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2. Highly efficient reprogrammable mouse lines with integrated reporters to track the route to pluripotency

Author

Elbaz, Judith, primary, Puri, Mira C., additional, Faiz, Maryam, additional, Bang, K. W. Annie, additional, Nguyen, Lena, additional, Makovoz, Bar, additional, Gertsenstein, Marina, additional, Hussein, Samer M. I., additional, Zandstra, Peter W., additional, Briollais, Laurent, additional, Shakiba, Nika, additional, and Nagy, Andras, additional

Published
2022
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5. Genome-wide characterization of the routes to pluripotency

Author

Hussein, Samer M.I., Puri, Mira C., Tonge, Peter D., Benevento, Marco, Corso, Andrew J., Clancy, Jennifer L., Mosbergen, Rowland, Li, Mira, Lee, Dong-Sung, Cloonan, Nicole, Wood, David L.A., Munoz, Javier, Middleton, Robert, Korn, Othmar, Patel, Hardip R., White, Carl A., Shin, Jong-Yeon, Gauthier, Maely E., Cao, Kim-Anh Le, Mar, Jessica C., Shakiba, Nika, Ritchie, William, Rasko, John E.J., Grimmond, Sean M., Zandstra, Peter W., Wells, Christine A., Preiss, Thomas, Seo, Jeong-Sun, Heck, Albert J.R., Rogers, Ian M., and Nagy, Andras

Subjects
Somatic cells -- Physiological aspects, Stem cell research, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Somatic cell reprogramming to a pluripotent state continues to challenge many of our assumptions about cellular specification, and despite major efforts, we lack a complete molecular characterization of the reprograming process. To address this gap in knowledge, we generated extensive transcriptomic, epigenomic and proteomic data sets describing the reprogramming routes leading from mouse embryonic fibroblasts to induced pluripotency. Through integrative analysis, we reveal that cells transition through distinct gene expression and epigenetic signatures and bifurcate towards reprogramming transgene-dependent and -independent stable pluripotent states. Early transcriptional events, driven by high levels of reprogramming transcription factor expression, are associated with widespread loss of histone H3 lysine 27 (H3K27me3) trimethylation, representing a general opening of the chromatin state. Maintenance of high transgene levels leads to re-acquisition of H3K27me3 and a stable pluripotent state that is alternative to the embryonic stem cell (ESC)-like fate. Lowering transgene levels at an intermediate phase, however, guides the process to the acquisition of ESC-like chromatin and DNA methylation signature. Our data provide a comprehensive molecular description of the reprogramming routes and is accessible through the Project Grandiose portal at http://www.stemformatics.org., Forced expression of four transcription factors--Oct4 (also called Pou5f1), Sox2, Klf4 and Myc (OSKM) (1)--induces molecular changes in somatic cells, which lead to pluripotency. The exogenous expression of these transcription [...]

Published
2014
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6. Divergent reprogramming routes lead to alternative stem-cell states

Author

Tonge, Peter D., Corso, Andrew J., Monetti, Claudio, Hussein, Samer M.I., Puri, Mira C., Michael, Iacovos P., Li, Mira, Lee, Dong-Sung, Mar, Jessica C., Cloonan, Nicole, Wood, David L., Gauthier, Maely E., Korn, Othmar, Clancy, Jennifer L., Preiss, Thomas, Grimmond, Sean M., Shin, Jong-Yeon, Seo, Jeong-Sun, Wells, Christine A., Rogers, Ian M., and Nagy, Andras

Subjects
Somatic cells -- Physiological aspects, Stem cell research, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Pluripotency is defined by the ability of a cell to differentiate to the derivatives of all the three embryonic germ layers: ectoderm, mesoderm and endoderm. Pluripotent cells can be captured via the archetypal derivation of embryonic stem cells or via somatic cell reprogramming. Somatic cells are induced to acquire a pluripotent stem cell (iPSC) state through the forced expression of key transcription factors, and in the mouse these cells can fulfil the strictest of all developmental assays for pluripotent cells by generating completely iPSC-derived embryos and mice. However, it is not known whether there are additional classes of pluripotent cells, or what the spectrum of reprogrammed phenotypes encompasses. Here we explore alternative outcomes of somatic reprogramming by fully characterizing reprogrammed cells independent of preconceived definitions of iPSC states. We demonstrate that by maintaining elevated reprogramming factor expression levels, mouse embryonic fibroblasts go through unique epigenetic modifications to arrive at a stable, Nanog-positive, alternative pluripotent state. In doing so, we prove that the pluripotent spectrum can encompass multiple, unique cell states., Somatic cells that have lost their pluripotent properties through the acquisition of differentiation-associated epigenetic marks can be driven to acquire an induced pluripotent cell (iPSC) state by the forced expression [...]

Published
2014
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8. Vascular system defects and neuronal apoptosis in mice lacking Ras GTPase-activating protein

Author

Henkemeyer, Mark, Rossi, Derrick J., Holmyard, Douglas P., Puri, Mira C., Mbamalu, Geraldine, Harpal, Kendraprasad, Shih, T. Shane, Jacks, Tyler, and Pawson, Tony

Subjects
Embryology, Experimental -- Research, G proteins -- Research, Neurofibrils -- Research, Ras genes -- Research, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Embryos of mice which lack rasGAP demonstrate neuronal apoptosis and major defects in endothelial cell organization. The Ras activity during embryonic development is controlled by the dual action of rasGAP and neurofibromin. A synergistic effect results when the Gap and Nf1 genes undergo mutations. The resulting embryo displays a deteriorated Gap phenotype. Biochemical studies show that the rasGAP complex is a substrate for Flt-1 and Flk-1 tyrosine-kinase activity.

