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

Xiaoji Chen, Kyobi Skutt-Kakaria, Jerry Davison, Yang Li Ou, Edward Choi, Punam Malik, Keith Loeb, Brent Wood, George Georges, Beverly Torok-Storb, Patrick J. Paddison

Research output: Contribution to journalArticlepeer-review

112 Scopus citations


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 sp eckles in committedHSPCs, 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 andthat its inhibition delays HSPC lineage commitment. They also inform clinical manipulation of donor-derived HSPCs.

Original languageEnglish (US)
Pages (from-to)2499-2511
Number of pages13
JournalGenes and Development
Issue number22
StatePublished - Nov 15 2012


  • Differentiation
  • G9a
  • GLP
  • H3K9me2
  • Hematopoietic stem and progenitor cell
  • UNC0638

ASJC Scopus subject areas

  • General Medicine


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