High glucose alters the DNA methylation pattern of neurodevelopment associated genes in human neural progenitor cells in vitro

Maternal diabetes alters the global epigenetic mechanisms and expression of genes involved in neural tube development in mouse embryos. Since DNA methylation is a critical epigenetic mechanism that regulates gene functions, gene-specific DNA methylation alterations were estimated in human neural progenitor cells (hNPCs) exposed to high glucose (HG) in the present study. The DNA methylation pattern of genes involved in several signalling pathways including axon guidance (SLIT1-ROBO2 pathway), and Hippo pathway (YAP and TAZ) was altered in hNPCs exposed to HG. The expression levels of SLIT1-ROBO2 pathways genes (including its effectors, SRGAP1 and CDC42) which mediates diverse cellular processes such as proliferation, neurogenesis and axon guidance, and Hippo pathway genes (YAP and TAZ) which regulates proliferation, stemness, differentiation and organ size were downregulated in hNPCs exposed to HG. A recent report suggests a possible cross-talk between SLIT1-ROBO2 and TAZ via CDC42, a mediator of actin dynamics. Consistent with this, SLIT1 knockdown downregulated the expression of its effectors and TAZ in hNPCs, suggesting that HG perturbs the cross-talk between SLIT1-ROBO2 and TAZ in hNPCs. Overall, this study demonstrates that HG epigenetically alters the SLIT1-ROBO2 and Hippo signalling pathways in hNPCs, forming the basis for neurodevelopmental disorders in offspring of diabetic pregnancy.