Histone H3K4 methylation-dependent and -independent functions of set1A/COMPASS in embryonic stem cell self-renewal and differentiation

Christie C. Sze, Kaixiang Cao, Clayton K. Collings, Stacy A. Marshall, Emily J. Rendleman, Patrick A. Ozark, Fei Xavier Chen, Marc A. Morgan, Lu Wang, Ali Shilatifard*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

69 Scopus citations

Abstract

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 (Set1AΔSET); 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 Set1AΔSET cells, suggesting a role for Set1A independent of its catalytic domain in ESC self-renewal. However, Set1AΔSET 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-renew-ing-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.

Original languageEnglish (US)
Pages (from-to)1732-1737
Number of pages6
JournalGenes and Development
Volume31
Issue number17
DOIs
StatePublished - Sep 1 2017

Funding

We are grateful to members of the Shilatifard laboratory for their critical feedback on this manuscript. We thank Dr. E.R. Smith for critical reading and editing of this manuscript. C.C.S. is supported in part by National Institutes of Health/National Cancer Institute (NIH/NCI) training grant T32CA09560. Studies in the Shilatifard laboratory regarding the role of the COMPASS family in development and cancer are supported by NCI’s Outstanding Investigator Award (R35CA197569).

Keywords

  • COMPASS
  • Differentiation
  • H3K4 methylation
  • Pluripotency
  • Self-renewal
  • Set1A

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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