Published
1995

9. Novel zinc finger proteins that interact with the mouse gammaF-crystallin promoter and are expressed in the sclerotome during early somitogenesis

Author

Liu, Qiurong, Shalaby, Fouad, Puri, Mira C., Tang, Shaojun, and Breitman, Martin L.

Subjects
Promoters (Genetics) -- Research, Proteins -- Research, Biological sciences
Abstract

Three protein encoding cDNA sequences isolated from chicken share a zinc finger domain that attaches to the gamma F-1 binding motif, and are differential spliced products of the same gamma FBP gene in the chicken. The protein isoforms have specific transregulatory activities on the gamma F-crystalline promoter region, with gamma FBP-B protein acting as a transcription suppressor. The sequential expression of gamma FBP gene in somite, presomitic mesoderm and sclerotome indicates that the protein isoforms regulate the sclerotome differentiation.

Published
1994

10. Cell competition during reprogramming gives rise to dominant clones

Author

Shakiba, Nika, primary, Fahmy, Ahmed, additional, Jayakumaran, Gowtham, additional, McGibbon, Sophie, additional, David, Laurent, additional, Trcka, Daniel, additional, Elbaz, Judith, additional, Puri, Mira C., additional, Nagy, Andras, additional, van der Kooy, Derek, additional, Goyal, Sidhartha, additional, Wrana, Jeffrey L., additional, and Zandstra, Peter W., additional

Published
2019
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11. Corrigendum: Genome-wide characterization of the routes to pluripotency

Author

Hussein, Samer M I, Puri, Mira C, Tonge, Peter D, Benevento, Marco, Corso, Andrew J, Clancy, Jennifer L, Mosbergen, Rowland, Li, Mira, Lee, Dong-Sung, Cloonan, Nicole, Wood, David L A, Munoz, Javier, Middleton, Robert, Korn, Othmar, Patel, Hardip R, White, Carl A, Shin, Jong-Yeon, Gauthier, Maely E, Cao, Kim-Anh Lê, Kim, Jong-Il, Mar, Jessica C, Shakiba, Nika, Ritchie, William, Rasko, John E J, Grimmond, Sean M, Zandstra, Peter W, Wells, Christine A, Preiss, Thomas, Seo, Jeong-Sun, Heck, Albert J R, Rogers, Ian M, Nagy, Andras, Biomolecular Mass Spectrometry and Proteomics, Sub Biomol.Mass Spectrometry & Proteom., and Sub Biomol.Mass Spect. and Proteomics

Published
2015

12. CD24 tracks divergent pluripotent states in mouse and human cells

Author

Shakiba, Nika, White, Carl A, Lipsitz, Yonatan Y, Yachie-Kinoshita, Ayako, Tonge, Peter D, Hussein, Samer M I, Puri, Mira C, Elbaz, Judith, Morrissey-Scoot, James, Li, Mira, Munoz Peralta, Javier, Benevento, Marco, Rogers, Ian M, Hanna, Jacob H, Heck, Albert J R, Wollscheid, Bernd, Nagy, Andras, Zandstra, Peter W, Biomolecular Mass Spectrometry and Proteomics, Sub Biomol.Mass Spectrometry & Proteom., Sub Biomol.Mass Spect. and Proteomics, Biomolecular Mass Spectrometry and Proteomics, Sub Biomol.Mass Spectrometry & Proteom., Sub Biomol.Mass Spect. and Proteomics, Ontario Government, Canadian Institutes of Health Research, and NSERC Vanier Canada Graduate Scholarship

Subjects
Cell biology, Human Embryonic Stem Cells, Induced Pluripotent Stem Cells, General Physics and Astronomy, Germ layer, Embryoid body, Biology, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Mice, 0302 clinical medicine, Developmental biology, Animals, Humans, Induced pluripotent stem cell, 030304 developmental biology, Genetics, 0303 health sciences, Multidisciplinary, Stem Cells, CD24 Antigen, Mouse Embryonic Stem Cells, General Chemistry, Cellular Reprogramming, Embryonic stem cell, Biological sciences, Epiblast, Stem cell, Reprogramming, 030217 neurology & neurosurgery, Germ Layers
Abstract

Reprogramming is a dynamic process that can result in multiple pluripotent cell types emerging from divergent paths. Cell surface protein expression is a particularly desirable tool to categorize reprogramming and pluripotency as it enables robust quantification and enrichment of live cells. Here we use cell surface proteomics to interrogate mouse cell reprogramming dynamics and discover CD24 as a marker that tracks the emergence of reprogramming-responsive cells, while enabling the analysis and enrichment of transgene-dependent (F-class) and -independent (traditional) induced pluripotent stem cells (iPSCs) at later stages. Furthermore, CD24 can be used to delineate epiblast stem cells (EpiSCs) from embryonic stem cells (ESCs) in mouse pluripotent culture. Importantly, regulated CD24 expression is conserved in human pluripotent stem cells (PSCs), tracking the conversion of human ESCs to more naive-like PSC states. Thus, CD24 is a conserved marker for tracking divergent states in both reprogramming and standard pluripotent culture., Nature Communications, 6, ISSN:2041-1723

Published
2015
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13. Proteome adaptation in cell reprogramming proceeds via distinct transcriptional networks

