SOX2 Co-Occupies Distal Enhancer Elements with Distinct POU Factors in ESCs and NPCs to Specify Cell State
SOX2 is a master regulator of both pluripotent embryonic stem cells (ESCs) and multipotent neural progenitor cells (NPCs); however, we currently lack a detailed understanding of how SOX2 controls these distinct stem cell populations. Here we show by genome-wide analysis that, while SOX2 bound to a d...
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| Format: | Article |
| Language: | en_US |
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Public Library of Science
2013
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| Online Access: | http://hdl.handle.net/1721.1/78345 https://orcid.org/0000-0002-5239-9557 https://orcid.org/0000-0002-2902-7288 https://orcid.org/0000-0003-1381-4313 https://orcid.org/0000-0001-9249-8181 https://orcid.org/0000-0003-3491-4962 |
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| author | Lodato, Michael Anthony Ng, Christopher W. Wamstad, Joseph Alan Cheng, Albert W. Thai, Kevin Kinh Fraenkel, Ernest Jaenisch, Rudolf Boyer, Laurie |
| author2 | Massachusetts Institute of Technology. Computational and Systems Biology Program |
| author_facet | Massachusetts Institute of Technology. Computational and Systems Biology Program Lodato, Michael Anthony Ng, Christopher W. Wamstad, Joseph Alan Cheng, Albert W. Thai, Kevin Kinh Fraenkel, Ernest Jaenisch, Rudolf Boyer, Laurie |
| author_sort | Lodato, Michael Anthony |
| collection | MIT |
| description | SOX2 is a master regulator of both pluripotent embryonic stem cells (ESCs) and multipotent neural progenitor cells (NPCs); however, we currently lack a detailed understanding of how SOX2 controls these distinct stem cell populations. Here we show by genome-wide analysis that, while SOX2 bound to a distinct set of gene promoters in ESCs and NPCs, the majority of regions coincided with unique distal enhancer elements, important cis-acting regulators of tissue-specific gene expression programs. Notably, SOX2 bound the same consensus DNA motif in both cell types, suggesting that additional factors contribute to target specificity. We found that, similar to its association with OCT4 (Pou5f1) in ESCs, the related POU family member BRN2 (Pou3f2) co-occupied a large set of putative distal enhancers with SOX2 in NPCs. Forced expression of BRN2 in ESCs led to functional recruitment of SOX2 to a subset of NPC-specific targets and to precocious differentiation toward a neural-like state. Further analysis of the bound sequences revealed differences in the distances of SOX and POU peaks in the two cell types and identified motifs for additional transcription factors. Together, these data suggest that SOX2 controls a larger network of genes than previously anticipated through binding of distal enhancers and that transitions in POU partner factors may control tissue-specific transcriptional programs. Our findings have important implications for understanding lineage specification and somatic cell reprogramming, where SOX2, OCT4, and BRN2 have been shown to be key factors. |
| first_indexed | 2024-09-23T13:48:13Z |
| format | Article |
| id | mit-1721.1/78345 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T13:48:13Z |
| publishDate | 2013 |
| publisher | Public Library of Science |
| record_format | dspace |
