Interplay of H2A deubiquitinase 2A-DUB/Mysm1 and the p19ARF/p53 axis in hematopoiesis, early T-cell development and tissue differentiation

Abstract

Monoubiquitination of core histone 2A (H2A-K119u) has a critical role in gene regulation in hematopoietic differentiation and other developmental processes. To explore the interplay of histone H2A deubiquitinase Myb-like SWIRM and MPN domain containing1 (2A-DUB/Mysm1) with the p53 axis in the sequential differentiation of mature lymphocytes from progenitors, we systematically analyzed hematopoiesis and early T-cell development using Mysm1−/− and p53−/−Mysm1−/− mice. Mysm1−/− thymi were severely hypoplastic with <10% of wild-type cell numbers as a result of a reduction of early thymocyte progenitors in context with defective hematopoietic stem cells, a partial block at the double-negative (DN)1–DN2 transition and increased apoptosis of double-positive thymocytes. Increased rates of apoptosis were also detected in other tissues affected by Mysm1 deficiency, including the developing brain and the skin. By quantitative PCR and chromatin immunoprecipitation analyses, we identified p19ARF, an important regulator of p53 tumor suppressor protein levels, as a potential Mysm1 target gene. In newly generated p53−/−Mysm1−/− double-deficient mice, anomalies of Mysm1−/− mice including reduction of lymphoid-primed multipotent progenitors, reduced thymocyte numbers and viability, and interestingly defective B-cell development, growth retardation, neurological defects, skin atrophy, and tail malformation were almost completely restored as well, substantiating the involvement of the p53 pathway in the alterations caused by Mysm1 deficiency. In conclusion, this investigation uncovers a novel link between H2A deubiquitinase 2A-DUB/Mysm1 and suppression of p53-mediated apoptotic programs during early lymphoid development and other developmental processes.

Mysm1 is required for interferon regulatory factor expression in maintaining HSC quiescence and thymocyte development

“…Previous studies detected an enhanced thymic p53 expression in Mysm1 −/− mice, 35 which implies that Mysm1 −/− affects the thymus in addition to reducing input of CLPs from BM. Hence, we directly analyzed Mysm1 −/− thymocytes for IRF2 and IRF8 expression.…”

“…Belle et al 34 and Gatzka et al 35 independently generated Mysm1 −/− p53 −/− mice that largely restored Mysm1 deficiency-associated defects. Moreover, Gatzka et al 35 revealed that increased p53 levels in Mysm1 −/− mice may result from the upregulation of p19 ARF that stabilizes p53 by blocking nucleo-cytoplasmic shuttling of Mdm2. 35 However, Mysm1 is a H2ADUB that generally functions as a transcription activator.…”

“…Moreover, Gatzka et al 35 revealed that increased p53 levels in Mysm1 −/− mice may result from the upregulation of p19 ARF that stabilizes p53 by blocking nucleo-cytoplasmic shuttling of Mdm2. 35 However, Mysm1 is a H2ADUB that generally functions as a transcription activator. How the transcription activator deficiency leads to upregulation of p53 or p19 ARF , therefore, remained elusive.…”

MYSM1/miR-150/FLT3 inhibits B1a cell proliferation

“…Our groups as well as other independent groups have observed an essential role of MYSM1 for bone marrow hematopoietic development and lymphocyte generation [15–21]. In spite of these observations, knowledge of the biological functions of MYSM1 remains limited, and its function in B1a cell proliferation had not been investigated.…”

EZH2 Regulates the Developmental Timing of Effectors of the Pre–Antigen Receptor Checkpoints

“…Rag1 −/− or Cd3 γ −/− mice), which fail β-selection but can by-pass this checkpoint when Trp53 (p53) is deleted or mutated(6, 7). Stabilization of p53 prevents B and T cell development beyond the pre-antigen receptor checkpoints, as evidenced in mice lacking genes that directly regulate p53 at the transcriptional (WIP1(8, 9), MYSM1(10)), post-transcriptional (CNOT(11)), translational (RPL22(12, 13), MIZ1(14, 15)), or post-translational (YY1(16–18), BCL11A(19), NIR(20)) levels. Remarkably, B and T cell maturation are substantially restored in these mice upon deletion of p53.…”