Anne, A. | Search bioRxiv

bioRxiv2026

A new set of DNA methylation variants in the human genome show predominant tissue specificity and sensitivity to reprogramming with a potential for disease susceptibility.

Analyses of 3,370 normal human tissues of ectodermal, endodermal and mesodermal origins identified 12,587 regions averaging [~]585 bp with significant differences in DNA methylation levels within identical tissues. These methylation variants (MeVars) occurred in 8,037 genes enriched in neurological disorders and cancers of which, majority were tissue-specific rather than being systemic. This somatic variation was reduced by reprogramming in vitro into iPSCs and in vivo during spermatogenesis. Analysis of prefrontal cortices showed a higher incidence of MeVars in the candidate genes in controls than schizophrenia patients wherein a subset showed significantly altered transcript levels. Similar effects were observed for oral tissues and skin fibroblast cells. MeVars showed significant association with SINE1, simple and low complexity repeats, H3K27me3, H3k9me3 and H3K4me1 modifications and EZH2, SUZ12 and REST binding sites. Collectively, MeVars have postzygotic origins with an ability to reset during reprogramming, adding a new dimension in the form of epigenetic diversity and its relevance to disease susceptibility in humans.

bioinformatics↗

bioRxiv2024

Human promoter CpG islands contain primate-specific repeats, cluster and resist reprogramming

A subset of imprinting control regions (ICRs) in the human and mouse possess CpG islands associated with imperfect tandem repeats (TRs) that were shown to be essential for genomic imprinting through genetic studies. To identify whether this feature is also present in non-imprinted CpG island promoters, we performed extensive dot plot analyses and identified 365 CpG island gene promoters associated with imperfect TRs of [≥] 400nt. These TRs are absent in the orthologous mouse CGI promoters, and most occur as clusters at the human chromosome ends, distinct from the clusters of imprinted genes. These genes showed an enrichment in neurodevelopmental/behavioral disorders and show interindividual variation in methylation levels. A subset of TR-CGIs is highly methylated and remains so during reprogramming to primed iPSCs, but become unmethylated in naive iPSCs, as has been shown for the ICRs. Transcript levels correlate with methylation levels for some TR-CGI genes suggesting their gene regulatory potential. Orthologs of the subset of methylated TR-CGIs are unmethylated in mouse, suggesting the role of TRs in imparting methylation in humans. The human TR-CGIs accompanied primate evolution after divergence from the rodent lineage with evidence of recent additions in human evolution. In summary, the incorporation of TRs in certain CGI promoters in primate evolution results in the unique ability to acquire methylation during embryonic development and resist reprogramming to a pluripotent stem cell state with a possible effect on gene expression.

developmental biology↗