| spelling | mit-1721.1/783452022-10-01T17:15:39Z SOX2 Co-Occupies Distal Enhancer Elements with Distinct POU Factors in ESCs and NPCs to Specify Cell State Lodato, Michael Anthony Ng, Christopher W. Wamstad, Joseph Alan Cheng, Albert W. Thai, Kevin Kinh Fraenkel, Ernest Jaenisch, Rudolf Boyer, Laurie Massachusetts Institute of Technology. Computational and Systems Biology Program Massachusetts Institute of Technology. Department of Biological Engineering Massachusetts Institute of Technology. Department of Biology Massachusetts Institute of Technology. School of Science Whitehead Institute for Biomedical Research Lodato, Michael Anthony Ng, Christopher W. Wamstad, Joseph Alan Cheng, Albert W. Thai, Kevin Kinh Fraenkel, Ernest Jaenisch, Rudolf Boyer, Laurie SOX2 is a master regulator of both pluripotent embryonic stem cells (ESCs) and multipotent neural progenitor cells (NPCs); however, we currently lack a detailed understanding of how SOX2 controls these distinct stem cell populations. Here we show by genome-wide analysis that, while SOX2 bound to a distinct set of gene promoters in ESCs and NPCs, the majority of regions coincided with unique distal enhancer elements, important cis-acting regulators of tissue-specific gene expression programs. Notably, SOX2 bound the same consensus DNA motif in both cell types, suggesting that additional factors contribute to target specificity. We found that, similar to its association with OCT4 (Pou5f1) in ESCs, the related POU family member BRN2 (Pou3f2) co-occupied a large set of putative distal enhancers with SOX2 in NPCs. Forced expression of BRN2 in ESCs led to functional recruitment of SOX2 to a subset of NPC-specific targets and to precocious differentiation toward a neural-like state. Further analysis of the bound sequences revealed differences in the distances of SOX and POU peaks in the two cell types and identified motifs for additional transcription factors. Together, these data suggest that SOX2 controls a larger network of genes than previously anticipated through binding of distal enhancers and that transitions in POU partner factors may control tissue-specific transcriptional programs. Our findings have important implications for understanding lineage specification and somatic cell reprogramming, where SOX2, OCT4, and BRN2 have been shown to be key factors. 2013-04-11T15:50:18Z 2013-04-11T15:50:18Z 2013-02 2012-06 Article http://purl.org/eprint/type/JournalArticle 1553-7390 1553-7404 http://hdl.handle.net/1721.1/78345 Lodato, Michael A. et al. “SOX2 Co-Occupies Distal Enhancer Elements with Distinct POU Factors in ESCs and NPCs to Specify Cell State.” Ed. Gregory S. Barsh. PLoS Genetics 9.2 (2013): e1003288. https://orcid.org/0000-0002-5239-9557 https://orcid.org/0000-0002-2902-7288 https://orcid.org/0000-0003-1381-4313 https://orcid.org/0000-0001-9249-8181 https://orcid.org/0000-0003-3491-4962 en_US http://dx.doi.org/10.1371/journal.pgen.1003288 PLoS Genetics Creative Commons Attribution http://creativecommons.org/licenses/by/2.5/ application/pdf Public Library of Science PLoS |
| spellingShingle | Lodato, Michael Anthony Ng, Christopher W. Wamstad, Joseph Alan Cheng, Albert W. Thai, Kevin Kinh Fraenkel, Ernest Jaenisch, Rudolf Boyer, Laurie SOX2 Co-Occupies Distal Enhancer Elements with Distinct POU Factors in ESCs and NPCs to Specify Cell State |
| title | SOX2 Co-Occupies Distal Enhancer Elements with Distinct POU Factors in ESCs and NPCs to Specify Cell State |
| title_full | SOX2 Co-Occupies Distal Enhancer Elements with Distinct POU Factors in ESCs and NPCs to Specify Cell State |
| title_fullStr | SOX2 Co-Occupies Distal Enhancer Elements with Distinct POU Factors in ESCs and NPCs to Specify Cell State |
| title_full_unstemmed | SOX2 Co-Occupies Distal Enhancer Elements with Distinct POU Factors in ESCs and NPCs to Specify Cell State |
| title_short | SOX2 Co-Occupies Distal Enhancer Elements with Distinct POU Factors in ESCs and NPCs to Specify Cell State |
| title_sort | sox2 co occupies distal enhancer elements with distinct pou factors in escs and npcs to specify cell state |
| url | http://hdl.handle.net/1721.1/78345 https://orcid.org/0000-0002-5239-9557 https://orcid.org/0000-0002-2902-7288 https://orcid.org/0000-0003-1381-4313 https://orcid.org/0000-0001-9249-8181 https://orcid.org/0000-0003-3491-4962 |
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