Hnf1α (MODY3) Controls Tissue-Specific Transcriptional Programs and Exerts Opposed Effects on Cell Growth in Pancreatic Islets and Liver

Abstract

Heterozygous HNF1A mutations cause pancreatic-islet ␤-cell dysfunction and monogenic diabetes (MODY3). Hnf1␣ is known to regulate numerous hepatic genes, yet knowledge of its function in pancreatic islets is more limited. We now show that Hnf1a deficiency in mice leads to highly tissue-specific changes in the expression of genes involved in key functions of both islets and liver. To gain insights into the mechanisms of tissue-specific Hnf1␣ regulation, we integrated expression studies of Hnf1a-deficient mice with identification of direct Hnf1␣ targets. We demonstrate that Hnf1␣ can bind in a tissue-selective manner to genes that are expressed only in liver or islets. We also show that Hnf1␣ is essential only for the transcription of a minor fraction of its direct-target genes. Even among genes that were expressed in both liver and islets, the subset of targets showing functional dependence on Hnf1␣ was highly tissue specific. This was partly explained by the compensatory occupancy by the paralog Hnf1␤ at selected genes in Hnf1a-deficient liver. In keeping with these findings, the biological consequences of Hnf1a deficiency were markedly different in islets and liver. Notably, Hnf1a deficiency led to impaired large-T-antigen-induced growth and oncogenesis in ␤ cells yet enhanced proliferation in hepatocytes. Collectively, these findings show that Hnf1␣ governs broad, highly tissue-specific genetic programs in pancreatic islets and liver and reveal key consequences of Hnf1a deficiency relevant to the pathophysiology of monogenic diabetes.

Reduction of circulating PCSK9 and LDL-C levels by liver-specific knockdown of HNF1α in normolipidemic mice

“…by guest, on May 10, 2018 www.jlr.org Downloaded from 20-fold ( 30 ). These studies pointed to the possibility that, like some other HNF1 ␣ target genes, the in vivo regulation of PCSK9 may exhibit redundancy in the ability of HNF1 ␤ to complement absence of HNF1 ␣ .…”

“…Although HNF1 ␤ is expressed at very low levels in adult hepatocytes, a recent report implicated that its expression is induced in HNF1 ␣ Ϫ / Ϫ livers ( 30 ). In vivo binding studies further indicated that loss of HNF1 ␣ triggers signifi cantly higher HNF1 ␤ binding at several HNF1 ␣ target loci, including the PCSK9 promoter region ( 30 ).…”

“…Although HNF1 ␤ is expressed at very low levels in adult hepatocytes, a recent report implicated that its expression is induced in HNF1 ␣ Ϫ / Ϫ livers ( 30 ). In vivo binding studies further indicated that loss of HNF1 ␣ triggers signifi cantly higher HNF1 ␤ binding at several HNF1 ␣ target loci, including the PCSK9 promoter region ( 30 ). However, there is currently limited in vivo evidence linking the binding of these transcription factors on the PCSK9 promoter to the individual contributions of HNF1 ␣ and HNF1 ␤ in the regulation of PCSK9 expression in liver tissue, as well as on circulating cholesterol levels.…”

Recessive Mutations in PCBD1 Cause a New Type of Early-Onset Diabetes

“…Thus, their binding partner PCBD1 might have different effects on the pancreas at different time points. Finally, PCBD1 mutations probably cause HPA and diabetes by affecting not one particular pathway but several genetic, metabolic, and signaling programs in different tissues, as shown for HNF1A gene (24). Future studies will aim to fully understand how PCBD1 regulates b-cell functions and the mechanisms leading to diabetes.…”

Alx3-deficient mice exhibit decreased insulin in beta cells, altered glucose homeostasis and increased apoptosis in pancreatic islets

“…Some of these transcription factors regulate complex transcriptional programmes of gene expression by acting on pancreatic cell specific target gene networks [15,16]. Furthermore, in combination with other transcription factors present in mature cells, they interact co-ordinately on the insulin gene promoter to regulate insulin gene expression [4,17].…”