Gatzka M, Tasdogan A, Hainzl A, Allies G, Maity P, Wilms C, Wlaschek M, Scharffetter-Kochanek K
Department of Dermatology and Allergic Diseases, University of Ulm, Ulm 89091, Germany.
Institute of Immunology, University of Ulm, Ulm 89091, Germany.
Cell Death Differ. 2015 Sep;22(9):1451-62. doi: 10.1038/cdd.2014.231. Epub 2015 Jan 23.
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 p19(ARF), 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.
核心组蛋白2A（H2A-K119u）的单泛素化在造血分化及其他发育过程的基因调控中起关键作用。为了探究组蛋白H2A去泛素化酶Myb样SWIRM和含MPN结构域蛋白1（2A-DUB/Mysm1）与p53轴在祖细胞向成熟淋巴细胞顺序分化过程中的相互作用，我们使用Mysm1基因敲除小鼠（Mysm1-/-）和p53基因敲除Mysm1基因敲除双缺陷小鼠（p53-/-Mysm1-/-）系统地分析了造血作用和早期T细胞发育。由于早期胸腺细胞祖细胞减少，同时伴有造血干细胞缺陷、双阴性（DN）1-DN2转变部分受阻以及双阳性胸腺细胞凋亡增加，Mysm1-/-小鼠的胸腺严重发育不全，细胞数量不到野生型的10%。在受Mysm1缺陷影响的其他组织中，包括发育中的脑和皮肤，也检测到凋亡率增加。通过定量PCR和染色质免疫沉淀分析，我们确定p19（ARF），一种p53肿瘤抑制蛋白水平的重要调节因子，为潜在的Mysm1靶基因。在新生成的p53-/-Mysm1-/-双缺陷小鼠中，Mysm1-/-小鼠的异常情况，包括淋巴系多能祖细胞减少、胸腺细胞数量和活力降低，以及有趣的B细胞发育缺陷、生长迟缓、神经缺陷、皮肤萎缩和尾巴畸形，几乎也完全恢复了，这证实了p53通路参与了由Mysm1缺陷引起的改变。总之，本研究揭示了H2A去泛素化酶2A-DUB/Mysm1与早期淋巴细胞发育及其他发育过程中p53介导的凋亡程序抑制之间的新联系。
