Regulation of LSD1 histone demethylase activity by its associated factors
Regulation of LSD1 histone demethylase activity by its associated factors
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DOI：
10.1016/j.molcel.2005.08.027
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发表时间：
2005-09-16
期刊：
影响因子：
16
通讯作者：
Shi, Y
中科院分区：
文献类型：
--
作者：
Shi, YJ;Matson, C;Shi, Y
LSD1是最近发现的一种人类赖氨酸(K)专一性的组蛋白去甲基酶。LSD1与HDAC1/2、含有SANT结构域的辅阻遏子Corest和含有PHD结构域的蛋白质BHC80等有关。我们证明COREST赋予LSD1去甲基化核小体底物的能力，并保护LSD1免受体内蛋白酶体的降解。我们发现高乙酰化的核小体不太容易受到COREST/LSD1介导的去甲基化的影响，这表明低乙酰化的核小体可能是首选的生理底物。这增加了组蛋白脱乙酰酶和LSD1合作产生抑制染色质环境的可能性。与这一模型一致，TSA治疗导致LSD1靶基因的表达下调。COREST正向调节LSD1功能，而BHC80在体外抑制COREST/LSD1介导的去甲基化，因此可能提供负调节。综上所述，这些发现表明LSD1介导组蛋白去甲基化在体内是动态调节的。这有望对生理和病理条件下的基因表达产生深远的影响。
LSD1 is a recently identified human lysine (K)-specific histone demethylase. LSD1 is associated with HDAC1/2; CoREST, a SANT domain-containing corepressor; and BHC80, a PHD domain-containing protein, among others. We show that CoREST endows LSD1 with the ability to demethylate nucleosomal substrates and that it protects LSD1 from proteasomal degradation in vivo. We find hyperacetylated nucleosomes less susceptible to CoREST/LSD1-mediated demethylation, suggesting that hypoacetylated nucleosomes may be the preferred physiological substrates. This raises the possibility that histone deacetylases and LSD1 may collaborate to generate a repressive chromatin environment. Consistent with this model, TSA treatment results in derepression of LSD1 target genes. While CoREST positively regulates LSD1 function, BHC80 inhibits CoREST/LSD1-mediated demethylation in vitro and may therefore confer negative regulation. Taken together, these findings suggest that LSD1-mediated histone demethylation is regulated dynamically in vivo. This is expected to have profound effects on gene expression under both physiological and pathological conditions.