Biology subjects

Banerjee, R. R.

Publications and source records attributed to Banerjee, R. R..

3 recordsLinked to original sources

bioRxiv2026

Single-cell ATAC-seq Reveals OVOL2 as a Downstream Negative Regulator of PRL-Mediated Chromatin Accessibility

Maternal pancreatic {beta}-cells undergo functional and structural changes to adapt to increased metabolic demands during pregnancy. Lactogen signaling via the prolactin receptor (PRLR) contributes to these adaptations by increasing {beta}-cell mass, insulin transcription and glucose-stimulated insulin secretion[1-4]. In other lactogen-responsive tissues such as the mammary glands and specific hypothalamic nuclei, gestation induces epigenetic changes, some of which persist long after birth[5, 6]. We have previously found that prolactin treatment in islets regulates the expression of epigenetic modifiers[7, 8]. However, whether lactogen signaling in {beta}-cells mediates epigenetic changes to regulate chromatin accessibility has not been examined. Therefore, our objective was to determine whether PRLR signaling alters chromatin accessibility of {beta}-cells to facilitate transcriptional regulation. Using single-cell ATAC-sequencing, we identified differentially accessible regions (DARs) in {beta}-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, including several previously linked to PRLR signaling within {beta}-cells, including Myc, Mafb and Esr1. Importantly, we also identified TFs not previously associated with PRLR signaling, including OVOL2 an established regulator of epigenetic landscape within cells. OVOL2 is a transcription factor involved in EMT inhibition and energy homeostasis with unknown roles in pancreatic {beta}-cells. Here, we establish that OVOL2 acts as a negative regulator of lactogen-dependent effects on {beta}-cell proliferation, establishing a novel regulator of PRLR signaling.

cell biology↗

bioRxiv2025

c-Jun regulates postpartum β-cell apoptosis and survival downstream of prolactin signaling

ObjectivePregnancy and postpartum states drive dynamic expansion and regression of maternal {beta}-cell mass. Little is known about what regulates postpartum regression. We recently profiled murine islets at different time points from late gestation to early postpartum to identify regulators of {beta}-cell apoptosis or survival. One hit was c-Jun, a transcription factor which regulates proliferation, apoptosis, and survival in various tissues and cells. Here, we examine c-Jun regulation and function during gestation and postpartum and in murine and human islets. MethodsTo examine regulation of c-Jun within {beta}-cells we used a mouse genetic model lacking {beta}-cell prolactin receptor (PRLR) and stimulation of cultured islets with recombinant prolactin. We used chemical inhibitors of signal transduction pathways to examine signaling downstream of PRLR. TUNEL was used to detect endogenous or dexamethasone-induced apoptosis. Q-PCR, Western blotting, and immunostaining were used to assess gene and protein expression. Knockdown of c-Jun in MIN6 cells was accomplished using siRNA and lentiviral-shRNA. We examined both murine and human islets and tissues. ResultsWe found that expression of c-Jun transcript in murine {beta}-cells is temporally restricted to late gestation and early postpartum and requires prolactin signaling. Moreover, c-Jun protein expression was mutually exclusive with apoptotic {beta}-cells identified by TUNEL staining. In both murine and human islets, prolactin treatment is sufficient to induce c-Jun expression and downstream MAPK/ERK signaling. Pharmacologic inhibition of c-Jun blocks prolactin-mediated survival of {beta}-cells following pro-apoptotic stress, including failure to upregulate pro-survival factors Bcl2l1 (Bcl-xL) and Birc5 (Survivin). Finally, human islets during pregnancy also exhibit increased c-Jun expression in {beta}-cells, but c-Jun induction is absent in {beta}-cells from pregnant donors with gestational diabetes (GDM). Conclusionsc-Jun contributes to pro-survival effects of lactogens downstream of PRLR / MAPK signaling in {beta}-cells. c-Jun regulation is conserved in human islets and pregnancy and dysregulated in GDM.

cell biology↗

bioRxiv2018

Prolactin Receptor Signaling Regulates a Pregnancy-Specific Transcriptional Program in Mouse Islets

Pancreatic {beta}-cells undergo profound hyperplasia during pregnancy to maintain maternal euglycemia. Failure to reprogram {beta}-cells into a more replicative state has been found to underlie susceptibility to gestational diabetes mellitus (GDM). We recently identified a requirement for prolactin receptor (PRLR) signaling in the metabolic adaptations to pregnancy, where mice lacking {beta}-cell PRLR ({beta}PRLRKO) exhibit a metabolic phenotype consistent with GDM. However, the underlying transcriptional program that is responsible for the PRLR-dependent metabolic adaptations during gestation remains incompletely understood. To identify PRLR signaling gene regulatory networks and target genes within {beta}-cells during pregnancy, we performed a transcriptomic analysis of pancreatic islets isolated from either {beta}PRLRKO mice or littermate controls in late gestation. Gene set enrichment analysis identified Forkhead box protein M1 (Foxm1) and polycomb repressor complex 2 (PRC2) subunits, Suz12 and Ezh2, as novel candidate regulators of PRLR-dependent {beta}-cell adaptation. GO-term pathway enrichment revealed both established and novel PRLR signaling target genes that together describe a state of increased cellular metabolism and/or proliferation. In contrast to the requirement for {beta}-cell PRLR signaling in maintaining euglycemia during pregnancy, PRLR target genes were not induced following high-fat-diet feeding. Altogether, the current study expands our understanding of which transcriptional regulators and networks mediate gene expression required for islet adaptation during pregnancy. The current work also supports the presence of pregnancy-specific adaptive mechanisms distinct from those activated by nutritional stress.

bioinformatics↗