PLX029250

GSE81390: Dpy30 Is Critical for Maintaining the Identity and Function of Adult Hematopoietic Stem Cells

• Organsim mouse
• Type RNASEQ
• Target gene
• Project ARCHS4

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. SOURCE: Alireza Khodadadi-Jamayran Stem Cell Institute