| First Author | Ediger BN | Year | 2017 |
| Journal | J Clin Invest | Volume | 127 |
| Issue | 1 | Pages | 215-229 |
| PubMed ID | 27941246 | Mgi Jnum | J:239844 |
| Mgi Id | MGI:5881863 | Doi | 10.1172/JCI88016 |
| Citation | Ediger BN, et al. (2017) LIM domain-binding 1 maintains the terminally differentiated state of pancreatic beta cells. J Clin Invest 127(1):215-229 |
| abstractText | The recognition of beta cell dedifferentiation in type 2 diabetes raises the translational relevance of mechanisms that direct and maintain beta 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 beta cells. Inducible ablation of LDB1 in mature beta cells impaired insulin secretion and glucose homeostasis. Transcriptomic analysis of LDB1-depleted beta cells revealed the collapse of the terminally differentiated gene program, indicated by a loss of beta cell identity genes and induction of the endocrine progenitor factor neurogenin 3 (NEUROG3). Lineage tracing confirmed that LDB1-depleted, insulin-negative beta 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 beta cells and is a component of active enhancers in both murine and human islets. |
