NFIA determines the cis-effect of genetic variation on adipocyte browning in mice [ChIP-Seq]. NFIA determines the cis-effect of genetic variation on adipocyte browning in mice [ChIP-Seq]

Thermogenic brown and beige adipocytes counteract obesity by enhancing energy dissipation via uncoupling proein-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 cis-regulatory variant rs47238345 that is responsible for differential Ucp1 expression. The alternative T allele of rs47238345 at the Ucp1 -12kb enhancer in 129 facilitates the allele-specific binding of nuclear factor I-A (NFIA) to mediate allele-specific enhancer-promoter interaction and Ucp1 transcription. We also identified Lim homeobox protein 8 (Lhx8), whose expression is higher in 129 than in B6, as a trans-acting regulator of Ucp1 in mice and humans. These results demonstrate the cis- and trans-acting effects of genetic variation on Ucp1 expression that underlie phenotypic diversity. Overall design: ChIP-seq analysis of beige adipocytes from F1 offspring of obesity prone C57BL/6J and obesity-resistant 129X1/SvJ (129).

产热棕色与米色脂肪细胞可通过解偶联蛋白1（uncoupling protein-1, Ucp1）增强能量耗散以对抗肥胖。然而，遗传变异对这类细胞——疾病易感性的主要来源——的影响尚未得到充分研究。本研究对易肥胖C57BL/6J（B6）与抗肥胖129X1/SvJ（129）小鼠品系的米色脂肪细胞开展分析，鉴定出一种可介导Ucp1表达差异的顺式调控变异（cis-regulatory variant）rs47238345。129品系小鼠Ucp1基因-12kb增强子区域的rs47238345变异等位基因T，可促进核因子I-A（nuclear factor I-A, NFIA）的等位基因特异性结合，进而介导等位基因特异性的增强子-启动子相互作用与Ucp1转录。本研究同时鉴定出同源框蛋白8（Lim homeobox protein 8, Lhx8）：其在129品系中的表达水平显著高于B6品系，可作为小鼠与人类中Ucp1的反式作用调控因子（trans-acting regulator）。上述结果阐明了遗传变异通过顺式与反式作用调控Ucp1表达的分子机制，该机制是表型多样性的基础。整体实验设计：对易肥胖C57BL/6J与抗肥胖129X1/SvJ（129）小鼠的杂交一代子代的米色脂肪细胞进行染色质免疫共沉淀测序（ChIP-seq）分析。