Format

Send to

Choose Destination
J Exp Med. 2016 Oct 17;213(11):2349-2364. Epub 2016 Sep 19.

Dpy30 is critical for maintaining the identity and function of adult hematopoietic stem cells.

Author information

1
Department of Biochemistry and Molecular Genetics, UAB Stem Cell Institute, University of Alabama School of Medicine, Birmingham, AL 35210.
2
Department of Biochemistry and Molecular Genetics, UAB Stem Cell Institute, University of Alabama School of Medicine, Birmingham, AL 35210 haojiang@uab.edu.

Abstract

As the major histone H3K4 methyltransferases in mammals, the Set1/Mll complexes play important roles in animal development and are associated with many diseases, including hematological malignancies. However, the role of the H3K4 methylation activity of these complexes in fate determination of hematopoietic stem and progenitor cells (HSCs and HPCs) remains elusive. 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 up-regulate 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 and preferentially controls H3K4 methylation and expression of many hematopoietic development-associated genes including several key transcriptional and chromatin regulators involved in HSC function. Collectively, our results establish a critical and selective role of Dpy30 and the H3K4 methylation activity of the Set1/Mll complexes for maintaining the identity and function of adult HSCs.

PMID:
27647347
PMCID:
PMC5068233
DOI:
10.1084/jem.20160185
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center