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

Loss of ß-cell identity is a main mechanism of ß-cell dysfunction in diabetes, controlled by transcription factors that induce ß-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 ß-like 1 x-linked (TBL1X) and its homolog TBL1X-related (TBL1XR1) (short: TBL/R1) as crucial regulators of ß-cell identity and function, as ß-cell specific knockout in mice leads to progressive hypoinsulinemia and hyperglycemia. Single-cell RNA sequencing revealed loss of ß-cells, the emergence of polyhormonal cells, and reduced ß-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 ß-cell identity, crucial for diabetes development and progression. Overall design: To investigate the transcriptomic changes in pancreatic beta-cells upon TBL1X and TBL1XR1, pancreatic islets from mice with a beta-cell specific TBL1X and TBL1XR1 kockout (n=4) and control littermates (n=4) were isolated and subjected to RNA-Seq