title: TCF7L2 is a master regulator of insulin production and processing.
abstract: Genome-wide association studies have revealed >60 loci associated with type 2 diabetes (T2D), but the underlying causal variants and functional mechanisms remain largely elusive. Although variants in TCF7L2 confer the strongest risk of T2D among common variants by presumed effects on islet function, the molecular mechanisms are not yet well understood. Using RNA-sequencing, we have identified a TCF7L2-regulated transcriptional network responsible for its effect on insulin secretion in rodent and human pancreatic islets. ISL1 is a primary target of TCF7L2 and regulates proinsulin production and processing via MAFA, PDX1, NKX6.1, PCSK1, PCSK2 and SLC30A8, thereby providing evidence for a coordinated regulation of insulin production and processing. The risk T-allele of rs7903146 was associated with increased TCF7L2 expression, and decreased insulin content and secretion. Using gene expression profiles of 66 human pancreatic islets donors', we also show that the identified TCF7L2-ISL1 transcriptional network is regulated in a genotype-dependent manner. Taken together, these results demonstrate that not only synthesis of proinsulin is regulated by TCF7L2 but also processing and possibly clearance of proinsulin and insulin. These multiple targets in key pathways may explain why TCF7L2 has emerged as the gene showing one of the strongest associations with T2D.
authors.affiliation: Department of Clinical Sciences, CRC, Lund University, Malmö 20502, Sweden.
authors.forename: Yuedan
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Medicine and.
authors.forename: Soo-Young
authors.initials: SY
authors.lastname: Park
authors.affiliation: European Bioinformatics Institute, Functional Genomics, Hinxton, Cambridge CB10 1SD, UK.
authors.forename: Jing
authors.initials: J
authors.lastname: Su
authors.affiliation: Department of Human Genetics, University of Chicago, IL 60637, USA.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Bailey
authors.affiliation: Department of Clinical Sciences, CRC, Lund University, Malmö 20502, Sweden.
authors.forename: Emilia
authors.initials: E
authors.lastname: Ottosson-Laakso
authors.affiliation: Department of Clinical Sciences, CRC, Lund University, Malmö 20502, Sweden.
authors.forename: Liliya
authors.initials: L
authors.lastname: Shcherbina
authors.affiliation: Department of Clinical Sciences, CRC, Lund University, Malmö 20502, Sweden.
authors.forename: Nikolay
authors.initials: N
authors.lastname: Oskolkov
authors.affiliation: Department of Clinical Sciences, CRC, Lund University, Malmö 20502, Sweden.
authors.forename: Enming
authors.initials: E
authors.lastname: Zhang
authors.affiliation: Department of Clinical Sciences, CRC, Lund University, Malmö 20502, Sweden.
authors.forename: Thomas
authors.initials: T
authors.lastname: Thevenin
authors.affiliation: Department of Clinical Sciences, CRC, Lund University, Malmö 20502, Sweden.
authors.forename: João
authors.initials: J
authors.lastname: Fadista
authors.affiliation: Department of Clinical Sciences, CRC, Lund University, Malmö 20502, Sweden.
authors.forename: Hedvig
authors.initials: H
authors.lastname: Bennet
authors.affiliation: Department of Clinical Sciences, CRC, Lund University, Malmö 20502, Sweden.
authors.forename: Petter
authors.initials: P
authors.lastname: Vikman
authors.affiliation: Department of Clinical Sciences, CRC, Lund University, Malmö 20502, Sweden.
authors.forename: Nils
authors.initials: N
authors.lastname: Wierup
authors.affiliation: Department of Clinical Sciences, CRC, Lund University, Malmö 20502, Sweden.
authors.forename: Malin
authors.initials: M
authors.lastname: Fex
authors.affiliation: Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala 75185, Sweden and.
authors.forename: Johan
authors.initials: J
authors.lastname: Rung
authors.affiliation: Department of Clinical Sciences, CRC, Lund University, Malmö 20502, Sweden, Department of Cell Physiology and Metabolism, Université de Genève, University Medical Centre, 1 rue Michel-Servet, Geneva 4 1211, Switzerland.
authors.forename: Claes
authors.initials: C
authors.lastname: Wollheim
authors.affiliation: Department of Human Genetics, University of Chicago, IL 60637, USA.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Nobrega
authors.affiliation: Department of Clinical Sciences, CRC, Lund University, Malmö 20502, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Renström
authors.affiliation: Department of Clinical Sciences, CRC, Lund University, Malmö 20502, Sweden.
authors.forename: Leif
authors.initials: L
authors.lastname: Groop
authors.affiliation: Department of Clinical Sciences, CRC, Lund University, Malmö 20502, Sweden, Ola.Hansson@med.lu.se.
authors.forename: Ola
authors.initials: O
authors.lastname: Hansson
mesh_terms: D000483:Alleles; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D059014:High-Throughput Nucleotide Sequencing; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000235:genetics* / Q000378:metabolism; D007515:Islets of Langerhans / Q000378:metabolism / Q000473:pathology; D060850:LIM-Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D051473:Maf Transcription Factors, Large / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D020641:Polymorphism, Single Nucleotide; D011384:Proinsulin / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D058118:Transcription Factor 7-Like 2 Protein / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D018398:Homeodomain Proteins; D007328:Insulin; D060850:LIM-Homeodomain Proteins; D051473:Maf Transcription Factors, Large; D011384:Proinsulin; D015534:Trans-Activators; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors; C485159:MAFA protein, human; C093970:NEUROD1 protein, human; C544894:TCF7L2 protein, human; C063843:insulin gene enhancer binding protein Isl-1; C084010:pancreatic and duodenal homeobox 1 protein