Rare genetic variation at transcription factor binding sites modulates local DNA methylation profiles
Autoři:
Alejandro Martin-Trujillo aff001; Nihir Patel aff001; Felix Richter aff001; Bharati Jadhav aff001; Paras Garg aff001; Sarah U. Morton aff002; David M. McKean aff003; Steven R. DePalma aff004; Elizabeth Goldmuntz aff006; Dorota Gruber aff008; Richard Kim aff009; Jane W. Newburger aff010; George A. Porter, Jr. aff012; Alessandro Giardini aff013; Daniel Bernstein aff014; Martin Tristani-Firouzi aff015; Jonathan G. Seidman aff004; Christine E. Seidman aff003; Wendy K. Chung aff016; Bruce D. Gelb aff001; Andrew J. Sharp aff001
Působiště autorů:
The Mindich Child Health and Development Institute and Department of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
aff001; Department of Newborn Medicine, Boston Children’s Hospital, Boston, Massachusetts, United States of America
aff002; Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, United States of America
aff003; Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States of America
aff004; Howard Hughes Medical Institute, Harvard University, Boston, Massachusetts, United States of America
aff005; Division of Cardiology, Children’s Hospital of Philadelphia, Philadelphia, PA, United States of America
aff006; Department of Pediatrics, University of Pennsylvania Perlman School of Medicine, Philadelphia, PA, United States of America
aff007; Department of Pediatrics, Cohen Children’s Medical Center, Northwell Health, New Hyde Park, NY, Unites States of America
aff008; Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America
aff009; Department of Cardiology, Boston Children's Hospital, Boston, Massachusetts, United States of America
aff010; Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, United States of America
aff011; Department of Pediatrics, University of Rochester Medical Center, Rochester, NY, United States of America
aff012; Cardiothoracic Unit, Great Ormond Street Hospital, London, England
aff013; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, United States of America
aff014; Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, United States of America
aff015; Departments of Pediatrics and Medicine, Columbia University, New York, NY, United States of America
aff016; Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, United States of America
aff017; Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
aff018
Vyšlo v časopise:
Rare genetic variation at transcription factor binding sites modulates local DNA methylation profiles. PLoS Genet 16(11): e1009189. doi:10.1371/journal.pgen.1009189
Kategorie:
Research Article
doi:
https://doi.org/10.1371/journal.pgen.1009189
Souhrn
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.
Klíčová slova:
DNA methylation – Gene disruption – Gene expression – Genetic polymorphism – Genetics – Genomics – Methylation – Sequence motif analysis
Zdroje
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