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

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

doi:10.1172/jci88016

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

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 WonCatherine Lee May, Doris A Stoffers

39 Citationer (Scopus)

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.

Originalsprog	Engelsk
Tidsskrift	The Journal of Clinical Investigation
Vol/bind	127
Udgave nummer	1
Sider (fra-til)	215-229
Antal sider	15
ISSN	0021-9738
DOI	https://doi.org/10.1172/jci88016
Status	Udgivet - 3 jan. 2017
Udgivet eksternt	Ja

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10.1172/jci88016

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Ediger, B. N., Lim, H.-W., Juliana, C., Groff, D. N., Williams, L. T., Dominguez, G., Liu, J.-H., Taylor, B. L., Walp, E. R., Kameswaran, V., Yang, J., Liu, C., Hunter, C. S., Kaestner, K. H., Naji, A., Li, C., Sander, M., Stein, R., Sussel, L., ... Stoffers, D. A. (2017). LIM domain-binding 1 maintains the terminally differentiated state of pancreatic β cells. The Journal of Clinical Investigation, 127(1), 215-229. https://doi.org/10.1172/jci88016

Ediger, BN, Lim, H-W, Juliana, C, Groff, DN, Williams, LT, Dominguez, G, Liu, J-H, Taylor, BL, Walp, ER, Kameswaran, V, Yang, J, Liu, C, Hunter, CS, Kaestner, KH, Naji, A, Li, C, Sander, M, Stein, R, Sussel, L, Won, K-J, May, CL & Stoffers, DA 2017, 'LIM domain-binding 1 maintains the terminally differentiated state of pancreatic β cells', The Journal of Clinical Investigation, bind 127, nr. 1, s. 215-229. https://doi.org/10.1172/jci88016

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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.",

keywords = "Animals, Basic Helix-Loop-Helix Transcription Factors/genetics, Cell Differentiation, DNA-Binding Proteins/genetics, Diabetes Mellitus, Type 2/genetics, Hepatocyte Nuclear Factor 3-beta/genetics, Homeodomain Proteins/genetics, Humans, Insulin-Secreting Cells/metabolism, LIM Domain Proteins/genetics, LIM-Homeodomain Proteins/genetics, Mice, Mice, Transgenic, Nerve Tissue Proteins/genetics, Trans-Activators/genetics, Transcription Factors/genetics",

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

year = "2017",

month = jan,

day = "3",

doi = "10.1172/jci88016",

language = "English",

volume = "127",

pages = "215--229",

journal = "The Journal of Clinical Investigation",

issn = "0021-9738",

publisher = "American Society for Clinical Investigation",

number = "1",

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TY - JOUR

T1 - LIM domain-binding 1 maintains the terminally differentiated state of pancreatic β cells

AU - Ediger, Benjamin N

AU - Lim, Hee-Woong

AU - Juliana, Christine

AU - Groff, David N

AU - Williams, LaQueena T

AU - Dominguez, Giselle

AU - Liu, Jin-Hua

AU - Taylor, Brandon L

AU - Walp, Erik R

AU - Kameswaran, Vasumathi

AU - Yang, Juxiang

AU - Liu, Chengyang

AU - Hunter, Chad S

AU - Kaestner, Klaus H

AU - Naji, Ali

AU - Li, Changhong

AU - Sander, Maike

AU - Stein, Roland

AU - Sussel, Lori

AU - Won, Kyoung-Jae

AU - May, Catherine Lee

AU - Stoffers, Doris A

PY - 2017/1/3

Y1 - 2017/1/3

N2 - 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.

AB - 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.

KW - Animals

KW - Basic Helix-Loop-Helix Transcription Factors/genetics

KW - Cell Differentiation

KW - DNA-Binding Proteins/genetics

KW - Diabetes Mellitus, Type 2/genetics

KW - Hepatocyte Nuclear Factor 3-beta/genetics

KW - Homeodomain Proteins/genetics

KW - Humans

KW - Insulin-Secreting Cells/metabolism

KW - LIM Domain Proteins/genetics

KW - LIM-Homeodomain Proteins/genetics

KW - Mice

KW - Mice, Transgenic

KW - Nerve Tissue Proteins/genetics

KW - Trans-Activators/genetics

KW - Transcription Factors/genetics

U2 - 10.1172/jci88016

DO - 10.1172/jci88016

M3 - Journal article

C2 - 27941246

SN - 0021-9738

VL - 127

SP - 215

EP - 229

JO - The Journal of Clinical Investigation

JF - The Journal of Clinical Investigation

IS - 1

ER -

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

Abstract

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