Different Epigenetic Alterations Are Associated with Abnormal IGF2/Igf2 Upregulation in Neural Tube Defects

Abstract

The methylation status of DNA methylation regions (DMRs) of the imprinted gene IGF2/Igf2 is associated with neural tube defects (NTDs), which are caused by a failure of the neural tube to fold and close and are the second-most common birth defect; however, the characterization of the expression level of IGF2/Igf2 in neural tissue from human fetuses affected with NTDs remains elusive. More importantly, whether abnormal chromatin structure also influences IGF2/Igf2 expression in NTDs is unclear. Here, we investigated the transcriptional activity of IGF2/Igf2 in normal and NTD spinal cord tissues, the methylation status of different DMRs, and the chromatin structure of the promoter. Our data indicated that in NTD samples from both human fetuses and retinoic acid (RA)-treated mouse fetuses, the expression level of IGF2/Igf2 was upregulated 6.41-fold and 1.84-fold, respectively, compared to controls. H19 DMR1, but not IGF2 DMR0, was hypermethylated in human NTD samples. In NTD mice, h19 DMR1 was stable, whereas the chromatin structure around the promoter of Igf2 might be loosened, which was displayed by higher H3K4 acetylation and lower H3K27 trimethylation. Therefore, the data revealed that IGF2/Igf2 expression can be ectopically up-regulated by dual epigenetic factors in NTDs. In detail, the upregulation of IGF2/Igf2 is likely controlled by hypermethylation of H19 DMR1 in human NTDs, however, in acute external RA-induced NTD mice it is potentially determined by more open chromatin structure.

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“…H19 has been reported to play a regulatory role in promoting glioma cell invasion by inducing miR-675 expression [16] and promoting angiogenesis, stemness, and drug resistance of glioblastomas [17,18]. In addition, H19 is associated with neural tube defects [19]. PRKCQ-AS1 has been reported to be involved in oligodendrocyte differentiation and CNS myelination [20].…”

Deletion of BAF250a affects oocyte epigenetic modifications and embryonic development

“…Neural tube defect was reported in correlation with gene imprinting (Bai et al, 2014; Wang et al, 2017; Wu et al, 2013). Supplemental intake of formate during pregnancy was suggested as a method of preventing some neural tube defects owing to its function as methyl donor (Caffrey, McNulty, Irwin, Walsh, & Pentieva, 2018; Rochtus, Jansen, Van Geet, & Freson, 2015).…”

Differentiation and localization of interneurons in the developing spinal cord depends on DOT1L expression

“…Both genetic and epigenetic factors have been studied to identify the etiology of NTDs, especially since folate deficiency has been indicated as a cofactor of NTD occurrence (34). Recent studies suggested that histone modifications such as acetylation or methylation correlated with the occurrence of NTD in mouse or chick embryos (35)(36)(37)(38)(39). Further, chromatin modifications have been linked to defective neurogenesis and patterning of the embryonic spinal cord (40-42).…”