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Histone H3K4 methylation-dependent and -independent functions of Set1A/COMPASS in embryonic stem cell self-renewal and differentiation
Of the six members of the COMPASS (complex of proteins associated with Set1) family of histone H3 Lys4 (H3K4) methyltransferases identified in mammals, Set1A has been shown to be essential for early embryonic development and the maintenance of embryonic stem cell (ESC) self-renewal. Like its familia...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cold Spring Harbor Laboratory Press
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5666672/ https://www.ncbi.nlm.nih.gov/pubmed/28939616 http://dx.doi.org/10.1101/gad.303768.117 |
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author | Sze, Christie C. Cao, Kaixiang Collings, Clayton K. Marshall, Stacy A. Rendleman, Emily J. Ozark, Patrick A. Chen, Fei Xavier Morgan, Marc A. Wang, Lu Shilatifard, Ali |
author_facet | Sze, Christie C. Cao, Kaixiang Collings, Clayton K. Marshall, Stacy A. Rendleman, Emily J. Ozark, Patrick A. Chen, Fei Xavier Morgan, Marc A. Wang, Lu Shilatifard, Ali |
author_sort | Sze, Christie C. |
collection | PubMed |
description | Of the six members of the COMPASS (complex of proteins associated with Set1) family of histone H3 Lys4 (H3K4) methyltransferases identified in mammals, Set1A has been shown to be essential for early embryonic development and the maintenance of embryonic stem cell (ESC) self-renewal. Like its familial relatives, Set1A possesses a catalytic SET domain responsible for histone H3K4 methylation. Whether H3K4 methylation by Set1A/COMPASS is required for ESC maintenance and during differentiation has not yet been addressed. Here, we generated ESCs harboring the deletion of the SET domain of Set1A (Set1A(ΔSET)); surprisingly, the Set1A SET domain is dispensable for ESC proliferation and self-renewal. The removal of the Set1A SET domain does not diminish bulk H3K4 methylation in ESCs; instead, only a subset of genomic loci exhibited reduction in H3K4me3 in Set1A(ΔSET) cells, suggesting a role for Set1A independent of its catalytic domain in ESC self-renewal. However, Set1A(ΔSET) ESCs are unable to undergo normal differentiation, indicating the importance of Set1A-dependent H3K4 methylation during differentiation. Our data also indicate that during differentiation, Set1A but not Mll2 functions as the H3K4 methylase on bivalent genes and is required for their expression, supporting a model for transcriptional switch between Mll2 and Set1A during the self-renewing-to-differentiation transition. Together, our study implicates a critical role for Set1A catalytic methyltransferase activity in regulating ESC differentiation but not self-renewal and suggests the existence of context-specific H3K4 methylation that regulates transcriptional outputs during ESC pluripotency. |
format | Online Article Text |
id | pubmed-5666672 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Cold Spring Harbor Laboratory Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-56666722018-03-01 Histone H3K4 methylation-dependent and -independent functions of Set1A/COMPASS in embryonic stem cell self-renewal and differentiation Sze, Christie C. Cao, Kaixiang Collings, Clayton K. Marshall, Stacy A. Rendleman, Emily J. Ozark, Patrick A. Chen, Fei Xavier Morgan, Marc A. Wang, Lu Shilatifard, Ali Genes Dev Research Communication Of the six members of the COMPASS (complex of proteins associated with Set1) family of histone H3 Lys4 (H3K4) methyltransferases identified in mammals, Set1A has been shown to be essential for early embryonic development and the maintenance of embryonic stem cell (ESC) self-renewal. Like its familial relatives, Set1A possesses a catalytic SET domain responsible for histone H3K4 methylation. Whether H3K4 methylation by Set1A/COMPASS is required for ESC maintenance and during differentiation has not yet been addressed. Here, we generated ESCs harboring the deletion of the SET domain of Set1A (Set1A(ΔSET)); surprisingly, the Set1A SET domain is dispensable for ESC proliferation and self-renewal. The removal of the Set1A SET domain does not diminish bulk H3K4 methylation in ESCs; instead, only a subset of genomic loci exhibited reduction in H3K4me3 in Set1A(ΔSET) cells, suggesting a role for Set1A independent of its catalytic domain in ESC self-renewal. However, Set1A(ΔSET) ESCs are unable to undergo normal differentiation, indicating the importance of Set1A-dependent H3K4 methylation during differentiation. Our data also indicate that during differentiation, Set1A but not Mll2 functions as the H3K4 methylase on bivalent genes and is required for their expression, supporting a model for transcriptional switch between Mll2 and Set1A during the self-renewing-to-differentiation transition. Together, our study implicates a critical role for Set1A catalytic methyltransferase activity in regulating ESC differentiation but not self-renewal and suggests the existence of context-specific H3K4 methylation that regulates transcriptional outputs during ESC pluripotency. Cold Spring Harbor Laboratory Press 2017-09-01 /pmc/articles/PMC5666672/ /pubmed/28939616 http://dx.doi.org/10.1101/gad.303768.117 Text en © 2017 Sze et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/4.0/ This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/. |
spellingShingle | Research Communication Sze, Christie C. Cao, Kaixiang Collings, Clayton K. Marshall, Stacy A. Rendleman, Emily J. Ozark, Patrick A. Chen, Fei Xavier Morgan, Marc A. Wang, Lu Shilatifard, Ali Histone H3K4 methylation-dependent and -independent functions of Set1A/COMPASS in embryonic stem cell self-renewal and differentiation |
title | Histone H3K4 methylation-dependent and -independent functions of Set1A/COMPASS in embryonic stem cell self-renewal and differentiation |
title_full | Histone H3K4 methylation-dependent and -independent functions of Set1A/COMPASS in embryonic stem cell self-renewal and differentiation |
title_fullStr | Histone H3K4 methylation-dependent and -independent functions of Set1A/COMPASS in embryonic stem cell self-renewal and differentiation |
title_full_unstemmed | Histone H3K4 methylation-dependent and -independent functions of Set1A/COMPASS in embryonic stem cell self-renewal and differentiation |
title_short | Histone H3K4 methylation-dependent and -independent functions of Set1A/COMPASS in embryonic stem cell self-renewal and differentiation |
title_sort | histone h3k4 methylation-dependent and -independent functions of set1a/compass in embryonic stem cell self-renewal and differentiation |
topic | Research Communication |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5666672/ https://www.ncbi.nlm.nih.gov/pubmed/28939616 http://dx.doi.org/10.1101/gad.303768.117 |
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