Inagaki Takeshi
Laboratory of Epigenetics and Metabolism, Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Showa-machi, Maebashi, Gunma 371-8512 Japan.
Diabetol Int. 2018 Aug 16;9(4):215-223. doi: 10.1007/s13340-018-0366-y. eCollection 2018 Oct.
Adipocytes play a pivotal role in the regulation of energy metabolism. While white adipocyte stores energy, brown adipocyte dissipates energy by producing heat. In addition, another type of heat-producing adipocyte, beige adipocyte, emerges in white adipose tissue in response to chronic coldness. This phenotypic adaptation to the cold environment is considered to be attributed to the epigenetic modifications. Histone methylation is a chemically stable epigenetic modification and thus a proper mechanism for long-lasting cellular memory. Several histone methyl-modifying enzymes such as EHMT1, JMJD1A, JMJD3, and LSD1 are reported to be involved in the beige adipose cell fate determination. Among these, a histone demethylase JMJD1A senses cold environment by being phosphorylated at S265 in response to β-adrenergic receptor stimulation. Phosphorylated JMJD1A regulates both acute and cold thermogenesis. Under acute coldness, phosphorylated JMJD1A forms a complex with chromatin remodeler SWI/SNF and DNA-bound PPARγ, which recruits JMJD1A to the target genomic regions in brown adipocyte. This complex formation, in turn, induces the expression of target genes by bringing the enhancer and the promoter into close proximity. During chronic coldness, phosphorylated JMJD1A regulates beige adipogenesis through a two-step mechanism. In the first step, phosphorylated JMJD1A is recruited to the regulatory regions of target genes by forming a complex with PRDM16, PGC1α, and DNA-bound PPARγ. In the second step, JMJD1A demethylates histone H3K9me2 and induces stable expression of beige-selective genes. The phenotypic analyses of Jmjd1a-null mice and non-phosphorylated mutant S265A Jmjd1a knock-in mice indicate that JMJD1A is a potential therapeutic target for the treatment of obesity-related diseases including metabolic syndrome and type 2 diabetes.
脂肪细胞在能量代谢调节中起关键作用。白色脂肪细胞储存能量，而棕色脂肪细胞通过产热消耗能量。此外，另一种产热脂肪细胞——米色脂肪细胞，会在白色脂肪组织中因长期寒冷而出现。这种对寒冷环境的表型适应被认为归因于表观遗传修饰。组蛋白甲基化是一种化学稳定的表观遗传修饰，因此是长期细胞记忆的合适机制。据报道，几种组蛋白甲基修饰酶，如EHMT1、JMJD1A、JMJD3和LSD1，参与米色脂肪细胞命运的决定。其中，组蛋白去甲基化酶JMJD1A通过在S265位点磷酸化来感知寒冷环境，以响应β-肾上腺素能受体刺激。磷酸化的JMJD1A调节急性和寒冷产热。在急性寒冷条件下，磷酸化的JMJD1A与染色质重塑因子SWI/SNF和与DNA结合的PPARγ形成复合物，将JMJD1A招募到棕色脂肪细胞的目标基因组区域。这种复合物的形成反过来通过使增强子和启动子靠近来诱导目标基因的表达。在长期寒冷期间，磷酸化的JMJD1A通过两步机制调节米色脂肪生成。第一步，磷酸化的JMJD1A通过与PRDM16、PGC1α和与DNA结合的PPARγ形成复合物，被招募到目标基因的调控区域。第二步，JMJD1A使组蛋白H3K9me2去甲基化，并诱导米色选择性基因的稳定表达。Jmjd1a基因敲除小鼠和非磷酸化突变体S265A Jmjd1a基因敲入小鼠的表型分析表明，JMJD1A是治疗包括代谢综合征和2型糖尿病在内的肥胖相关疾病的潜在治疗靶点。
