HIRA, a DiGeorge Syndrome Candidate Gene, Confers Proper Chromatin Accessibility on HSCs and Supports All Stages of Hematopoiesis
Chao Chen,
Ming-an Sun,
Claude Warzecha,
Mahesh Bachu,
Anup Dey,
Tiyun Wu,
Peter D Adams,
Todd Macfarlan,
Paul Love,
Keiko Ozato
Affiliations
Chao Chen
Molecular Genetics of Immunity Section, Division of Developmental Biology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA
Ming-an Sun
Mammalian Epigenome Reprogramming Section, Division of Developmental Biology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA
Claude Warzecha
Hematopoiesis and Lymphocyte Biology Section, Division of Developmental Biology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA
Mahesh Bachu
Molecular Genetics of Immunity Section, Division of Developmental Biology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA
Anup Dey
Molecular Genetics of Immunity Section, Division of Developmental Biology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA
Tiyun Wu
Molecular Genetics of Immunity Section, Division of Developmental Biology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA
Peter D Adams
Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA
Todd Macfarlan
Mammalian Epigenome Reprogramming Section, Division of Developmental Biology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA
Paul Love
Hematopoiesis and Lymphocyte Biology Section, Division of Developmental Biology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA
Keiko Ozato
Molecular Genetics of Immunity Section, Division of Developmental Biology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA; Corresponding author
Summary: HIRA is a histone chaperone that deposits the histone variant H3.3 in transcriptionally active genes. In DiGeorge syndromes, a DNA stretch encompassing HIRA is deleted. The syndromes manifest varied abnormalities, including immunodeficiency and thrombocytopenia. HIRA is essential in mice, as total knockout (KO) results in early embryonic death. However, the role of HIRA in hematopoiesis is poorly understood. We investigate hematopoietic cell-specific Hira deletion in mice and show that it dramatically reduces bone marrow hematopoietic stem cells (HSCs), resulting in anemia, thrombocytopenia, and lymphocytopenia. In contrast, fetal hematopoiesis is normal in Hira-KO mice, although fetal HSCs lack the reconstitution capacity. Transcriptome analysis reveals that HIRA is required for expression of many transcription factors and signaling molecules critical for HSCs. ATAC-seq analysis demonstrates that HIRA establishes HSC-specific DNA accessibility, including the SPIB/PU.1 sites. Together, HIRA provides a chromatin environment essential for HSCs, thereby steering their development and survival. : Chen et al. show that the histone H3.3 chaperone HIRA directs development and survival of adult hematopoietic stem cells (HSCs). Hira deletion impairs development of all lineages of hematopoiesis. Keywords: HIRA, histone chaperone, H3.3, hematopoietic stem cells, DiGeorge syndrome
