The critical role of histone H2A-deubiquitinase Mysm1 in hematopoiesis and lymphocyte differentiation

Abstract

Stem cell differentiation and lineage specification depend on coordinated programs of gene expression, but our knowledge of the chromatin-modifying factors regulating these events remains incomplete. Ubiquitination of histone H2A (H2A-K119u) is a common chromatin modification associated with gene silencing, and controlled by the ubiquitin-ligase polycomb repressor complex 1 (PRC1) and H2A-deubiquitinating enzymes (H2A-DUBs). The roles of H2A-DUBs in mammalian development, stem cells, and hematopoiesis have not been addressed. Here we characterized an H2A-DUB targeted mouse line Mysm1(tm1a/tm1a) and demonstrated defects in BM hematopoiesis, resulting in lymphopenia, anemia, and thrombocytosis. Development of lymphocytes was impaired from the earliest stages of their differentiation, and there was also a depletion of erythroid cells and a defect in erythroid progenitor function. These phenotypes resulted from a cell-intrinsic requirement for Mysm1 in the BM. Importantly, Mysm1(tm1a/tm1a) HSCs were functionally impaired, and this was associated with elevated levels of reactive oxygen species, γH2AX DNA damage marker, and p53 protein in the hematopoietic progenitors. Overall, these data establish a role for Mysm1 in the maintenance of BM stem cell function, in the control of oxidative stress and genetic stability in hematopoietic progenitors, and in the development of lymphoid and erythroid lineages.

The control of hematopoietic stem cell maintenance, self-renewal, and differentiation by Mysm1-mediated epigenetic regulation

“…31,32 Together, these data add more to the finding of Nijnik et al 32 by demonstrating that Mysm1 is required for differentiation of HSC, specifically during the transition to MPPs.…”

“…Nijnik et al 32 recently reported the role of Mysm1 in BM hematopoiesis and function. In this study, we attempted to investigate the importance of Mysm1 in HSC differentiation and function in a more detailed manner.…”

“…31, 32 Nijnik et al 32 have reported the role of Mysm1 in BM hematopoiesis and function. However, the detailed role of Mysm1 exclusively in HSC's biology and the mechanisms associated with it has not been investigated.…”

Deubiquitylases From Genes to Organism

“…Orchestration of histone modifications by MYSM1 has recently been shown to function as part of an epigenetic switch controlling B-cell development (107). Accordingly, mice deficient in MYSM1 show defects in lymphocyte and erythroid development (188).…”

MYSM1 is mutated in a family with transient transfusion-dependent anemia, mild thrombocytopenia, and low NK- and B-cell counts

“…[1][2][3][4] Moreover, the variants in this locus have been shown to strongly affect the severity of sickle cell disease and thalassemia, emphasizing their clinical importance. 2,[5][6][7] The associated region is intergenic between 2 genes: HBS1L and MYB.…”