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G9a/GLP-dependent histone H3K9me2 patterning during human hematopoietic stem cell lineage commitment
Xiaoji Chen1, Kyobi Skutt-Kakaria, Jerry Davison
1Molecular and Cell Biology (MCB) Program, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
Genes & Development
|October 30, 2012
Summary
G9a/GLP activity patterns histone H3K9me2 during hematopoietic stem and progenitor cell (HSPC) lineage commitment. Inhibiting G9a/GLP maintains HSPC stemness, suggesting clinical applications.
Area of Science:
- Epigenetics and Gene Regulation
- Stem Cell Biology
- Hematopoiesis
Background:
- Protein methyltransferases G9a and GLP modify histone H3 Lys 9 (H3K9me1/2), linked to transcriptional repression.
- H3K9me2 chromatin territories are observed during embryogenesis, potentially influencing lineage choice.
- The role of H3K9me2 patterning in adult hematopoietic stem and progenitor cells (HSPCs) during lineage commitment is not fully understood.
Purpose of the Study:
- To investigate the formation and dynamics of H3K9me2 chromatin territories in adult human HSPCs.
- To determine the role of G9a/GLP activity in H3K9me2 patterning during HSPC lineage specification.
- To evaluate the effect of G9a/GLP inhibition on HSPC phenotype and function during in vitro expansion.
Main Methods:
- Immunofluorescence assays to visualize H3K9me2 nuclear speckles.
- Gene expression analysis to assess transcriptional changes.
- Treatment of HSPCs with the G9a/GLP inhibitor UNC0638 for in vitro expansion studies.
Main Results:
- H3K9me2 chromatin territories are absent in primitive HSPCs and form during lineage commitment.
- G9a/GLP activity initiates H3K9me2 marking at specific genomic sites, which spreads during differentiation.
- Inhibition of G9a/GLP with UNC0638 preserves stem cell-like phenotypes and function in expanded HSPCs.
- G9a/GLP activity suppresses promiscuous transcription of lineage-affiliated genes.
Conclusions:
- G9a/GLP activity drives progressive H3K9me2 patterning during HSPC lineage specification.
- Inhibition of G9a/GLP delays HSPC lineage commitment and maintains stemness.
- Findings offer insights for clinical manipulation of donor-derived HSPCs.
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