Effect of signaling pathways on histone modifiers during differentiation of human pluripotent stem cells into pancreatic lineage

Abstract

Human embryonic stem cells (hESCs) are pluripotent cells that have the capacity for self-renewal newlineand have the innate potential to differentiate into specialized cell types. Clinical trials of the hESCderived newlineinsulin producing pancreatic cells are ongoing, however several aspects of the newlinedifferentiation remain a mystery. newlineGeneration of pancreatic progenitors from hESCs involves signaling pathways, transcription newlinefactors, and epigenetic modifiers. FGF, TGF-and#946;, BMP retinoic acid, WNT, Notch, and sonic newlinehedgehog signaling pathways from surrounding tissues regulate pancreas development. Pancreas newlinespecification and the maintenance of mature cell subtypes is regulated by chromatin regulators that newlinemediate such as DNA methylation, nucleosome remodeling, and histone modifications. Histone newlinemodifiers including histone acetyltransferases and deacetylases, histone methyltransferases and newlinedemethylases wherein histone methyltransferases such as the Trithorax group (TrxG) and Polycomb newlinegroup (PcG) play crucial roles in pancreas development. PcG proteins repress gene transcription newlinethrough histone modifications. PcG proteins come together in different combinations to generate newlinelarge multimeric complexes called the Polycomb Repressive Complexes (PRCs), of which PRC1 newlineand PRC2 are the most well characterized. newlinePRC1 catalyzes monoubiquitylation of lysine residue 119 on histone H2A (H2AK119ub1) while newlinePRC2 mediates di- and tri-methylation of lysine 27 on histone H3 (H3K27me2/3). PRC1 core newlinecomprises of E3 ubiquitin ligase RING1A/B subunit along with one of the six PCGF proteins. The newlinecanonical form of PRC1 interacts with PCGF2 or PCGF4 (also known as BMI1). In recent years, a newlinenumber of studies have focused on the roles of PRC2 and its repressive H3K27me3 marks during newlinepancreatic specification, progenitor proliferation and maturation of endocrine cell types. The roles newlineand regulation of PRC1 components during early pancreatic differentiation and specification in humans is not known.