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Dpy30 Is Critical for Maintaining the Identity and Function of Adult Hematopoietic Stem Cells

ABSTRACT: As the major histone H3K4 methyltransferases in mammals, the Set1/Mll complexes play important roles in animal development and are increasingly associated with diseases including hematological malignancies. The role of H3K4 methylation activity of these complexes, however, remains elusive in fate determination of hematopoietic stem and progenitor cells (HSCs and HPCs). Here we address this question by generating a conditional knockout mouse for Dpy30, which is a common core subunit of all Set1/Mll complexes and facilitates genome-wide H3K4 methylation in cells. Dpy30 loss in the adult hematopoietic system results in severe pancytopenia but striking accumulation of HSCs and early HPCs that are defective in multilineage reconstitution, suggesting a differentiation block. In mixed bone marrow chimeras, Dpy30-deficient HSCs cannot differentiate or efficiently upregulate lineage-regulatory genes, and eventually fail to sustain for long term with significant loss of HSC signature gene expression. Our molecular analyses reveal that Dpy30 directly regulates H3K4 methylation and expression of key transcriptional factors, cofactors, and chromatin modulators involved in HSC function. Collectively, our results establish a critical role of Dpy30 and the H3K4 methylation activity of the Set1/Mll complexes for maintaining the identity and function of adult hematopoietic stem cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE81390 | GEO | 2016/09/08

SECONDARY ACCESSION(S): PRJNA321433

REPOSITORIES: GEO

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Project description:Global analysis of H3K4 methylation defines MLL family member targets and points to a role for MLL1-mediated H3K4 methylation in the regulation of transcriptional initiation by RNA polymerase II A common landmark of activated genes is the presence of trimethylation on lysine 4 of histone H3 (H3K4) at promoter regions. The Set1/COMPASS was the founding member and the only H3K4 methylases in S. cerevisiae, however, in mammals at least six H3K4 methylases Set1A/B and MLL1-4 are found in COMPASS-like complexes capable of methylating H3K4. To gain further insight into the different roles and functional targets for the H3K4 methylases, we have undertaken a genome-wide analysis of H3K4 methylation pattern in wild-type Mll1+/+ and Mll1-/- mouse fibroblasts (MEFs). We found that Mll1 is required for the H3K4 trimethylation of less than 5% of promoters carrying this modification. Many of these genes, which include developmental regulators such as Hox genes show decreased levels of RNA polymerase II recruitment and expression concomitant with the loss of H3K4 methylation. Although Mll1 is only required for the methylation of a subset of Hox genes, Menin, a component of the Mll1 and Mll2 complexes, is required for the overwhelming majority of H3K4 methylation at Hox loci. However, the loss of MLL3/4 and/or the Set1 complexes have little to no effect on the Hox loci H3K4 methylation or expression levels in these MEFs. Together these data provide insight into redundancy and specialization of COMPASS-like complexes in mammals and provide evidence on a possible role for Mll1-mediated H3K4 methylation in the regulation of transcriptional initiation. Chromatin Immunoprecipitation was performed with antibodies for histone 3 lysine 4 trimethylation, histone 3, and PolII in Mll1+/+ and Mll1-/- mouse embryonic fibroblasts. DNA was hybridized to a custom Agilent tiling array (4x44k format) that covers three of the hox regions (A,B,D) and a collection of other genes.

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Dpy30 Is Critical for Maintaining the Identity and Function of Adult Hematopoietic Stem Cells

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