Biology subjects

Vinckier, N.

Publications and source records attributed to Vinckier, N..

2 recordsLinked to original sources

bioRxiv2019

A network of microRNAs acts to promote cell cycle exit and differentiation of human pancreatic endocrine cells

Pancreatic endocrine cell differentiation is orchestrated by transcription factors that operate in a gene regulatory network to activate endocrine lineage genes and repress lineage-inappropriate genes. MicroRNAs (miRNAs) are important modulators of gene expression, yet their role in endocrine cell differentiation has not been explored system-wide. Here we characterize miRNA-regulatory networks active in human endocrine cell differentiation by combining small RNA sequencing, miRNA overexpression experiments, and network modeling approaches. This analysis identifies Let-7g, Let-7a, miR-200a, and miR-375 as endocrine-enriched miRNAs with high impact on driving endocrine differentiation-associated gene expression changes. These miRNAs target different sets of transcription factors, which converge on a network of genes involved in cell cycle regulation. When expressed in human embryonic stem cell-derived pancreatic progenitors these miRNAs induce cell cycle exit and promote endocrine cell differentiation. Our study delineates the role of miRNAs in human endocrine cell differentiation and identifies miRNAs that could facilitate endocrine cell reprogramming.

developmental biology↗

bioRxiv2018

Pancreatic islet chromatin accessibility and conformation defines distal enhancer networks of type 2 diabetes risk

The gene targets of enhancer activity in pancreatic islets are largely unknown, impeding discovery of islet regulatory networks involved in type 2 diabetes (T2D) risk. We mapped chromatin state, accessibility and conformation using ChIP-seq, ATAC-seq and Hi-C in human pancreatic islets, which we integrated with T2D genetic fine-mapping and islet expression QTL data. Active islet regulatory elements preferentially interacted with other active elements, often at distances over 1MB, and we identified target genes for thousands of distal islet enhancers. A third of T2D risk signals mapped in islet enhancers, and target genes regulated by these signals were specifically involved in processes related to protein transport and secretion. Among implicated target genes of T2D islet enhancer signals with no prior known role in islet function, we demonstrated that reduced IGF2BP2 activity in mouse islets leads to impaired glucose-stimulated insulin secretion. These results link distal islet enhancer regulation of protein secretion and transport to genetic risk of T2D, and highlight the utility of high-throughput chromatin conformation maps to uncover the gene regulatory networks of complex disease.

genomics↗