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Maintenance of β-cell identity through the transcription co-factors TBL1X and TBL1XR1

ABSTRACT: Diabetes occurs because of inadequate insulin secretion from pancreatic β-cells, relative to insulin requirements. One mechanism explaining β-cell malfunction in diabetes is their loss of identity, maintained by a series of well-defined transcription factors, which activate the transcription of β-cell genes including insulin, while repressing the transcription of “disallowed” genes. We have identified the transcriptional co-factors transducin β-like 1 x-linked (TBL1X) and its homolog TBL1X-related (TBL1XR1) as crucial regulators of β-cell identity and function, as β-cell specific knockout in mice leads to severe, progressive hypoinsulinemia and hyperglycemia. Single cell RNA sequencing showed loss of β-cells, gain of polyhormonal cells, and reduced β-cell maturity upon TBL/R knockout, indicative of dedifferentiated cells. Mechanistically, interactome screens and chromatin immunoprecipitation showed that TBL/R directly regulate insulin gene expression by forming a gene regulatory network with the islet cell master regulator paired box 6 (PAX6) and histone deacetylase 3 (HDAC3). Overall, our study provides evidence for an as yet unknown regulatory layer maintaining β-cell identity, relevant for development and progression of diabetes.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Cell Culture

DISEASE(S): Type 1 Diabetes Mellitus 2

SUBMITTER: Stefanie Hauck

LAB HEAD: Maria Rohm

PROVIDER: PXD054677 | Pride | 2026-03-25

REPOSITORIES: Pride

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			Action	DRS
	WAA14244X002__MIN6_Flag_Rep1_92-302056.raw	Raw
	WAA14244X003__MIN6_TBL1X_Rep1_92-302057.raw	Raw
	WAA14244X004__MIN6_TBL1XR1_Rep1_92-302058.raw	Raw
	WAA14244X006__MIN6_Flag_Rep2_92-302060.raw	Raw
	WAA14244X007__MIN6_TBL1X_Rep2_92-302061.raw	Raw

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Maintenance of β-cell identity through the transcription co-factors TBL1X and TBL1XR1

Project description:Loss of β-cell identity is a main mechanism of β-cell dysfunction in diabetes, controlled by transcription factors that induce β-cell identity gene expression and “disallowed” gene repression. How transcription factors facilitate simultaneous expression and repression is not fully understood, representing a serious knowledge gap in diabetes research. We identified the transcriptional co-factors transducin β-like 1 x-linked (TBL1X) and its homolog TBL1X-related (TBL1XR1) (short: TBL/R1) as crucial regulators of β-cell identity and function, as β-cell specific knockout in mice leads to progressive hypoinsulinemia and hyperglycemia. Single-cell RNA sequencing revealed loss of β-cells, the emergence of polyhormonal cells, and reduced β-cell maturity upon TBL/R1 knockout, indicating dedifferentiation. Interactome screens and chromatin immunoprecipitation showed TBL/R1 directly regulate insulin gene expression by forming a gene regulatory network with PAX6 and HDAC3, which was also evident in human models. Our study uncovers a new regulatory layer maintaining β-cell identity, crucial for diabetes development and progression.

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