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

Abstract

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.

Diabetes, Oxidative Stress, and DNA Damage Modulate Cranial Neural Crest Cell Development and the Phenotype Variability of Craniofacial Disorders

“…Alteration of miRNA activity can impair autophagy and lead to neural tube defects such as exencephaly ( Xu et al, 2013 ; Wang et al, 2017 ). The same phenomena were also observed in human neural progenitor cells in which high glucose modifies the DNA methylation pattern of neurodevelopment-associated genes, hence affecting their activity ( Kandilya et al, 2020 ). These findings suggest that hyperglycemia can interact with genetic loci by influencing the activities of histone-modifying and DNA methyltransferase enzymes.…”

Maternal diabetes-mediated RORA suppression in mice contributes to autism-like offspring through inhibition of aromatase

“…Also, many others have reported that the in vitro neural cell culture requires glucose concentrations >15 mM, which are much higher than normal physiological levels 31 , 32 . We thus chose 5 mM glucose as the low glucose condition, similar to that used by other researchers 33 , 34 , and chose 25 mM as the HG treatment 22 . We agree that our in vitro study has potential limitations by using glucose levels that are higher than reported physiological brain levels, but this does not invalidate our findings.…”

Excess Glucose Impedes the Proliferation of Skeletal Muscle Satellite Cells Under Adherent Culture Conditions

“…Enhancements of myogenic factor expressions imply that the specificities of the cultured satellite cells were increased by lowering glucose concentration. High glucose potentially alters the DNA methylation status of several important genes which could regulate the cell proliferation and stemness of neural progenitor cells ( Kandilya et al, 2020 ). Also, the other report suggested that glucose is required for histone acetylation in proliferating satellite cells and the determination of myogenic differentiation potential ( Yucel et al, 2019 ).…”