Hiraike Yuta, Tsutsumi Shuichi, Wada Takahito, Oguchi Misato, Saito Kaede, Nakamura Masahiro, Ota Satoshi, Koebis Michinori, Nakao Harumi, Aiba Atsu, Nagano Gaku, Ohno Haruya, Oki Kenji, Yoneda Masayasu, Kadowaki Takashi, Aburatani Hiroyuki, Waki Hironori, Yamauchi Toshimasa
Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, the University of Tokyo, Tokyo 113-8655, Japan.
Division for Health Service Promotion, the University of Tokyo, Tokyo 113-0033, Japan.
iScience. 2022 Jul 7;25(8):104729. doi: 10.1016/j.isci.2022.104729. eCollection 2022 Aug 19.
Thermogenic brown and beige adipocytes counteract obesity by enhancing energy dissipation via uncoupling protein-1 (Ucp1). However, the effect of genetic variation on these cells, a major source of disease susceptibility, has been less well studied. Here we examined beige adipocytes from obesity-prone C57BL/6J (B6) and obesity-resistant 129X1/SvJ (129) mouse strains and identified a -regulatory variant rs47238345 that is responsible for differential Ucp1 expression. The alternative T allele of rs47238345 at the -12kb enhancer in 129 facilitates the allele-specific binding of nuclear factor I-A (NFIA) to mediate allele-specific enhancer-promoter interaction and transcription. Furthermore, CRISPR-Cas9/Cpf1-mediated single nucleotide polymorphism (SNP) editing of rs47238345 resulted in increased Ucp1 expression. We also identified Lim homeobox protein 8 (Lhx8), whose expression is higher in 129 than in B6, as a acting regulator of Ucp1 in mice and humans. These results demonstrate the - and acting effects of genetic variation on Ucp1 expression that underlie phenotypic diversity.
产热的棕色和米色脂肪细胞通过解偶联蛋白-1（Ucp1）增强能量消耗来对抗肥胖。然而，遗传变异对这些细胞（疾病易感性的主要来源）的影响尚未得到充分研究。在这里，我们研究了易肥胖的C57BL/6J（B6）和抗肥胖的129X1/SvJ（129）小鼠品系的米色脂肪细胞，并鉴定出一个调控变体rs47238345，它负责Ucp1的差异表达。129品系中位于-12kb增强子处的rs47238345的替代T等位基因促进了核因子I-A（NFIA）的等位基因特异性结合，以介导等位基因特异性增强子-启动子相互作用和转录。此外，CRISPR-Cas9/Cpf1介导的rs47238345单核苷酸多态性（SNP）编辑导致Ucp1表达增加。我们还鉴定出Lim同源盒蛋白8（Lhx8），其在129品系中的表达高于B6品系，它是小鼠和人类中Ucp1的作用调节因子。这些结果证明了遗传变异对Ucp1表达的调控和作用影响，这是表型多样性的基础。
