| First Author | Papizan JB | Year | 2011 |
| Journal | Genes Dev | Volume | 25 |
| Issue | 21 | Pages | 2291-305 |
| PubMed ID | 22056672 | Mgi Jnum | J:177838 |
| Mgi Id | MGI:5296389 | Doi | 10.1101/gad.173039.111 |
| Citation | Papizan JB, et al. (2011) Nkx2.2 repressor complex regulates islet beta-cell specification and prevents beta-to-alpha-cell reprogramming. Genes Dev 25(21):2291-305 |
| abstractText | Regulation of cell differentiation programs requires complex interactions between transcriptional and epigenetic networks. Elucidating the principal molecular events responsible for the establishment and maintenance of cell fate identities will provide important insights into how cell lineages are specified and maintained and will improve our ability to recapitulate cell differentiation events in vitro. In this study, we demonstrate that Nkx2.2 is part of a large repression complex in pancreatic beta cells that includes DNMT3a, Grg3, and HDAC1. Mutation of the endogenous Nkx2.2 tinman (TN) domain in mice abolishes the interaction between Nkx2.2 and Grg3 and disrupts beta-cell specification. Furthermore, we demonstrate that Nkx2.2 preferentially recruits Grg3 and HDAC1 to the methylated Aristaless homeobox gene (Arx) promoter in beta cells. The Nkx2.2 TN mutation results in ectopic expression of Arx in beta cells, causing beta-to-alpha-cell transdifferentiation. A corresponding beta-cell-specific deletion of DNMT3a is also sufficient to cause Arx-dependent beta-to-alpha-cell reprogramming. Notably, subsequent removal of Arx in the beta cells of Nkx2.2(TNmut/TNmut) mutant mice reverts the beta-to-alpha-cell conversion, indicating that the repressor activities of Nkx2.2 on the methylated Arx promoter in beta cells are the primary regulatory events required for maintaining beta-cell identity. |
