Department of Cancer Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Mol Cell Biol. 2013 Oct;33(19):3864-78. doi: 10.1128/MCB.01495-12. Epub 2013 Jul 29.
During adipocyte differentiation, significant epigenomic changes occur in association with the implementation of the adipogenic program. We have previously shown that histone acetylation increases during differentiation in a manner dependent on acetyl coenzyme A (acetyl-CoA) production by the enzyme ATP-citrate lyase (ACL). Whether ACL regulates nuclear targets in addition to histones during differentiation is not clear. In this study, we report that DNA methyltransferase 1 (DNMT1) levels in adipocytes are controlled in part by ACL and that silencing of DNMT1 can accelerate adipocyte differentiation. DNMT1 gene expression is induced early in 3T3-L1 adipocyte differentiation during mitotic clonal expansion and is critical for maintenance of DNA and histone H3K9 methylation patterns during this period. In the absence of DNMT1, adipocyte-specific gene expression and lipid accumulation occur precociously. Later in differentiation, DNMT1 levels decline in an ACL-dependent manner. ACL-mediated suppression of DNMT1 occurs at least in part by promoting expression of microRNA 148a (miR-148a), which represses DNMT1. Ectopic expression of miR-148a accelerates differentiation under standard conditions and can partially rescue a hypermethylation-mediated differentiation block. The data suggest a role for DNMT1 in modulating the timing of differentiation and describe a novel ACL-miR-148a-dependent mechanism for regulating DNMT1 during adipogenesis.
在脂肪细胞分化过程中,会发生显著的表观基因组变化,这与脂肪生成程序的实施有关。我们之前已经表明,组蛋白乙酰化在分化过程中增加,这与酶 ATP-柠檬酸裂解酶 (ACL) 产生乙酰辅酶 A (acetyl-CoA) 有关。在分化过程中,ACL 是否除了组蛋白之外还调节核靶标尚不清楚。在这项研究中,我们报告说脂肪细胞中的 DNA 甲基转移酶 1 (DNMT1) 水平部分受到 ACL 的控制,并且沉默 DNMT1 可以加速脂肪细胞分化。DNMT1 基因表达在 3T3-L1 脂肪细胞分化的有丝分裂克隆扩增早期被诱导,并且在该期间对于维持 DNA 和组蛋白 H3K9 甲基化模式至关重要。在没有 DNMT1 的情况下,脂肪细胞特异性基因表达和脂质积累会过早发生。在分化后期,DNMT1 水平以 ACL 依赖的方式下降。ACL 介导的 DNMT1 抑制至少部分是通过促进 microRNA 148a (miR-148a) 的表达来实现的,miR-148a 抑制 DNMT1。miR-148a 的异位表达在标准条件下加速分化,并且可以部分挽救过度甲基化介导的分化阻滞。这些数据表明 DNMT1 在调节分化时间方面的作用,并描述了一种新型的 ACL-miR-148a 依赖性机制,用于调节脂肪生成过程中的 DNMT1。