title: 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 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.
authors.affiliation: Department of Biochemistry and Molecular Genetics, UAB Stem Cell Institute, University of Alabama School of Medicine, Birmingham, AL 35210.
authors.forename: Zhenhua
authors.identifier: 0000-0003-2573-9808
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Department of Biochemistry and Molecular Genetics, UAB Stem Cell Institute, University of Alabama School of Medicine, Birmingham, AL 35210.
authors.forename: Kushani
authors.identifier: 0000-0002-1052-1390
authors.initials: K
authors.lastname: Shah
authors.affiliation: Department of Biochemistry and Molecular Genetics, UAB Stem Cell Institute, University of Alabama School of Medicine, Birmingham, AL 35210.
authors.forename: Alireza
authors.identifier: 0000-0002-5619-1788
authors.initials: A
authors.lastname: Khodadadi-Jamayran
authors.affiliation: Department of Biochemistry and Molecular Genetics, UAB Stem Cell Institute, University of Alabama School of Medicine, Birmingham, AL 35210 haojiang@uab.edu.
authors.forename: Hao
authors.identifier: 0000-0003-1890-9813
authors.initials: H
authors.lastname: Jiang
mesh_terms: D053687:Adult Stem Cells / Q000166:cytology* / Q000378:metabolism; D000818:Animals; D001853:Bone Marrow / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics; D019070:Cell Lineage / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics; D017353:Gene Deletion; D016678:Genome; D006410:Hematopoiesis / Q000235:genetics; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D008239:Lysine / Q000378:metabolism; D008745:Methylation; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010198:Pancytopenia / Q000235:genetics / Q000473:pathology; D010641:Phenotype; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors
chemical_list: C000609217:Dpy30 protein, mouse; D006657:Histones; D014157:Transcription Factors; D011495:Histone-Lysine N-Methyltransferase; D008239:Lysine