The histone H2A deubiquitinase Usp16 regulates hematopoiesis and hematopoietic stem cell function

Abstract

Epigenetic mechanisms play important regulatory roles in hematopoiesis and hematopoietic stem cell (HSC) function. Subunits of polycomb repressive complex 1 (PRC1), the major histone H2A ubiquitin ligase, are critical for both normal and pathological hematopoiesis; however, it is unclear which of the several counteracting H2A deubiquitinases functions along with PRC1 to control H2A ubiquitination (ubH2A) level and regulates hematopoiesis in vivo. Here we investigated the function of Usp16 in mouse hematopoiesis. Conditional deletion of Usp16 in bone marrow resulted in a significant increase of global ubH2A level and lethality. Usp16 deletion did not change HSC number but was associated with a dramatic reduction of mature and progenitor cell populations, revealing a role in governing HSC lineage commitment. ChIP- and RNA-sequencing studies in HSC and progenitor cells revealed that Usp16 bound to many important hematopoietic regulators and that Usp16 deletion altered the expression of genes in transcription/chromosome organization, immune response, hematopoietic/lymphoid organ development, and myeloid/leukocyte differentiation. The altered gene expression was partly rescued by knockdown of PRC1 subunits, suggesting that Usp16 and PRC1 counterbalance each other to regulate cellular ubH2A level and gene expression in the hematopoietic system. We further discovered that knocking down Cdkn1a (p21cip1), a Usp16 target and regulated gene, rescued the altered cell cycle profile and differentiation defect of Usp16-deleted HSCs. Collectively, these studies identified Usp16 as one of the histone H2A deubiquitinases, which coordinates with the H2A ubiquitin ligase PRC1 to regulate hematopoiesis, and revealed cell cycle regulation by Usp16 as key for HSC differentiation.

USP10 Is an Essential Deubiquitinase for Hematopoiesis and Inhibits Apoptosis of Long-Term Hematopoietic Stem Cells

“…Several deubiquitinases, such as USP1, USP3, USP16, and A20, are reported to be essential for proper HSC functions (Gu et al., 2016, Lancini et al., 2014, Nagamachi et al., 2014, Nakagawa et al., 2015, Parmar et al., 2010). For example, a lack of A20 in mice leads to defective HSC quiescence and reduced HSC numbers caused by enhanced NF-κB activation (Nagamachi et al., 2014, Nakagawa et al., 2015).…”

A role for the histone H2A deubiquitinase MYSM1 in maintenance of CD8+ T cells

“…6 Recent work demonstrated that deficiency in the histone H2A deubiquitinase MYSM1 results in a severe defect in the development of immune cells in mice and humans, outlining evolutionarily conserved mechanisms governing haematopoiesis in both species. [14][15][16][17] The work of our and several other groups indicated that MYSM1 regulates the maintenance of haematopoietic stem cells and their differentiation into B cells, natural killer cells, dendritic cells and erythrocytes. 7,11,12 MYSM1 is a chromatin-binding protein with deubiquitinase catalytic activity that has been shown to mediate the deubiquitination of lysine 119 of histone H2A.…”

“…13 Other histone H2A deubiquitinases such as USP16, USP21 and USP22 are known to influence B-cell and T-cell lymphopoiesis or lymphocyte activation. [14][15][16][17] The work of our and several other groups indicated that MYSM1 regulates the maintenance of haematopoietic stem cells and their differentiation into B cells, natural killer cells, dendritic cells and erythrocytes. 7,12,18,19 In this setting, MYSM1 exerts its role by controlling essential lineage-specific developmental regulators like Ebf1, Gfi1, Id2 and Flt3 at a transcriptional level.…”

Dysregulation of Ubiquitin-Proteasome System in Neurodegenerative Diseases

“…USP16 is upregulated in Down’s syndrome (DS) cells due to extrachromosomal triplication in trisomy 21, downregulation of USP16 partially restores the impaired proliferation in DS somatic stem cells (Adorno et al, 2013). It has been reported that USP16 acts as a H2A DUB and regulates hematopoiesis and hematopoietic stem cell function (Gu et al, 2016). Moreover, USP16 is required for embryonic stem cell differentiation, where USP16 deficiency leads to embryonic lethality in mouse deletion models (Yang et al, 2014).…”