Author

Benevento, Marco, Tonge, Peter D, Puri, Mira C, Hussein, Samer M I, Cloonan, Nicole, Wood, David L, Grimmond, Sean M, Nagy, Andras, Munoz, Javier, Heck, Albert J R, Sub Biomol.Mass Spectrometry & Proteom., Sub Biomol.Mass Spect. and Proteomics, Molecular Pharmacy, Sub Biomol.Mass Spectrometry & Proteom., Sub Biomol.Mass Spect. and Proteomics, and Molecular Pharmacy

Subjects
Induced stem cells, Multidisciplinary, General Physics and Astronomy, General Chemistry, Embryoid body, Biology, Proteomics, General Biochemistry, Genetics and Molecular Biology, Cell biology, KLF4, Proteome, Induced pluripotent stem cell, Reprogramming, Cell potency
Abstract

The ectopic expression of Oct4, Klf4, c-Myc and Sox2 (OKMS) transcription factors allows reprogramming of somatic cells into induced pluripotent stem cells (iPSCs). The reprogramming process, which involves a complex network of molecular events, is not yet fully characterized. Here we perform a quantitative mass spectrometry-based analysis to probe in-depth dynamic proteome changes during somatic cell reprogramming. Our data reveal defined waves of proteome resetting, with the first wave occurring 48 h after the activation of the reprogramming transgenes and involving specific biological processes linked to the c-Myc transcriptional network. A second wave of proteome reorganization occurs in a later stage of reprogramming, where we characterize the proteome of two distinct pluripotent cellular populations. In addition, the overlay of our proteome resource with parallel generated -omics data is explored to identify post-transcriptionally regulated proteins involved in key steps during reprogramming.

Published
2014

14. Small RNA changes en route to distinct cellular states of induced pluripotency

Author

Clancy, Jennifer L, Patel, Hardip R, Hussein, Samer M I, Tonge, Peter D, Cloonan, Nicole, Corso, Andrew J, Li, Mira, Lee, Dong-Sung, Shin, Jong-Yeon, Wong, Justin J L, Bailey, Charles G, Benevento, Marco, Munoz, Javier, Chuah, Aaron, Wood, David, Rasko, John E J, Heck, Albert J R, Grimmond, Sean M, Rogers, Ian M, Seo, Jeong-Sun, Wells, Christine A, Puri, Mira C, Nagy, Andras, Preiss, Thomas, Sub Biomol.Mass Spectrometry & Proteom., Sub Biomol.Mass Spect. and Proteomics, Biomolecular Mass Spectrometry and Proteomics, Molecular Pharmacy, Sub Biomol.Mass Spectrometry & Proteom., Sub Biomol.Mass Spect. and Proteomics, Biomolecular Mass Spectrometry and Proteomics, and Molecular Pharmacy

Subjects
Gene isoform, Genetics, 0303 health sciences, Small RNA, Multidisciplinary, General Physics and Astronomy, General Chemistry, Biology, General Biochemistry, Genetics and Molecular Biology, Cell biology, 03 medical and health sciences, 0302 clinical medicine, Transcription (biology), 030220 oncology & carcinogenesis, Gene expression, DNA methylation, microRNA, Induced pluripotent stem cell, Reprogramming, 030304 developmental biology
Abstract

MicroRNAs (miRNAs) are critical to somatic cell reprogramming into induced pluripotent stem cells (iPSCs), however, exactly how miRNA expression changes support the transition to pluripotency requires further investigation. Here we use a murine secondary reprogramming system to sample cellular trajectories towards iPSCs or a novel pluripotent 'F-class' state and perform small RNA sequencing. We detect sweeping changes in an early and a late wave, revealing that distinct miRNA milieus characterize alternate states of pluripotency. miRNA isoform expression is common but surprisingly varies little between cell states. Referencing other omic data sets generated in parallel, we find that miRNA expression is changed through transcriptional and post-transcriptional mechanisms. miRNA transcription is commonly regulated by dynamic histone modification, while DNA methylation/demethylation consolidates these changes at multiple loci. Importantly, our results suggest that a novel subset of distinctly expressed miRNAs supports pluripotency in the F-class state, substituting for miRNAs that serve such roles in iPSCs.

Published
2014

15. Corrigendum: Genome-wide characterization of the routes to pluripotency

Author

Biomolecular Mass Spectrometry and Proteomics, Sub Biomol.Mass Spectrometry & Proteom., Sub Biomol.Mass Spect. and Proteomics, Hussein, Samer M I, Puri, Mira C, Tonge, Peter D, Benevento, Marco, Corso, Andrew J, Clancy, Jennifer L, Mosbergen, Rowland, Li, Mira, Lee, Dong-Sung, Cloonan, Nicole, Wood, David L A, Munoz, Javier, Middleton, Robert, Korn, Othmar, Patel, Hardip R, White, Carl A, Shin, Jong-Yeon, Gauthier, Maely E, Cao, Kim-Anh Lê, Kim, Jong-Il, Mar, Jessica C, Shakiba, Nika, Ritchie, William, Rasko, John E J, Grimmond, Sean M, Zandstra, Peter W, Wells, Christine A, Preiss, Thomas, Seo, Jeong-Sun, Heck, Albert J R, Rogers, Ian M, Nagy, Andras, Biomolecular Mass Spectrometry and Proteomics, Sub Biomol.Mass Spectrometry & Proteom., Sub Biomol.Mass Spect. and Proteomics, Hussein, Samer M I, Puri, Mira C, Tonge, Peter D, Benevento, Marco, Corso, Andrew J, Clancy, Jennifer L, Mosbergen, Rowland, Li, Mira, Lee, Dong-Sung, Cloonan, Nicole, Wood, David L A, Munoz, Javier, Middleton, Robert, Korn, Othmar, Patel, Hardip R, White, Carl A, Shin, Jong-Yeon, Gauthier, Maely E, Cao, Kim-Anh Lê, Kim, Jong-Il, Mar, Jessica C, Shakiba, Nika, Ritchie, William, Rasko, John E J, Grimmond, Sean M, Zandstra, Peter W, Wells, Christine A, Preiss, Thomas, Seo, Jeong-Sun, Heck, Albert J R, Rogers, Ian M, and Nagy, Andras

