Prolactin receptor signaling mediates beta-cell epigenetic adaptations to promote OVOL2-binding

We identified differentially accessible regions in wild type β-cells which had 718 overrepresented motifs following prolactin treatment of murine islets. Validating this approach, these included motifs bound by established PRLR signaling effectors such as the STAT family of transcription factors (TFs). Using RNA-sequencing we identified transcriptional changes in 41 TFs whose motifs were overrepresented in DARs.

These TFs included several previously linked to PRLR signaling within β-cells, including Myc, Mafb and Esr1. Importantly, we also identified several TFs not previously associated with PRLR signaling, which included OVOL2 which is often associated with epigenetic regulation. OVOL2 is a transcription factor involved in EMT inhibition and energy homeostasis with unknown roles in β-cell functions.

Here, we establish that OVOL2 acts as a negative regulator of PRL-dependent effects on glucose stimulated insulin secretion and β-cell proliferation, establishing a novel regulatory pathway for PRLR signaling.