During decidualization in rodents, uterine stroma undergoes extensive reprograming into distinct cells, forming the discrete regions defined as the primary decidual zone (PDZ), the secondary decidual zone (SDZ) and the layer of undifferentiated stromal cells respectively. Here we show that uterine deletion of Men1, a member of the histone H3K4 methyltransferase complex, disrupts the terminal differentiation of stroma, resulting in chaotic decidualization and pregnancy failure. Genome-wide epigenetic profile reveals that Men1 binding in chromatin recapitulates H3K4me3 distribution. Further transcriptomic investigation demonstrates that Men1 directly regulates the expression of PTX3, an extra-cellular trap for FGF2 in decidual cells. Decreased Ptx3 upon Men1 ablation leads to aberrant activation of ERK1/2 in the SDZ due to the unrestrained FGF2 signal emanated from undifferentiated stromal cells, which blunt BMP2 induction and decidualization. In brief, our study provides genetic and molecular mechanisms for epigenetic rewiring mediated decidual regionalization by Men1 and sheds new light on pregnancy maintenance.

Pax4 and MafA (v-maf musculoaponeurotic fibrosarcoma oncogene homolog A) are two transcription factors crucial for normal functions of islet beta cells in the mouse. Intriguingly, recent studies indicate the existence of notable difference between human and rodent islet in terms of gene expression and functions. To better understand the biological role of human PAX4 and MAFA, we investigated their expression in normal and diseased human islets, using validated antibodies. PAX4 was detected in 43.0±5.0% and 39.1±4.0% of normal human alpha and beta cells respectively. We found that MAFA, detected in 88.3±6.3% insulin⁺cells as in the mouse, turned out to be also expressed in 61.2±6.4% of human glucagons⁺ cells with less intensity than in insulin⁺ cells, whereas MAFB expression was found not only in the majority of glucagon⁺ cells (67.2±7.6%), but also in 53.6±10.5% of human insulin⁺ cells. Interestingly, MAFA nuclear expression in both alpha and beta cells, and the percentage of alpha cells expressing PAX4 were found altered in a substantial proportion of patients with type 2 diabetes. Both MAFA and PAX4 display, therefore, a distinct expression pattern in human islet cells, suggesting more potential plasticity of human islets as compared with rodent islets.

The cells of origin of pancreatic gastrinomas remain an enigma, since no gastrin-expressing cells are found in normal adult pancreas. It was proposed that the cellular origin of pancreatic gastrinoma may come from either the pancreatic cells themselves or gastrin-expressing cells which have migrated from the duodenum. In the current study, we further characterised previously described transient pancreatic gastrin-expressing cells using cell lineage-tracing in a pan-pancreatic progenitor and a pancreatic endocrine progenitor model. We provide evidence showing that pancreatic gastrin-expressing cells, found from E12.5 until P7, are derived from pancreatic Ptf1a⁺- and Ngn3⁺-progenitors. Importantly, the majority of them co-express glucagon, with 4% co-expressing insulin, indicating that they are a temporary subpopulation of both alpha and beta cells. Interestingly, Men1-disruption in both Ngn3-progenitors, and beta and alpha cells resulted in the development of pancreatic gastrin-expressing tumours, suggesting that the latter developed from islet cells. Finally, we detected gastrin expression using three human cohorts of pancreatic endocrine tumours (pNETs) that have not been diagnosed as gastrinomas, in 9/34 MEN1 pNETs from 6/14 MEN1 patients, in 5/35 sporadic non-functioning pNETs and in 2/20 sporadic insulinomas, consistent with observations made in mouse models. Our work provides insight into histogenesis of pancreatic gastrin-expressing tumours.

Foxa2, known as one of the pioneer factors, plays a crucial role in islet development and endocrine functions. Its expression and biological functions are regulated by various factors, including, in particular, insulin and glucagon. However, its expression and biological role in adult pancreatic α‐cells remain elusive. In the current study, we showed that Foxa2 was overexpressed in islets from α‐cell‐specific Men1 mutant mice, at both the transcriptional level and the protein level. More importantly, immunostaining analyses showed its prominent nuclear accumulation, specifically in α‐cells, at a very early stage after Men1 disruption. Similar nuclear FOXA2 expression was also detected in a substantial proportion (12/19) of human multiple endocrine neoplasia type 1 (MEN1) glucagonomas. Interestingly, our data revealed an interaction between Foxa2 and menin encoded by the Men1 gene. Furthermore, using several approaches, we demonstrated the relevance of this interaction in the regulation of two tested Foxa2 target genes, including the autoregulation of the Foxa2 promoter by Foxa2 itself. The current study establishes menin, a novel protein partner of Foxa2, as a regulator of Foxa2, the biological functions of which extend beyond the pancreatic endocrine cells. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.