title: Nkx2.2 repressor complex regulates islet β-cell specification and prevents β-to-α-cell reprogramming.
abstract: 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 β 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 β-cell specification. Furthermore, we demonstrate that Nkx2.2 preferentially recruits Grg3 and HDAC1 to the methylated Aristaless homeobox gene (Arx) promoter in β cells. The Nkx2.2 TN mutation results in ectopic expression of Arx in β cells, causing β-to-α-cell transdifferentiation. A corresponding β-cell-specific deletion of DNMT3a is also sufficient to cause Arx-dependent β-to-α-cell reprogramming. Notably, subsequent removal of Arx in the β cells of Nkx2.2(TNmut/TNmut) mutant mice reverts the β-to-α-cell conversion, indicating that the repressor activities of Nkx2.2 on the methylated Arx promoter in β cells are the primary regulatory events required for maintaining β-cell identity.
authors: Department of Genetics and Development, Institute of Human Nutrition, Columbia University, New York 10032, USA.
authors: James B
authors: JB
authors: Papizan
authors: Ruth A
authors: RA
authors: Singer
authors: Shuen-Ing
authors: SI
authors: Tschen
authors: Sangeeta
authors: S
authors: Dhawan
authors: Jessica M
authors: JM
authors: Friel
authors: Susan B
authors: SB
authors: Hipkens
authors: Mark A
authors: MA
authors: Magnuson
authors: Anil
authors: A
authors: Bhushan
authors: Lori
authors: L
authors: Sussel
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D056970:Co-Repressor Proteins; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics; D000090205:DNA Methyltransferase 3A; D003920:Diabetes Mellitus / Q000503:physiopathology; D005786:Gene Expression Regulation; D054439:Ghrelin / Q000378:metabolism; D005934:Glucagon / Q000378:metabolism; D050416:Glucagon-Secreting Cells / Q000166:cytology* / Q000378:metabolism; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D009687:Nuclear Proteins; D009928:Organ Specificity / Q000235:genetics; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D029961:Zebrafish Proteins
chemical_list: C469265:ARX protein, mouse; D056970:Co-Repressor Proteins; C000717967:DNMT3A protein, human; C000715535:Dnmt3a protein, mouse; D054439:Ghrelin; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins; D007328:Insulin; C000715631:NKX2-2 protein, human; C000715627:Nkx2-2 protein, mouse; D009687:Nuclear Proteins; D011506:Proteins; C104849:Tle3 protein, mouse; D014157:Transcription Factors; D029961:Zebrafish Proteins; C000715630:nkx2.2b protein, zebrafish; D005934:Glucagon; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A