Pancreatic β cell identity requires continual repression of non–β cell programs
Giselle Domínguez Gutiérrez, Aaron S. Bender, Vincenzo Cirulli, Teresa L. Mastracci, Stephen M. Kelly, Aristotelis Tsirigos, Klaus H. Kaestner, Lori Sussel
Giselle Domínguez Gutiérrez, Aaron S. Bender, Vincenzo Cirulli, Teresa L. Mastracci, Stephen M. Kelly, Aristotelis Tsirigos, Klaus H. Kaestner, Lori Sussel
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Research Article Metabolism

Pancreatic β cell identity requires continual repression of non–β cell programs

Abstract

Loss of β cell identity, the presence of polyhormonal cells, and reprogramming are emerging as important features of β cell dysfunction in patients with type 1 and type 2 diabetes. In this study, we have demonstrated that the transcription factor NKX2.2 is essential for the active maintenance of adult β cell identity as well as function. Deletion of Nkx2.2 in β cells caused rapid onset of a diabetic phenotype in mice that was attributed to loss of insulin and downregulation of many β cell functional genes. Concomitantly, NKX2.2-deficient murine β cells acquired non–β cell endocrine features, resulting in populations of completely reprogrammed cells and bihormonal cells that displayed hybrid endocrine cell morphological characteristics. Molecular analysis in mouse and human islets revealed that NKX2.2 is a conserved master regulatory protein that controls the acquisition and maintenance of a functional, monohormonal β cell identity by directly activating critical β cell genes and actively repressing genes that specify the alternative islet endocrine cell lineages. This study demonstrates the highly volatile nature of the β cell, indicating that acquiring and sustaining β cell identity and function requires not only active maintaining of the expression of genes involved in β cell function, but also continual repression of closely related endocrine gene programs.

Authors

Giselle Domínguez Gutiérrez, Aaron S. Bender, Vincenzo Cirulli, Teresa L. Mastracci, Stephen M. Kelly, Aristotelis Tsirigos, Klaus H. Kaestner, Lori Sussel

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Figure 8

Model of NKX2.2 function in the adult β cell.

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Model of NKX2.2 function in the adult β cell. NKX2.2 appears to be a mas...
NKX2.2 appears to be a master regulatory protein that is essential for the acquisition and maintenance of β cell identity. Loss of NKX2.2 in β cell results in the formation of different β cell subpopulations that were identified by the expression of the β cell–specific Tomato reporter. Dysfunctional β cells: This category includes lineage-labeled (red dots) insulin-expressing cells (purple dots) unable to mount a proper insulin response and represents the largest population of mutant β cells. Polyhormonal β cells: Lineage-labeled (red dots), insulin-positive (purple dots) β cells that are misexpressing the other islet endocrine hormones (green dots). It is possible that these cells represent incomplete transdifferentiation. Insulin-negative β cells: Lineage-labeled (red dots) β cells that have lost insulin expression, but have acquired the expression of other non-β endocrine hormones (green dots). Empty β cells: A rarer population of lineage-labeled cells (red dots) without expression of any endocrine hormones. It is unknown whether these populations originate independently or are able to interconvert. Arrows represent the possible transitioning between the different populations.