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

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.