeh, Mohammed, additional, Yuan, Shiaulou, additional, Boyer, Laurie, additional, MacRae, Calum, additional, Nguyen, Christopher, additional, Pu, William T., additional, Burns, Caroline E., additional, and Burns, C. Geoffrey, additional

Published
2022
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31. Cell size is a determinant of stem cell potential during aging

Author

Massachusetts Institute of Technology. Department of Biology, Lengefeld, Jette, Cheng, Chia-Wei, Maretich, Pema, Blair, Marguerite, Hagen, Hannah, McReynolds, Melanie R, Sullivan, Emily, Majors, Kyra, Roberts, Christina, Kang, Joon Ho, Steiner, Joachim D, Miettinen, Teemu P, Manalis, Scott R, Antebi, Adam, Morrison, Sean J, Lees, Jacqueline A, Boyer, Laurie A, Yilmaz, Ömer H, Amon, Angelika, Massachusetts Institute of Technology. Department of Biology, Lengefeld, Jette, Cheng, Chia-Wei, Maretich, Pema, Blair, Marguerite, Hagen, Hannah, McReynolds, Melanie R, Sullivan, Emily, Majors, Kyra, Roberts, Christina, Kang, Joon Ho, Steiner, Joachim D, Miettinen, Teemu P, Manalis, Scott R, Antebi, Adam, Morrison, Sean J, Lees, Jacqueline A, Boyer, Laurie A, Yilmaz, Ömer H, and Amon, Angelika

Abstract

Small cell size preserves the function of hematopoietic stem cells (HSCs); HSC enlargement during aging causes their dysfunction.

Published
2022

32. A dual role for H2A.Z.1 in modulating the dynamics of RNA polymerase II initiation and elongation

Author

Massachusetts Institute of Technology. Department of Biology, Massachusetts Institute of Technology. Department of Physics, Massachusetts Institute of Technology. Department of Biological Engineering, Mylonas, Constantine, Lee, Choongman, Auld, Alexander L, Cisse, Ibrahim I, Boyer, Laurie A, Massachusetts Institute of Technology. Department of Biology, Massachusetts Institute of Technology. Department of Physics, Massachusetts Institute of Technology. Department of Biological Engineering, Mylonas, Constantine, Lee, Choongman, Auld, Alexander L, Cisse, Ibrahim I, and Boyer, Laurie A

Abstract

RNA polymerase II (RNAPII) pausing immediately downstream of the transcription start site is a critical rate-limiting step for the expression of most metazoan genes. During pause release, RNAPII encounters a highly conserved +1 H2A.Z nucleosome, yet how this histone variant contributes to transcription is poorly understood. Here, using an inducible protein degron system combined with genomic approaches and live cell super-resolution microscopy, we show that H2A.Z.1 modulates RNAPII dynamics across most genes in murine embryonic stem cells. Our quantitative analysis shows that H2A.Z.1 slows the rate of RNAPII pause release and consequently impacts negative elongation factor dynamics as well as nascent transcription. Consequently, H2A.Z.1 also impacts re-loading of the pre-initiation complex components TFIIB and TBP. Altogether, this work provides a critical mechanistic link between H2A.Z.1 and the proper induction of mammalian gene expression programs through the regulation of RNAPII dynamics and pause release.

Published
2022

35. Cell size is a determinant of stem cell potential during aging

Author

Lengefeld, Jette, primary, Cheng, Chia-Wei, additional, Maretich, Pema, additional, Blair, Marguerite, additional, Hagen, Hannah, additional, McReynolds, Melanie R., additional, Sullivan, Emily, additional, Majors, Kyra, additional, Roberts, Christina, additional, Kang, Joon Ho, additional, Steiner, Joachim D., additional, Miettinen, Teemu P., additional, Manalis, Scott R., additional, Antebi, Adam, additional, Morrison, Sean J., additional, Lees, Jacqueline A., additional, Boyer, Laurie A., additional, Yilmaz, Ömer H., additional, and Amon, Angelika, additional

