title: LIM domain-binding 1 maintains the terminally differentiated state of pancreatic β cells.
abstract: The recognition of β cell dedifferentiation in type 2 diabetes raises the translational relevance of mechanisms that direct and maintain β cell identity. LIM domain-binding protein 1 (LDB1) nucleates multimeric transcriptional complexes and establishes promoter-enhancer looping, thereby directing fate assignment and maturation of progenitor populations. Many terminally differentiated endocrine cell types, however, remain enriched for LDB1, but its role is unknown. Here, we have demonstrated a requirement for LDB1 in maintaining the terminally differentiated status of pancreatic β cells. Inducible ablation of LDB1 in mature β cells impaired insulin secretion and glucose homeostasis. Transcriptomic analysis of LDB1-depleted β cells revealed the collapse of the terminally differentiated gene program, indicated by a loss of β cell identity genes and induction of the endocrine progenitor factor neurogenin 3 (NEUROG3). Lineage tracing confirmed that LDB1-depleted, insulin-negative β cells express NEUROG3 but do not adopt alternate endocrine cell fates. In primary mouse islets, LDB1 and its LIM homeodomain-binding partner islet 1 (ISL1) were coenriched at chromatin sites occupied by pancreatic and duodenal homeobox 1 (PDX1), NK6 homeobox 1 (NKX6.1), forkhead box A2 (FOXA2), and NK2 homeobox 2 (NKX2.2) - factors that co-occupy active enhancers in 3D chromatin domains in human islets. Indeed, LDB1 was enriched at active enhancers in human islets. Thus, LDB1 maintains the terminally differentiated state of β cells and is a component of active enhancers in both murine and human islets.
authors.forename: Benjamin N
authors.initials: BN
authors.lastname: Ediger
authors.forename: Hee-Woong
authors.initials: HW
authors.lastname: Lim
authors.forename: Christine
authors.initials: C
authors.lastname: Juliana
authors.forename: David N
authors.initials: DN
authors.lastname: Groff
authors.forename: LaQueena T
authors.initials: LT
authors.lastname: Williams
authors.forename: Giselle
authors.initials: G
authors.lastname: Dominguez
authors.forename: Jin-Hua
authors.initials: JH
authors.lastname: Liu
authors.forename: Brandon L
authors.initials: BL
authors.lastname: Taylor
authors.forename: Erik R
authors.initials: ER
authors.lastname: Walp
authors.forename: Vasumathi
authors.initials: V
authors.lastname: Kameswaran
authors.forename: Juxiang
authors.initials: J
authors.lastname: Yang
authors.forename: Chengyang
authors.initials: C
authors.lastname: Liu
authors.forename: Chad S
authors.initials: CS
authors.lastname: Hunter
authors.forename: Klaus H
authors.initials: KH
authors.lastname: Kaestner
authors.forename: Ali
authors.initials: A
authors.lastname: Naji
authors.forename: Changhong
authors.initials: C
authors.lastname: Li
authors.forename: Maike
authors.initials: M
authors.lastname: Sander
authors.forename: Roland
authors.initials: R
authors.lastname: Stein
authors.forename: Lori
authors.initials: L
authors.lastname: Sussel
authors.forename: Kyoung-Jae
authors.initials: KJ
authors.lastname: Won
authors.forename: Catherine Lee
authors.initials: CL
authors.lastname: May
authors.forename: Doris A
authors.initials: DA
authors.lastname: Stoffers
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051542:Hepatocyte Nuclear Factor 3-beta / Q000235:genetics / Q000378:metabolism; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology; D060588:LIM Domain Proteins / Q000235:genetics / Q000378:metabolism*; D060850:LIM-Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D029961:Zebrafish Proteins
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D051542:Hepatocyte Nuclear Factor 3-beta; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins; D060588:LIM Domain Proteins; D060850:LIM-Homeodomain Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D029961:Zebrafish Proteins; C496502:FOXA2 protein, human; C496503:Foxa2 protein, mouse; C486312:LDB1 protein, human; C102084:Ldb1 protein, mouse; C498695:NEUROG3 protein, human; C000715631:NKX2-2 protein, human; C105201:NKX6-1 protein, human; C407737:Neurog3 protein, mouse; C000715627:Nkx2-2 protein, mouse; C491328:Nkx6-1 protein, mouse; C063843:insulin gene enhancer binding protein Isl-1; C000715630:nkx2.2b protein, zebrafish; C084010:pancreatic and duodenal homeobox 1 protein