G9a/GLP-dependent histone H3K9me2 patterning during human hematopoietic stem cell lineage commitment

Abstract

G9a and GLP are conserved protein methyltransferases that play key roles during mammalian development through mono-and dimethylation of histone H3 Lys 9 (H3K9me1/2), modifications associated with transcriptional repression. During embryogenesis, large H3K9me2 chromatin territories arise that have been proposed to reinforce lineage choice by affecting high-order chromatin structure. Here we report that in adult human hematopoietic stem and progenitor cells (HSPCs), H3K9me2 chromatin territories are absent in primitive cells and are formed de novo during lineage commitment. In committed HSPCs, G9a/GLP activity nucleates H3K9me2 marks at CpG islands and other genomic sites within genic regions, which then spread across most genic regions during differentiation. Immunofluorescence assays revealed the emergence of H3K9me2 nuclear speckles in committed HSPCs, consistent with progressive marking. Moreover, gene expression analysis indicated that G9a/GLP activity suppresses promiscuous transcription of lineage-affiliated genes and certain gene clusters, suggestive of regulation of HSPC chromatin structure. Remarkably, HSPCs continuously treated with UNC0638, a G9a/GLP small molecular inhibitor, better retain stem cell-like phenotypes and function during in vitro expansion. These results suggest that G9a/GLP activity promotes progressive H3K9me2 patterning during HSPC lineage specification and that its inhibition delays HSPC lineage commitment. They also inform clinical manipulation of donor-derived HSPCs.

Histone Arginine Methylation by PRMT7 Controls Germinal Center Formation via Regulating Bcl6 Transcription

“…However, we observed that PRMT7 was not required for immature and mature B cell differentiation in mice with the B cell-specific PRMT7 deletion. A similar case was reported in mice deficient for the lysine methyltransferase G9a, which showed delayed hematopoietic progenitor cell lineage commitment without apparent defects in early lymphocyte development (43,44).…”

The expanding role of the Ehmt2/G9a complex in neurodevelopment

“…29 However, H3K9me2 has been implicated in the terminal commitment of blood, cardiac, retinal, neural, muscle and germline lineages. 23,25,29,[40][41][42][43] For example, H3K9me2 plays a dynamic role in retinal progenitor cells 44 and loss of Ehmt2 mediated epigenetic repression leads to profound defects in the early retina. Zebrafish ehmt2 morphants show severe decreases in crx, neuroD and irbp gene expression; markers of retinal cell differentiation.…”

Epigenetic dysregulation by nickel through repressive chromatin domain disruption

“…Recent evidence indicates that the H3K9me2 domains are highly dynamic and important for differentiation and maintaining cell identity (8)(9)(10). Although H3K9me2 marks large domains of mostly transcriptionally silent regions of the genome, small windows of active chromatin have been characterized within the large heterochromatin domains, termed euchromatin islands (EIs) (9,11).…”