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LIM domain–binding 1 maintains the terminally differentiated state of pancreatic β cells
Benjamin N. Ediger, … , Catherine Lee May, Doris A. Stoffers
Benjamin N. Ediger, … , Catherine Lee May, Doris A. Stoffers
Published December 12, 2016
Citation Information: J Clin Invest. 2017;127(1):215-229. https://doi.org/10.1172/JCI88016.
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Research Article Genetics

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

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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

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

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Figure 7

Working model of LDB1-mediated complexes in terminally differentiated β cells.

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Working model of LDB1-mediated complexes in terminally differentiated β ...
Schematic of the LDB1-ISL1 complex at a generalized active enhancer in a terminally differentiated β cell. The dashed-line box indicates a speculative role for LDB1-ISL1 complexes mediating the higher-order chromatin structures necessary for appropriate gene regulation. Flanking the central model are schematics representing the status of LDB1-ISL1 complexes in the respective loss-of-function models. In the Ldb1fl/fl MIP-CreERTM schematic, the described intramolecular binding between the tandem LIM domains and the ISL1 LIM-interacting domain (LID) is indicated. SAD, self-association domain; HD, homeo-domain; LIM1,2, tandem LIM domains; TFs, transcription factors; H3, histone h3.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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