PDF(Pubmed)
Abstract：
HNF4A and HNF1A encode transcription factors that are important for the development and function of the pancreas and liver. Mutations in both genes have been directly linked to Maturity Onset Diabetes of the Young (MODY) and type 2 diabetes (T2D) risk. To better define the pleiotropic gene regulatory roles of HNF4A and HNF1A, we generated a comprehensive genome-wide map of their binding targets in pancreatic and hepatic cells using ChIP-Seq. HNF4A was found to bind and regulate known (ACY3, HAAO, HNF1A, MAP3K11) and previously unidentified (ABCD3, CDKN2AIP, USH1C, VIL1) loci in a tissue-dependent manner. Functional follow-up highlighted a potential role for HAAO and USH1C as regulators of beta cell function. Unlike the loss-of-function HNF4A/MODY1 variant I271fs, the T2D-associated HNF4A variant (rs1800961) was found to activate AKAP1, GAD2 and HOPX gene expression, potentially due to changes in DNA-binding affinity. We also found HNF1A to bind to and regulate GPR39 expression in beta cells. Overall, our studies provide a rich resource for uncovering downstream molecular targets of HNF4A and HNF1A that may contribute to beta cell or hepatic cell (dys)function, and set up a framework for gene discovery and functional validation.
摘要：
HNF4A和HNF1A编码对胰腺和肝脏的发育和功能重要的转录因子。这两个基因的突变都与年轻人的成年糖尿病（MODY）和2型糖尿病（T2D）风险直接相关。为了更好地定义HNF4A和HNF1A的多效性基因调控作用，我们使用ChIP-Seq生成了其在胰腺和肝细胞中的结合靶标的全面全基因组图谱。HNF4A被发现结合和调节已知(ACY3，HAAO，HNF1A,MAP3K11)和先前未识别的(ABCD3、CDKN2AIP、USH1C,VIL1)以组织依赖性方式定位。功能随访强调了HAAO和USH1C作为β细胞功能调节剂的潜在作用。与功能丧失型HNF4A/MODY1变体I271fs不同，发现T2D相关的HNF4A变体（rs1800961）激活AKAP1，GAD2和HOPX基因表达，可能是由于DNA结合亲和力的变化。我们还发现HNF1A结合并调节β细胞中的GPR39表达。总的来说,我们的研究为揭示可能有助于β细胞或肝细胞（dys）功能的HNF4A和HNF1A的下游分子靶标提供了丰富的资源，并建立了基因发现和功能验证的框架。