Published
2015

16. CD24 tracks divergent pluripotent states in mouse and human cells

Author

Biomolecular Mass Spectrometry and Proteomics, Sub Biomol.Mass Spectrometry & Proteom., Sub Biomol.Mass Spect. and Proteomics, Shakiba, Nika, White, Carl A, Lipsitz, Yonatan Y, Yachie-Kinoshita, Ayako, Tonge, Peter D, Hussein, Samer M I, Puri, Mira C, Elbaz, Judith, Morrissey-Scoot, James, Li, Mira, Munoz Peralta, Javier, Benevento, Marco, Rogers, Ian M, Hanna, Jacob H, Heck, Albert J R, Wollscheid, Bernd, Nagy, Andras, Zandstra, Peter W, Biomolecular Mass Spectrometry and Proteomics, Sub Biomol.Mass Spectrometry & Proteom., Sub Biomol.Mass Spect. and Proteomics, Shakiba, Nika, White, Carl A, Lipsitz, Yonatan Y, Yachie-Kinoshita, Ayako, Tonge, Peter D, Hussein, Samer M I, Puri, Mira C, Elbaz, Judith, Morrissey-Scoot, James, Li, Mira, Munoz Peralta, Javier, Benevento, Marco, Rogers, Ian M, Hanna, Jacob H, Heck, Albert J R, Wollscheid, Bernd, Nagy, Andras, and Zandstra, Peter W

Published
2015

17. Corrigendum: divergent reprogramming routes lead to alternative stem-cell states

Author

Tonge, Peter D., Corso, Andrew J., Monetti, Claudio, Hussein, Samer M.I., Puri, Mira C., Michael, Iacovos P., Li, Mira, Lee, Dong-Sung, Mar, Jessica C., Cloonan, Nicole, Wood, David L., Gauthier, Maely E., Korn, Othmar, Clancy, Jennifer L., Preiss, Thomas, Grimmond, Sean M., Shin, Jong-Yeon, Jeong-SunSeo, Wells, Christine A., Rogers, Ian M., and Nagy, Andras

Subjects
Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Nature 516, 192-197 (2014); doi:10.1038/nature14047 In this Article, the address listed as Nicole Cloonan's present address (QIMR Berghofer Medical Research Institute, Queensland 4006, Australia) should have been listed as her [...]

Published
2015
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18. Corrigendum: genome-wide characterization of the routes to pluripotency

Author

Hussein, Samer M.I., Puri, Mira C., Tonge, Peter D., Benevento, Marco, Corso, Andrew J., Clancy, Jennifer L., Mosbergen, Rowland, Li, Mira, Lee, Dong-Sung, Cloonan, Nicole, Wood, David L.A., Munoz, Javier, Middleton, Robert, Korn, Othmar, Patel, Hardip R., White, Carl A., Shin, Jong-Yeon, Gauthier, Maely E., Cao, Kim-Anh Le, Kim, Jong-Il, Mar, Jessica C., Shakiba, Nika, Ritchie, William, Rasko, John E.J., Grimmond, Sean M., Zandstra, Peter W., Wells, Christine A., Preiss, Thomas, Seo, Jeong-Sun, Heck, Albert J.R., Rogers, Ian M., and Nagy, Andras

Subjects
Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Nature 516, 198-206 (2014); doi:10.1038/nature14046 In this Article, the address listed as Nicole Cloonan's present address (QIMR Berghofer Medical Research Institute, Queensland 4006, Australia) should have been listed as her [...]

Published
2015
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20. Erratum: Corrigendum: Divergent reprogramming routes lead to alternative stem-cell states

Author

Tonge, Peter D., primary, Corso, Andrew J., additional, Monetti, Claudio, additional, Hussein, Samer M. I., additional, Puri, Mira C., additional, Michael, Iacovos P., additional, Li, Mira, additional, Lee, Dong-Sung, additional, Mar, Jessica C., additional, Cloonan, Nicole, additional, Wood, David L., additional, Gauthier, Maely E., additional, Korn, Othmar, additional, Clancy, Jennifer L., additional, Preiss, Thomas, additional, Grimmond, Sean M., additional, Shin, Jong-Yeon, additional, Seo, Jeong-Sun, additional, Wells, Christine A., additional, Rogers, Ian M., additional, and Nagy, Andras, additional

Published
2015
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21. Erratum: Corrigendum: Genome-wide characterization of the routes to pluripotency

