Dissecting the brown adipogenic regulatory network using integrative genomics.
Dissecting the brown adipogenic regulatory network using integrative genomics.
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DOI：
10.1038/srep42130
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发表时间：
2017-02-09
影响因子：
4.6
通讯作者：
Deplancke B
中科院分区：
文献类型：
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作者：
Pradhan RN;Bues JJ;Gardeux V;Schwalie PC;Alpern D;Chen W;Russeil J;Raghav SK;Deplancke B
棕色脂肪细胞通过线粒体解偶联调节能量消耗，这使得它们成为解决肥胖问题的有吸引力的治疗靶点。然而，棕色脂肪生成的调控机制仍然知之甚少。为了解决这个问题，我们分析了小鼠棕色脂肪细胞分化过程中的转录组和染色质状态，揭示了广泛的基因表达变化和染色质重塑，特别是在分化后的第一天。为了确定假定的因果调节因子，我们在活性染色质区域中进行了转录因子结合位点过度表达分析，并根据多个小鼠和人类数据集中的真实棕色脂肪形成标记物 Ucp1 的表达相关性对因子进行了优先排序。使用功能丧失测定，我们评估了几种假定的调控因子对分化过程的表型效应以及转录组影响，发现 ZFP467、HOXA4 和核因子 I A (NFIA) 是新型转录调控因子。其中，NFIA 作为调节者出现，产生最强的分子和细胞表型。为了检查其调节功能，我们分析了 NFIA 的基因组定位，将其确定为终末棕色脂肪细胞分化的关键早期调节因子。
Brown adipocytes regulate energy expenditure via mitochondrial uncoupling, which makes them attractive therapeutic targets to tackle obesity. However, the regulatory mechanisms underlying brown adipogenesis are still poorly understood. To address this, we profiled the transcriptome and chromatin state during mouse brown fat cell differentiation, revealing extensive gene expression changes and chromatin remodeling, especially during the first day post-differentiation. To identify putatively causal regulators, we performed transcription factor binding site overrepresentation analyses in active chromatin regions and prioritized factors based on their expression correlation with the bona-fide brown adipogenic marker Ucp1 across multiple mouse and human datasets. Using loss-of-function assays, we evaluated both the phenotypic effect as well as the transcriptomic impact of several putative regulators on the differentiation process, uncovering ZFP467, HOXA4 and Nuclear Factor I A (NFIA) as novel transcriptional regulators. Of these, NFIA emerged as the regulator yielding the strongest molecular and cellular phenotypes. To examine its regulatory function, we profiled the genomic localization of NFIA, identifying it as a key early regulator of terminal brown fat cell differentiation.