Published
2021
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38. 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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41. Cell size is a determinant of stem cell potential during aging

Author

Lengefeld, Jette, Cheng, Chia-Wei, Maretich, Pema, Blair, Marguerite, Hagen, Hannah, McReynolds, Melanie R., Sullivan, Emily, Majors, Kyra, Roberts, Christina, Kang, Joon Ho, Steiner, Joachim D., Miettinen, Teemu P., Manalis, Scott R., Antebi, Adam, Morrison, Sean J., Lees, Jacqueline A., Boyer, Laurie A., Yilmaz, Omer H., Amon, Angelika, Lengefeld, Jette, Cheng, Chia-Wei, Maretich, Pema, Blair, Marguerite, Hagen, Hannah, McReynolds, Melanie R., Sullivan, Emily, Majors, Kyra, Roberts, Christina, Kang, Joon Ho, Steiner, Joachim D., Miettinen, Teemu P., Manalis, Scott R., Antebi, Adam, Morrison, Sean J., Lees, Jacqueline A., Boyer, Laurie A., Yilmaz, Omer H., and Amon, Angelika

Abstract

Stem cells are remarkably small. Whether small size is important for stem cell function is unknown. We find that hematopoietic stem cells (HSCs) enlarge under conditions known to decrease stem cell function. This decreased fitness of large HSCs is due to reduced proliferation and was accompanied by altered metabolism. Preventing HSC enlargement or reducing large HSCs in size averts the loss of stem cell potential under conditions causing stem cell exhaustion. Last, we show that murine and human HSCs enlarge during aging. Preventing this age-dependent enlargement improves HSC function. We conclude that small cell size is important for stem cell function in vivo and propose that stem cell enlargement contributes to their functional decline during aging.

Published
2021

43. A Chromatin Landmark and Transcription Initiation at Most Promoters in Human Cells

Author

Guenther, Matthew G., Levine, Stuart S., Boyer, Laurie A., Jaenisch, Rudolf, and Young, Richard A.

Subjects
Chromatin, Biological sciences
Abstract

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cell.2007.05.042 Byline: Matthew G. Guenther (1), Stuart S. Levine (1), Laurie A. Boyer (1), Rudolf Jaenisch (1), Richard A. Young (1)(2) Keywords: DNA; RNA; STEMCELL Abstract: We describe the results of a genome-wide analysis of human cells that suggests that most protein-coding genes, including most genes thought to be transcriptionally inactive, experience transcription initiation. We found that nucleosomes with H3K4me3 and H3K9,14Ac modifications, together with RNA polymerase II, occupy the promoters of most protein-coding genes in human embryonic stem cells. Only a subset of these genes produce detectable full-length transcripts and are occupied by nucleosomes with H3K36me3 modifications, a hallmark of elongation. The other genes experience transcription initiation but show no evidence of elongation, suggesting that they are predominantly regulated at postinitiation steps. Genes encoding most developmental regulators fall into this group. Our results also identify a class of genes that are excluded from experiencing transcription initiation, at which mechanisms that prevent initiation must predominate. These observations extend to differentiated cells, suggesting that transcription initiation at most genes is a general phenomenon in human cells. Author Affiliation: (1) Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA (2) Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA Article History: Received 11 January 2007; Revised 6 April 2007; Accepted 17 May 2007 Article Note: (miscellaneous) Published: July 12, 2007

Published
2007

44. Control of developmental regulators by Polycomb in human embryonic stem cells

Author

Tong Ihn Lee, Guenther, Matthew G., Levine, Stuart S., Kumar, Roshan M., Jenner, Richard G., Boyer, Laurie, A., Chevalier, Brett, Johnstone, Sarah E., Cole, Megan F., Kyo-Ichi Isono, Haruhiko Koseki, Fuchikami Takuya, Zucker, Jacob P., Bingbing Yuan, Bell, George W., Abe, Kuniya, Murray, Heather L., Herbolshelmer, Elizabeth, Bartel, David P., Melton, Douglas A., Gifford, David K., Kaiming Sun, Odom, Duncan T., Otte, Arie P., Volkert, Thomas L., Hannett, Nancy M., Jaenisch, Rudolf, and Young, Richard A.