Author

Hussein, Samer M. I., primary, Puri, Mira C., additional, Tonge, Peter D., additional, Benevento, Marco, additional, Corso, Andrew J., additional, Clancy, Jennifer L., additional, Mosbergen, Rowland, additional, Li, Mira, additional, Lee, Dong-Sung, additional, Cloonan, Nicole, additional, Wood, David L. A., additional, Munoz, Javier, additional, Middleton, Robert, additional, Korn, Othmar, additional, Patel, Hardip R., additional, White, Carl A., additional, Shin, Jong-Yeon, additional, Gauthier, Maely E., additional, Cao, Kim-Anh Lê, additional, Kim, Jong-Il, additional, Mar, Jessica C., additional, Shakiba, Nika, additional, Ritchie, William, additional, Rasko, John E. J., additional, Grimmond, Sean M., additional, Zandstra, Peter W., additional, Wells, Christine A., additional, Preiss, Thomas, additional, Seo, Jeong-Sun, additional, Heck, Albert J. R., additional, Rogers, Ian M., additional, and Nagy, Andras, additional

Published
2015
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24. Proteome adaptation in cell reprogramming proceeds via distinct transcriptional networks

Author

Sub Biomol.Mass Spectrometry & Proteom., Sub Biomol.Mass Spect. and Proteomics, Molecular Pharmacy, Benevento, Marco, Tonge, Peter D, Puri, Mira C, Hussein, Samer M I, Cloonan, Nicole, Wood, David L, Grimmond, Sean M, Nagy, Andras, Munoz, Javier, Heck, Albert J R, Sub Biomol.Mass Spectrometry & Proteom., Sub Biomol.Mass Spect. and Proteomics, Molecular Pharmacy, Benevento, Marco, Tonge, Peter D, Puri, Mira C, Hussein, Samer M I, Cloonan, Nicole, Wood, David L, Grimmond, Sean M, Nagy, Andras, Munoz, Javier, and Heck, Albert J R

Published
2014

25. Genome-wide characterization of the routes to pluripotency

Author

Sub Biomol.Mass Spectrometry & Proteom., Sub Biomol.Mass Spect. and Proteomics, Biomolecular Mass Spectrometry and Proteomics, Molecular Pharmacy, Hussein, Samer M I, Puri, Mira C, Tonge, Peter D, Benevento, Marco, Corso, Andrew J, Clancy, Jennifer L, Mosbergen, Rowland, Li, Mira, Lee, Dong-Sung, Cloonan, Nicole, Wood, David L A, Munoz, Javier, Middleton, Robert, Korn, Othmar, Patel, Hardip R, White, Carl A, Shin, Jong-Yeon, Gauthier, Maely E, Lê Cao, Kim-Anh, Kim, Jong-Il, Mar, Jessica C, Shakiba, Nika, Ritchie, William, Rasko, John E J, Grimmond, Sean M, Zandstra, Peter W, Wells, Christine A, Preiss, Thomas, Seo, Jeong-Sun, Heck, Albert J R, Rogers, Ian M, Nagy, Andras, Sub Biomol.Mass Spectrometry & Proteom., Sub Biomol.Mass Spect. and Proteomics, Biomolecular Mass Spectrometry and Proteomics, Molecular Pharmacy, Hussein, Samer M I, Puri, Mira C, Tonge, Peter D, Benevento, Marco, Corso, Andrew J, Clancy, Jennifer L, Mosbergen, Rowland, Li, Mira, Lee, Dong-Sung, Cloonan, Nicole, Wood, David L A, Munoz, Javier, Middleton, Robert, Korn, Othmar, Patel, Hardip R, White, Carl A, Shin, Jong-Yeon, Gauthier, Maely E, Lê Cao, Kim-Anh, Kim, Jong-Il, Mar, Jessica C, Shakiba, Nika, Ritchie, William, Rasko, John E J, Grimmond, Sean M, Zandstra, Peter W, Wells, Christine A, Preiss, Thomas, Seo, Jeong-Sun, Heck, Albert J R, Rogers, Ian M, and Nagy, Andras

Published
2014

26. Small RNA changes en route to distinct cellular states of induced pluripotency

Author

Sub Biomol.Mass Spectrometry & Proteom., Sub Biomol.Mass Spect. and Proteomics, Biomolecular Mass Spectrometry and Proteomics, Molecular Pharmacy, Clancy, Jennifer L, Patel, Hardip R, Hussein, Samer M I, Tonge, Peter D, Cloonan, Nicole, Corso, Andrew J, Li, Mira, Lee, Dong-Sung, Shin, Jong-Yeon, Wong, Justin J L, Bailey, Charles G, Benevento, Marco, Munoz, Javier, Chuah, Aaron, Wood, David, Rasko, John E J, Heck, Albert J R, Grimmond, Sean M, Rogers, Ian M, Seo, Jeong-Sun, Wells, Christine A, Puri, Mira C, Nagy, Andras, Preiss, Thomas, Sub Biomol.Mass Spectrometry & Proteom., Sub Biomol.Mass Spect. and Proteomics, Biomolecular Mass Spectrometry and Proteomics, Molecular Pharmacy, Clancy, Jennifer L, Patel, Hardip R, Hussein, Samer M I, Tonge, Peter D, Cloonan, Nicole, Corso, Andrew J, Li, Mira, Lee, Dong-Sung, Shin, Jong-Yeon, Wong, Justin J L, Bailey, Charles G, Benevento, Marco, Munoz, Javier, Chuah, Aaron, Wood, David, Rasko, John E J, Heck, Albert J R, Grimmond, Sean M, Rogers, Ian M, Seo, Jeong-Sun, Wells, Christine A, Puri, Mira C, Nagy, Andras, and Preiss, Thomas

