Journal Article

LIM domain–binding 1 maintains the terminally differentiated state of pancreatic β cells

Walp, Erik R., Groff, David N., Kaestner, Klaus H., Stoffers, Doris A., Taylor, Brandon L., Liu, Jin-Hua, Hunter, Chad S., Ediger, Benjamin N., May, Catherine Lee, Won, Kyoung-Jae, Lim, Hee-Woong, Naji, Ali, Li, Changhong, Dominguez, Giselle, Sander, Maike, Stein, Roland, Kameswaran, Vasumathi, Juliana, Christine, Sussel, Lori, Liu, Chengyang, Williams, LaQueena T., Yang, Juxiang

2017

Overview

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.

• Publisher: American Society for Clinical Investigation
• Subject: Analysis / Animals / Basic Helix-Loop-Helix Transcription Factors - genetics / Basic Helix-Loop-Helix Transcription Factors - metabolism / Cell Differentiation / Diabetes Mellitus, Type 2 - genetics / Diabetes Mellitus, Type 2 - metabolism / Diabetes Mellitus, Type 2 - pathology / DNA-Binding Proteins - genetics / DNA-Binding Proteins - metabolism / Gene expression / Genetic transcription / Hepatocyte Nuclear Factor 3-beta - genetics / Hepatocyte Nuclear Factor 3-beta - metabolism / Homeodomain Proteins - genetics / Homeodomain Proteins - metabolism / Humans / Insulin-Secreting Cells - metabolism / Insulin-Secreting Cells - pathology / LIM Domain Proteins - genetics / LIM Domain Proteins - metabolism / LIM-Homeodomain Proteins - genetics / LIM-Homeodomain Proteins - metabolism / Mice / Mice, Transgenic / Nerve Tissue Proteins - genetics / Nerve Tissue Proteins - metabolism / Pancreatic beta cells / Trans-Activators - genetics / Trans-Activators - metabolism / Transcription Factors - genetics / Transcription Factors - metabolism