Abstract
High coverage sequences of archaic humans enabled the reconstruction of their DNA methylation patterns. This allowed comparing gene regulation between human groups, and linking such regulatory changes to phenotypic differences. In a previous work, a detailed comparison of DNA methylation in modern humans, archaic humans, and chimpanzees revealed 873 modern human-derived differentially methylated regions (DMRs). To understand the regulatory implications of these DMRs, we defined differentially methylated genes (DMGs) as genes that harbor DMRs in their promoter or gene body. While most of the modern human-derived DMRs could be linked to DMGs, many others remained unassigned. Here, we used information on 3D genome organization to link ~70 out of the remaining 288 unassigned DMRs to genes. Combined with the previously identified DMGs, we reinforce the enrichment of these genes with vocal and facial anatomy, and additionally find significant enrichment with the spinal column, chin, hair, and scalp. These results reveal the importance of 3D genomic organization in understanding gene regulation by DNA methylation.
Highlights
DNA methylation of cytosine residues is a key epigenetic mechanism in mammals [1]
We further show that these differentially methylated genes (DMGs) strengthen the association of methylation changes with the anatomy of the voice and face, and highlight additional body parts which are significantly enriched with DMGs, including the chin and spinal column
topologically associating domains (TADs) are highly conserved both between different cell types as well as between different species: of the 3331 domains annotated in mouse CH12-LX cells, 1649 (50%) are orthologous to domains in the human lymphoblastoid cells GM12878 [6]
Summary
DNA methylation of cytosine residues is a key epigenetic mechanism in mammals [1]. Almost all scattered cytosines within CpG dinucleotides are methylated in human cells. Regions known as CpG islands, which contain relatively dense clusters of CpGs are often protected from DNA methylation. CpG islands are mostly found in promoter regions of many house-keeping and other highly expressed genes. A genome-wide survey of DNA methylation of enhancers in healthy and cancerous cell types revealed a strong association between enhancer methylation and suppression of expression of the corresponding gene [2]. In addition to its fundamental role in regulating gene expression, DNA methylation regulates imprinting and the silencing of transposable elements and other repetitive and low-complexity regions of the genome. Aberrant DNA methylation is associated with diseases including many types
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