Published
2014

27. Small RNA changes en route to distinct cellular states of induced pluripotency

Author

Clancy, Jennifer L., Patel, Hardip R., Hussein, Samer M. I., Tonge, Peter D., Cloonan, Nicole, Corso, Andrew J., Li, Mira, Lee, Dong-Sung, Shin, Jong-Yeon, Wong, Justin J. L., Bailey, Charles G., Benevento, Marco, Munoz, Javier, Chuah, Aaron, Wood, David, Rasko, John E. J., Heck, Albert J. R., Grimmond, Sean M., Rogers, Ian M., Seo, Jeong-Sun, Wells, Christine A., Puri, Mira C., Nagy, Andras, Preiss, Thomas, Clancy, Jennifer L., Patel, Hardip R., Hussein, Samer M. I., Tonge, Peter D., Cloonan, Nicole, Corso, Andrew J., Li, Mira, Lee, Dong-Sung, Shin, Jong-Yeon, Wong, Justin J. L., Bailey, Charles G., Benevento, Marco, Munoz, Javier, Chuah, Aaron, Wood, David, Rasko, John E. J., Heck, Albert J. R., Grimmond, Sean M., Rogers, Ian M., Seo, Jeong-Sun, Wells, Christine A., Puri, Mira C., Nagy, Andras, and Preiss, Thomas

Abstract

MicroRNAs (miRNAs) are critical to somatic cell reprogramming into induced pluripotent stem cells (iPSCs), however, exactly how miRNA expression changes support the transition to pluripotency requires further investigation. Here we use a murine secondary reprogramming system to sample cellular trajectories towards iPSCs or a novel pluripotent 'F-class' state and perform small RNA sequencing. We detect sweeping changes in an early and a late wave, revealing that distinct miRNA milieus characterize alternate states of pluripotency. miRNA isoform expression is common but surprisingly varies little between cell states. Referencing other omic data sets generated in parallel, we find that miRNA expression is changed through transcriptional and post-transcriptional mechanisms. miRNA transcription is commonly regulated by dynamic histone modification, while DNA methylation/demethylation consolidates these changes at multiple loci. Importantly, our results suggest that a novel subset of distinctly expressed miRNAs supports pluripotency in the F-class state, substituting for miRNAs that serve such roles in iPSCs.

Published
2014

28. Genome-wide characterization of the routes to pluripotency

Author

Hussein, Samer M. I., Puri, Mira C., Tonge, Peter D., Benevento, Marco, Corso, Andrew J., Clancy, Jennifer, Mosbergen, Rowland, Li, Mira, Lee, D. S., Cloonan, Nicole, Wood, David L. A., Munoz, Javier, Middleton, Robert, Korn, Othmar, Patel, Hardip, White, Carl A., Shin, Jong-Yeon, Gauthier, Maely E., Lê Cao, Kim-Anh, Kim, Jong-Il, Mar, J. C., Shakiba, Nika, Ritchie, William, Rasko, John E. J., Grimmond, Sean M., Zandstra, Peter W., Wells, Christine, Preiss, Thomas, Seo, Jeong-Sun, Heck, Albert J. R., Rogers, Ian M., Nagy, Andras, Hussein, Samer M. I., Puri, Mira C., Tonge, Peter D., Benevento, Marco, Corso, Andrew J., Clancy, Jennifer, Mosbergen, Rowland, Li, Mira, Lee, D. S., Cloonan, Nicole, Wood, David L. A., Munoz, Javier, Middleton, Robert, Korn, Othmar, Patel, Hardip, White, Carl A., Shin, Jong-Yeon, Gauthier, Maely E., Lê Cao, Kim-Anh, Kim, Jong-Il, Mar, J. C., Shakiba, Nika, Ritchie, William, Rasko, John E. J., Grimmond, Sean M., Zandstra, Peter W., Wells, Christine, Preiss, Thomas, Seo, Jeong-Sun, Heck, Albert J. R., Rogers, Ian M., and Nagy, Andras

Abstract

Somatic cell reprogramming to a pluripotent state continues to challenge many of our assumptions about cellular specification, and despite major efforts, we lack a complete molecular characterization of the reprograming process. To address this gap in knowledge, we generated extensive transcriptomic, epigenomic and proteomic data sets describing the reprogramming routes leading from mouse embryonic fibroblasts to induced pluripotency. Through integrative analysis, we reveal that cells transition through distinct gene expression and epigenetic signatures and bifurcate towards reprogramming transgene-dependent and-independent stable pluripotent states. Early transcriptional events, driven by high levels of reprogramming transcription factor expression, are associated with widespread loss of histone H3 lysine 27 (H3K27me3) trimethylation, representing a general opening of the chromatin state. Maintenance of high transgene levels leads to re-acquisition of H3K27me3 and a stable pluripotent state that is alternative to the embryonic stem cell (ESC)-like fate. Lowering transgene levels at an intermediate phase, however, guides the process to the acquisition of ESC-like chromatin and DNA methylation signature. Our data provide a comprehensive molecular description of the reprogramming routes and is accessible through the Project Grandiose portal at http://www.stemformatics.org.

