The Transcription Factor ATF7 Controls Adipocyte Differentiation and Thermogenic Gene Programming.

The adipocytes functions as a central organ in the regulation of metabolic homeostasis. Factors which contribute to the adipocyte differentiation and function would be the promising targets to combat the obesity and associated metabolic disorders. The activating transcription factor 7 (ATF7), a stress-responsive chromatin regulator, has recently been shown to be involved in the energy metabolism; however, the underlying mechanisms are still unknown. Here, we show that ATF7 is required for adipocyte differentiation and it interacts with histone dimethyltransferase G9a in adipocyte to repress the interferon-stimulated genes (ISGs) expression, which suppresses adipogenesis. Ablation of ATF7 promotes the beige biogenesis and browning of inguinal white adipose tissue (iWAT). ATF7 binds to the transcription regulatory regions of Ucp1 gene, and silences it by maintaining the histone H3K9 dimethylation level. These results establish the multifunction of ATF7 in adipocyte and provide molecular insights into the epigenetic control of development and function of adipose tissues. Overall design: Beige adipocytes derived from WT and ATF7 KO inguinal WAT preadipocytes with rosiglitazone treatment, in duplicate; white adipocytes derived from WT and ATF7 KO inguinal WAT preadipocytes without rosiglitazone treatment, in duplicate; beige adipocytes derived from control and ATF7 overexpressing C3H10t1/2 with rosiglitazone treatment, in duplicate, using NextSeq500 Illumina.脂肪细胞（adipocytes）是调控代谢稳态的核心器官。能够影响脂肪细胞分化与功能的因子，有望成为对抗肥胖及其相关代谢紊乱的潜在靶点。激活转录因子7（activating transcription factor 7, ATF7）作为一种应激响应性染色质调控因子，近期被证实参与能量代谢过程，但其具体分子机制仍未阐明。本研究发现，ATF7是脂肪细胞分化所必需的，它可在脂肪细胞中与组蛋白二甲基转移酶G9a相互作用，抑制干扰素刺激基因（interferon-stimulated genes, ISGs）的表达，而该类基因的表达会抑制脂肪生成过程。敲除ATF7可促进腹股沟白色脂肪组织（inguinal white adipose tissue, iWAT）的米色脂肪生成与褐变。ATF7可结合解偶联蛋白1（uncoupling protein 1, Ucp1）基因的转录调控区域，并通过维持组蛋白H3K9二甲基化水平沉默该基因的表达。上述结果明确了ATF7在脂肪细胞中的多方面功能，并为脂肪组织发育与功能的表观遗传调控提供了分子层面的新见解。整体实验设计：采用罗格列酮处理野生型（WT）与ATF7基因敲除（KO）的腹股沟白色脂肪前体细胞，分化得到米色脂肪细胞，设置两份生物学重复；不施加罗格列酮处理，以野生型与ATF7 KO腹股沟白色脂肪前体细胞分化得到白色脂肪细胞，同样设置两份生物学重复；采用罗格列酮处理对照组与ATF7过表达的C3H10t1/2细胞，分化得到米色脂肪细胞，设置两份生物学重复，测序使用Illumina NextSeq500平台。