Subjects
Embryonic stem cells -- Research, Metazoa -- Genetic aspects, Genetic research, Biological sciences
Abstract

Polycomb group proteins are essential for early development in metazoans, and it is found that Polycomb Repressive Complex 2 (PRC2) target genes are preferentially activated during embryonic stem (ES) cell differentiation. The results indicate that PRC2 occupies a special set of developmental genes in ES cells that must be repressed to maintain pluripotency and that are poised for activation during ES cell differentiation.

Published
2006

45. RBPMS2 is a conserved regulator of alternative splicing that promotes myofibrillar organization and optimal calcium handling in cardiomyocytes

Author

Akerberg, Alexander A., primary, Trembley, Michael, additional, Butty, Vincent, additional, Schwertner, Asya, additional, Zhao, Long, additional, Beerens, Manu, additional, Liu, Xujie, additional, Mahamdeh, Mohammed, additional, Yuan, Shiaulou, additional, Boyer, Laurie, additional, MacRae, Calum, additional, Nguyen, Christopher, additional, Pu, William T., additional, Burns, Caroline E., additional, and Burns, C. Geoffrey, additional

Published
2021
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46. Core transcriptional regulatory circuitry in human embryonic stem cells

Author

Boyer, Laurie A., Tong Ihn Lee, Cole, Megan F., Johnstone, Sarah E., Levine, Saurt S., Guenther, Matthew G., Kumar, Roshan M., Murray, Heather L., Jenner, Richard G., Gifford, David K., Melton, Douglas A., Jaenisch, Rudolf, and Young, Richard A.

Subjects
Embryonic stem cells -- Research, Genetic research, Biological sciences
Abstract

Genomescale location analysis is used to identify the target genes of transcription factors OCT4, SOX2, and NANOG regulators in vivo. The result provides new insights into the transcriptional regulation of stem cells and reveal how OCT4, SOX2, and NANOG contribute to pluripotency and self-renewal.

Published
2005

48. Control of Developmental Regulators by Polycomb in Human Embryonic Stem Cells

Author

Lee, Tong Ihn, Jenner, Richard G., Boyer, Laurie A., Guenther, Matthew G., Levine, Stuart S., Kumar, Roshan M., Chevalier, Brett, Johnstone, Sarah E., Cole, Megan F., Isono, Kyo-ichi, Koseki, Haruhiko, Fuchikami, Takuya, Abe, Kuniya, Murray, Heather L., Zucker, Jacob P., Yuan, Bingbing, Bell, George W., Herbolsheimer, Elizabeth, Hannett, Nancy M., Sun, Kaiming, Odom, Duncan T., Otte, Arie P., Volkert, Thomas L., Bartel, David P., Melton, Douglas A., Gifford, David K., Jaenisch, Rudolf, and Young, Richard A.

Published
2006
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49. Cell size is a determinant of stem cell potential during aging

Author

Lengefeld, Jette, primary, Cheng, Chia-Wei, additional, Maretich, Pema, additional, Blair, Marguerite, additional, Hagen, Hannah, additional, McReynolds, Melanie R., additional, Sullivan, Emily, additional, Majors, Kyra, additional, Roberts, Christina, additional, Kang, Joon Ho, additional, Steiner, Joachim D., additional, Miettinen, Teemu P., additional, Manalis, Scott R., additional, Antebi, Adam, additional, Morrison, Sean J., additional, Lees, Jacqueline A., additional, Boyer, Laurie A., additional, Yilmaz, Ömer H., additional, and Amon, Angelika, additional

Published
2020
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