Published
2014

29. Divergent reprogramming routes lead to alternative stem-cell states

Author

Tonge, Peter D, Corso, Andrew J, Hussein, Samer M I, Monetti, Claudio, Puri, Mira C, Michael, Iacovos P, Li, Mira, Lee, DS, Clancy, Jennifer, Preiss, Thomas, Mar, JC, Cloonan, Nicole, Tonge, Peter D, Corso, Andrew J, Hussein, Samer M I, Monetti, Claudio, Puri, Mira C, Michael, Iacovos P, Li, Mira, Lee, DS, Clancy, Jennifer, Preiss, Thomas, Mar, JC, and Cloonan, Nicole

Abstract

Pluripotency is defined by the ability of a cell to differentiate to the derivatives of all the three embryonic germ layers: ectoderm, mesoderm and endoderm. Pluripotent cells can be captured via the archetypal derivation of embryonic stem cells or via somatic cell reprogramming. Somatic cells are induced to acquire a pluripotent stem cell (iPSC) state through the forced expression of key transcription factors, and in the mouse these cells can fulfil the strictest of all developmental assays for pluripotent cells by generating completely iPSC-derived embryos and mice. However, it is not known whether there are additional classes of pluripotent cells, or what the spectrum of reprogrammed phenotypes encompasses. Here we explore alternative outcomes of somatic reprogramming by fully characterizing reprogrammed cells independent of preconceived definitions of iPSC states. We demonstrate that by maintaining elevated reprogramming factor expression levels, mouse embryonic fibroblasts go through unique epigenetic modifications to arrive at a stable, Nanog-positive, alternative pluripotent state. In doing so, we prove that the pluripotent spectrum can encompass multiple, unique cell states.

Published
2014

30. An epigenomic roadmap to induced pluripotency reveals DNA methylation as a reprogramming modulator

Author

Lee, Dong-Sung, Shin, Jong-Yeon, Tonge, Peter D., Puri, Mira C., Lee, Seungbok, Park, Hansoo, Lee, Won-Chul, Hussein, Samer M. I., Bleazard, Thomas, Yun, Ji-Young, Kim, Jihye, Li, Mira, Cloonan, Nicole, Wood, David, Clancy, Jennifer L., Mosbergen, Rowland, Yi, Jae-Hyuk, Yang, Kap-Seok, Kim, Hyungtae, Rhee, Hwanseok, Wells, Christine A., Preiss, Thomas, Grimmond, Sean M., Rogers, Ian M., Nagy, Andras, Seo, Jeong-Sun, Lee, Dong-Sung, Shin, Jong-Yeon, Tonge, Peter D., Puri, Mira C., Lee, Seungbok, Park, Hansoo, Lee, Won-Chul, Hussein, Samer M. I., Bleazard, Thomas, Yun, Ji-Young, Kim, Jihye, Li, Mira, Cloonan, Nicole, Wood, David, Clancy, Jennifer L., Mosbergen, Rowland, Yi, Jae-Hyuk, Yang, Kap-Seok, Kim, Hyungtae, Rhee, Hwanseok, Wells, Christine A., Preiss, Thomas, Grimmond, Sean M., Rogers, Ian M., Nagy, Andras, and Seo, Jeong-Sun

Abstract

Reprogramming of somatic cells to induced pluripotent stem cells involves a dynamic rearrangement of the epigenetic landscape. To characterize this epigenomic roadmap, we have performed MethylC-seq, ChIP-seq (H3K4/K27/K36me3) and RNA-Seq on samples taken at several time points during murine secondary reprogramming as part of Project Grandiose. We find that DNA methylation gain during reprogramming occurs gradually, while loss is achieved only at the ESC-like state. Binding sites of activated factors exhibit focal demethylation during reprogramming, while ESC-like pluripotent cells are distinguished by extension of demethylation to the wider neighbourhood. We observed that genes with CpG-rich promoters demonstrate stable low methylation and strong engagement of histone marks, whereas genes with CpG-poor promoters are safeguarded by methylation. Such DNA methylation-driven control is the key to the regulation of ESC-pluripotency genes, including Dppa4, Dppa5a and Esrrb. These results reveal the crucial role that DNA methylation plays as an epigenetic switch driving somatic cells to pluripotency.

Published
2014

31. An epigenomic roadmap to induced pluripotency reveals DNA methylation as a reprogramming modulator

Author

Lee, Dong-Sung, primary, Shin, Jong-Yeon, additional, Tonge, Peter D., additional, Puri, Mira C., additional, Lee, Seungbok, additional, Park, Hansoo, additional, Lee, Won-Chul, additional, Hussein, Samer M. I., additional, Bleazard, Thomas, additional, Yun, Ji-Young, additional, Kim, Jihye, additional, Li, Mira, additional, Cloonan, Nicole, additional, Wood, David, additional, Clancy, Jennifer L., additional, Mosbergen, Rowland, additional, Yi, Jae-Hyuk, additional, Yang, Kap-Seok, additional, Kim, Hyungtae, additional, Rhee, Hwanseok, additional, Wells, Christine A., additional, Preiss, Thomas, additional, Grimmond, Sean M., additional, Rogers, Ian M., additional, Nagy, Andras, additional, and Seo, Jeong-Sun, additional

Published
2014
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39. Concise Review: Embryonic Stem Cells Versus Induced Pluripotent Stem Cells: The Game Is On.

