scholarly journals The interplay between DNA methylation and sequence divergence in recent human evolution

2015 ◽  
Author(s):  
Irene Hernando-Herraez ◽  
Holger Heyn ◽  
Marcos Fernandez-Callejo ◽  
Enrique Vidal ◽  
Hugo Fernandez-Bellon ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Transcription Factor ◽  
Binding Sites ◽  
Incomplete Lineage Sorting ◽  
Epigenetic Modification ◽  
Transcription Factor Binding Sites ◽  
Transcription Factor Binding ◽  
Factor Binding ◽  
Methylation Patterns ◽  
Human Specific

DNA methylation is a key regulatory mechanism in mammalian genomes. Despite the increasing knowledge about this epigenetic modification, the understanding of human epigenome evolution is in its infancy. We used whole genome bisulfite sequencing to study DNA methylation and nucleotide divergence between human and great apes. We identified 360 and 210 differentially hypo- and hypermethylated regions (DMRs) in humans compared to non-human primates and estimated that 20% and 36% of these regions, respectively, were detectable throughout several human tissues. Human DMRs were enriched for specific histone modifications and contrary to expectations, the majority were located distal to transcription start sites, highlighting the importance of regions outside the direct regulatory context. We also found a significant excess of endogenous retrovirus elements in human-specific hypomethylated regions suggesting their association with local epigenetic changes. We also reported for the first time a close interplay between inter-species genetic and epigenetic variation in regions of incomplete lineage sorting, transcription factor binding sites and human differentially hypermethylated regions. Specifically, we observed an excess of human-specific substitutions in transcription factor binding sites located within human DMRs, suggesting that alteration of regulatory motifs underlies some human-specific methylation patterns. We also found that the acquisition of DNA hypermethylation in the human lineage is frequently coupled with a rapid evolution at nucleotide level in the neighborhood of these CpG sites. Taken together, our results reveal new insights into the mechanistic basis of human-specific DNA methylation patterns and the interpretation of inter-species non-coding variation.

scholarly journals Rare genetic variation at transcription factor binding sites modulates local DNA methylation profiles

PLoS Genetics ◽  
2020 ◽  
Vol 16 (11) ◽  
pp. e1009189
Author(s):  
Alejandro Martin-Trujillo ◽  
Nihir Patel ◽  
Felix Richter ◽  
Bharati Jadhav ◽  
Paras Garg ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Transcription Factor ◽  
Genetic Variation ◽  
Dna Binding ◽  
Binding Sites ◽  
Transcription Factor Binding Sites ◽  
Transcription Factor Binding ◽  
Ctcf Binding ◽  
Factor Binding ◽  
Rare Genetic Variation

Although DNA methylation is the best characterized epigenetic mark, the mechanism by which it is targeted to specific regions in the genome remains unclear. Recent studies have revealed that local DNA methylation profiles might be dictated by cis-regulatory DNA sequences that mainly operate via DNA-binding factors. Consistent with this finding, we have recently shown that disruption of CTCF-binding sites by rare single nucleotide variants (SNVs) can underlie cis-linked DNA methylation changes in patients with congenital anomalies. These data raise the hypothesis that rare genetic variation at transcription factor binding sites (TFBSs) might contribute to local DNA methylation patterning. In this work, by combining blood genome-wide DNA methylation profiles, whole genome sequencing-derived SNVs from 247 unrelated individuals along with 133 predicted TFBS motifs derived from ENCODE ChIP-Seq data, we observed an association between the disruption of binding sites for multiple TFs by rare SNVs and extreme DNA methylation values at both local and, to a lesser extent, distant CpGs. While the majority of these changes affected only single CpGs, 24% were associated with multiple outlier CpGs within ±1kb of the disrupted TFBS. Interestingly, disruption of functionally constrained sites within TF motifs lead to larger DNA methylation changes at nearby CpG sites. Altogether, these findings suggest that rare SNVs at TFBS negatively influence TF-DNA binding, which can lead to an altered local DNA methylation profile. Furthermore, subsequent integration of DNA methylation and RNA-Seq profiles from cardiac tissues enabled us to observe an association between rare SNV-directed DNA methylation and outlier expression of nearby genes. In conclusion, our findings not only provide insights into the effect of rare genetic variation at TFBS on shaping local DNA methylation and its consequences on genome regulation, but also provide a rationale to incorporate DNA methylation data to interpret the functional role of rare variants.

scholarly journals SEMplMe: A tool for integrating DNA methylation effects in transcription factor binding affinity predictions

2020 ◽  
Author(s):  
Sierra S. Nishizaki ◽  
Alan P. Boyle
Keyword(s):  
Dna Methylation ◽  
Transcription Factor ◽  
Binding Sites ◽  
Human Disease ◽  
Transcription Factor Binding Sites ◽  
Transcription Factor Binding ◽  
Binding Motif ◽  
Factor Binding ◽  
Genome Bisulfite Sequencing ◽  
Aberrant Dna Methylation

AbstractMotivationAberrant DNA methylation in transcription factor binding sites has been shown to lead to anomalous gene regulation that is strongly associated with human disease. However, the majority of methylation-sensitive positions within transcription factor binding sites remain unknown. Here we introduce SEMplMe, a computational tool to generate predictions of the effect of methylation on transcription factor binding strength in every position within a transcription factor’s motif.ResultsSEMplMe uses ChIP-seq and whole genome bisulfite sequencing to predict effects of methylation within binding sites. SEMplMe validates known methylation sensitive and insensitive positions within a binding motif, identifies cell type specific transcription factor binding driven by methylation, and outperforms SELEX-based predictions. These predictions can be used to identify aberrant sites of DNA methylation contributing to human disease.Availability and ImplementationSEMplMe is available from https://github.com/Boyle-Lab/[email protected]

scholarly journals High Levels of Sequence Diversity in the 5′ UTRs of Human-Specific L1 Elements

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Jungnam Lee ◽  
Seyoung Mun ◽  
Thomas J. Meyer ◽  
Kyudong Han
Keyword(s):  
Transcription Factor ◽  
Human Genome ◽  
Binding Sites ◽  
Transcription Factor Binding Sites ◽  
Transcription Factor Binding ◽  
Sequence Diversity ◽  
Nucleotide Position ◽  
Factor Binding ◽  
High Level ◽  
Human Specific

Approximately 80 long interspersed element (LINE-1 or L1) copies are able to retrotranspose actively in the human genome, and these are termed retrotransposition-competent L1s. The 5′ untranslated region (UTR) of the human-specific L1 contains an internal promoter and several transcription factor binding sites. To better understand the effect of the L1 5′ UTR on the evolution of human-specific L1s, we examined this population of elements, focusing on the sequence diversity and accumulated substitutions within their 5′ UTRs. Using network analysis, we estimated the age of each L1 component (the 5′ UTR, ORF1, ORF2, and 3′ UTR). Through the comparison of the L1 components based on their estimated ages, we found that the 5′ UTR of human-specific L1s accumulates mutations at a faster rate than the other components. To further investigate the L1 5′ UTR, we examined the substitution frequency per nucleotide position among them. The results showed that the L1 5′ UTRs shared relatively conserved transcription factor binding sites, despite their high sequence diversity. Thus, we suggest that the high level of sequence diversity in the 5′ UTRs could be one of the factors controlling the number of retrotransposition-competent L1s in the human genome during the evolutionary battle between L1s and their host genomes.

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