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p53-Targeted LSD1 Functions in Repression of Chromatin Structure and Transcription In Vivo

机译：p53靶向的LSD1在抑制染色质结构和体内转录中的功能

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Despite years of study focused on the tumor suppressor p53, little is understood about its functions in normal, differentiated cells. We found that p53 directly interacts with lysine-specific demethylase 1 (LSD1) to alter chromatin structure and confer developmental repression of the tumor marker alpha-fetoprotein (AFP). Chromatin immunoprecipitation (ChIP) and sequential ChIP of developmentally staged liver showed that p53 and LSD1 cooccupy a p53 response element, concomitant with dimethylated histone H3 lysine 4 (H3K4me2) demethylation and postnatal repression of AFP transcription. In p53-null mice, LSD1 binding is depleted, H3K4me2 is increased, and H3K9me2 remains unchanged compared to those of the wild type, underscoring the specificity of p53-LSD1 complexes in demethylation of H3K4me2. We performed partial hepatectomy of wild-type mouse liver and induced a regenerative response, which led to a loss of p53, increased H3K4me2, and decreased LSD1 interaction at AFP chromatin, in parallel with reactivation of AFP expression. In contrast, nuclear translocation of p53 in mouse embryonic fibroblasts led to p53 interaction with p21/CIP1 chromatin, without recruitment of LSD1, and to activation of p21/CIP1. These findings reveal that LSD1 is targeted to chromatin by p53, likely in a gene-specific manner, and define a molecular mechanism by which p53 mediates transcription repression in vivo during differentiation.
机译：尽管多年的研究集中在肿瘤抑制因子p53上，但对其在正常分化细胞中的功能了解甚少。我们发现p53直接与 l ysine- s 特定的 d 甲基化酶1（LSD1）相互作用，以改变染色质结构并赋予肿瘤发育抑制作用标记甲胎蛋白（AFP）。发育阶段性肝的染色质免疫沉淀（ChIP）和顺序ChIP显示，p53和LSD1共同占据p53反应元件，并伴有二甲基化的组蛋白H3赖氨酸4（H3K4me2）去甲基化和产后对 AFP 转录的抑制。在p53无效的小鼠中，与野生型相比，LSD1的结合减少，H3K4me2增加，H3K9me2保持不变，从而强调了p53-LSD1复合物在H3K4me2脱甲基中的特异性。我们对野生型小鼠肝脏进行了部分肝切除术，并诱导了再生反应，导致 AFP 染色质上的p53丢失，H3K4me2增加和LSD1相互作用降低，同时激活AFP 表达式。相比之下，小鼠胚胎成纤维细胞中p53的核易位导致p53与p21 / CIP1染色质相互作用，而不募集LSD1，并激活 p21 / CIP1 。这些发现表明，LSD1可能以基因特异性方式被p53靶向染色质，并定义了p53在分化过程中介导体内转录抑制的分子机制。

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