Author

Puri, Mira C. and Nagy, Andras

Subjects
PLURIPOTENT stem cells, EMBRYONIC stem cells, THERAPEUTICS, CELLULAR therapy, DRUG development, MEDICAL model
Abstract

Extraordinary advances in pluripotent stem cell research have initiated an era of hope for regenerative strategies to treat human disease. Besides embryonic stem cells, the discovery of induced pluripotent stem cells widened the possibility of patient-specific cell therapy, drug discovery, and disease modeling. Although similar, it has become clear that these two pluripotent cell types display significant differences. In this review, we explore current knowledge of the molecular and functional similarities and differences between these two cell types to emphasize the necessity for thorough characterization of their properties as well as their differentiation capabilities in the pluripotent state. Such comparative studies will be crucial for determining the more suitable cell type for future stem cell-based therapies for human degenerative diseases. S TEM C ELLS 2012;30:10-14 [ABSTRACT FROM AUTHOR]

Published
2012
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40. Interaction of the TEK and TIE receptor tyrosine kinases during cardiovascular development

Author

Puri, Mira C., Partanen, Juha, Rossant, Janet, and Bernstein, Alan

Abstract

TEK (TIE2) and TIE (TIE1) are structurally related receptor tyrosine kinases expressed in endothelial cells and their precursors. Genetic studies in the mouse have revealed essential functions of both receptors in angiogenic expansion of the vasculature during development. As previously shown, mouse embryos homozygous for a disrupted Tek allele die by day 10.5 of embryogenesis due to endocardial defects, hemorrhaging, and impaired vascular network formation. Furthermore, TIE is required cell autonomously for endothelial cell survival and extension of the vascular network during late embryogenesis. Here we have investigated possible redundancy in the TEK and TIE signalling pathways during vascular development. Vasculogenesis proceeds normally in embryos lacking both TEK and TIE, although such embryos die early in gestation of multiple cardiovascular defects. Mosaic analysis revealed an absolute requirement for TEK in the endocardium at E10.5, whereas TEK and TIE are dispensable for the initial assembly of the rest of the vasculature. In contrast, both receptors are required in the microvasculature during late organogenesis and in essentially all blood vessels of the adult. This analysis demonstrates essential functions for TEK and TIE in maintaining the integrity of the mature vasculature.

Published
1999
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41. Cell autonomous functions of the receptor tyrosine kinase TIE in a late phase of angiogenic capillary growth and endothelial cell survival during murine development

Author

Partanen, Juha, Puri, Mira C., Schwartz, Lois, Fischer, Klaus-Dieter, Bernstein, Alan, and Rossant, Janet

Abstract

TIE is a receptor tyrosine kinase expressed in both mature endothelial cells and their precursors, as well as in some hematopoietic cells. Mouse embryos homozygous for a disrupted Tie allele die at midgestation due to impaired endothelial cell integrity and resulting hemorrhage. Here we have performed chimeric analysis to study further the function of the murine TIE in the development of embryonic vasculature and in the hematopoietic system. Cells lacking a functional Tie gene (tielcztielczn– cells) contributed to the embryonic vasculature at E10.5 as efficiently as cells heterozygous for a targeted Tie allele (tielcz+ cells). Thus, TIE does not play a significant role in vasculogenesis or in early angiogenic processes, such as formation of the intersomitic arteries and limb bud vascularization. At E15.5 tielcztielczn– cells still readily contributed to major blood vessels and to endothelial cells of organs such as lung and heart, which have been suggested to be vascularized by angioblast differentiation. In contrast, the tielcztielczn– cells were selected against in the capillary plexuses of several angiogenically vascularized tissues, such as brain and kidney. Our results thus support,a role for TIE in late phases of angiogenesis but not vasculogenesis. Furthermore, the results suggest that different mechanisms regulate early and late angiogenesis and provide support for a model of differential organ vascularization by vasculogenic or angiogenic processes. Analysis of adult chimeras suggested that TIE is required to support the survival or proliferation of certain types of endothelial cells demonstrating heterogeneity in the growth/survival factor requirements in various endothelial cell populations. Chimeric analysis of adult hematopoietic cell populations, including peripheral platelets and bone marrow progenitor cells, revealed that tielcztielczn– cells were able to contribute to these cell types in a way indistinguishable from tielcz+ or wild-type cells. Thus, the primary function of TIE appears to be restricted to the endothelial cell lineage.

Published
1996
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42. CD24 tracks divergent pluripotent states in mouse and human cells.

Author

Shakiba N, White CA, Lipsitz YY, Yachie-Kinoshita A, Tonge PD, Hussein SMI, Puri MC, Elbaz J, Morrissey-Scoot J, Li M, Munoz J, Benevento M, Rogers IM, Hanna JH, Heck AJR, Wollscheid B, Nagy A, and Zandstra PW

Subjects
Animals, Germ Layers cytology, Human Embryonic Stem Cells cytology, Humans, Induced Pluripotent Stem Cells cytology, Mice, Mouse Embryonic Stem Cells cytology, Stem Cells cytology, Stem Cells metabolism, CD24 Antigen metabolism, Cellular Reprogramming, Human Embryonic Stem Cells metabolism, Induced Pluripotent Stem Cells metabolism, Mouse Embryonic Stem Cells metabolism
Abstract

Reprogramming is a dynamic process that can result in multiple pluripotent cell types emerging from divergent paths. Cell surface protein expression is a particularly desirable tool to categorize reprogramming and pluripotency as it enables robust quantification and enrichment of live cells. Here we use cell surface proteomics to interrogate mouse cell reprogramming dynamics and discover CD24 as a marker that tracks the emergence of reprogramming-responsive cells, while enabling the analysis and enrichment of transgene-dependent (F-class) and -independent (traditional) induced pluripotent stem cells (iPSCs) at later stages. Furthermore, CD24 can be used to delineate epiblast stem cells (EpiSCs) from embryonic stem cells (ESCs) in mouse pluripotent culture. Importantly, regulated CD24 expression is conserved in human pluripotent stem cells (PSCs), tracking the conversion of human ESCs to more naive-like PSC states. Thus, CD24 is a conserved marker for tracking divergent states in both reprogramming and standard pluripotent culture.

Published
2015
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