FAD24 acts in concert with histone acetyltransferase HBO1 to promote adipogenesis by controlling DNA replication
FAD24 acts in concert with histone acetyltransferase HBO1 to promote adipogenesis by controlling DNA replication
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DOI：
10.1074/jbc.m707880200
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发表时间：
2008-01-25
影响因子：
4.8
通讯作者：
Imagawa, Masayoshi
中科院分区：
文献类型：
--
作者：
Johmura, Yoshikazu;Osada, Shigehiro;Imagawa, Masayoshi
前脂肪细胞通过大约两轮有丝分裂分化为脂肪细胞，称为有丝分裂克隆扩张(MCE)，但分化过程的早期事件尚不完全清楚。在此之前，我们鉴定并鉴定了一个新的基因，fad24(脂肪细胞分化因子24)，在脂肪细胞分化的早期阶段被诱导表达。尽管FAD24显然在脂肪形成中起着关键作用，但它的确切功能仍不清楚。在这里，我们证明了RNAi在3T3-L1前脂肪细胞中敲除Fad24抑制了MCE。此外，FAD24还与组蛋白乙酰转移酶HBO1相互作用，HBO1是DNA复制起始的正调控因子。Hbo1基因的敲除抑制了MCE和脂肪生成，表明FAD24与HBO1协同作用，通过控制DNA复制促进脂肪生成。关于FAD24调控DNA复制的分子机制，我们揭示了FAD24在有丝分裂后期与HBO1共定位于染色质，这是复制前起始复合体组装的时候。此外，染色质免疫沉淀实验表明，FAD24定位于DNA与HBO1的复制起点。当在脂肪细胞分化过程中抑制Fad24的表达时，HBO1向DNA复制起点的募集减少。因此，FAD24通过将HBO1招募到DNA复制的起点来控制DNA复制，并且在脂肪细胞分化过程中是MCE所必需的。
Preadipocytes differentiate into adipocytes through approximately two rounds of mitosis, referred to as mitotic clonal expansion (MCE), but the events early in the differentiation process are not fully understood. Previously, we identified and characterized a novel gene, fad24 (factor for adipocyte differentiation 24), induced to express at the early stages of adipocyte differentiation. Although fad24 clearly has crucial roles in adipogenesis, its precise functions remain unknown. Here we show that the knockdown of fad24 by RNAi in 3T3-L1 preadipocytes repressed MCE. Moreover, FAD24 interacts with HBO1, a histone acetyltransferase and positive regulator of DNA replication initiation. The knockdown of hbo1 repressed MCE and adipogenesis, indicating that FAD24 acts in concert with HBO1 to promote adipogenesis by controlling DNA replication. Regarding the molecular mechanisms behind the regulation of DNA replication by fad24, we revealed that FAD24 co- localizes with HBO1 to chromatin during late mitosis, which is when the pre-replication initiation complex is assembled. Furthermore, chromatin immunoprecipitation experiments indicated that FAD24 localizes to origins of DNA replication with HBO1. When fad24 expression was inhibited during adipocyte differentiation, the recruitment of HBO1 to origins of DNA replication was reduced. Thus, FAD24 controls DNA replication by recruiting HBO1 to origins of DNA replication and is required for MCE during adipocyte differentiation.