Methylation quantitative trait locus analysis of chronic postsurgical pain uncovers epigenetic mediators of genetic risk

Background: Overlap of pathways enriched by single nucleotide polymorphisms and DNA-methylation underlying chronic postsurgical pain (CPSP), prompted pilot study of CPSP-associated methylation quantitative trait loci (meQTL). Materials & methods: Children undergoing spine-fusion were recruited prospectively. Logistic-regression for genome- and epigenome-wide CPSP association and DNA-methylation-single nucleotide polymorphism association/mediation analyses to identify meQTLs were followed by functional genomics analyses. Results: CPSP (n = 20/58) and non-CPSP groups differed in pain-measures. Of 2753 meQTLs, DNA-methylation at 127 cytosine–guanine dinucleotides mediated association of 470 meQTLs with CPSP (p < 0.05). At PARK16 locus, CPSP risk meQTLs were associated with decreased DNA-methylation at RAB7L1 and increased DNA-methylation at PM20D1. Corresponding RAB7L1/PM20D1 blood eQTLs (GTEx) and cytosine–guanine dinucleotide-loci enrichment for histone marks, transcription factor binding sites and ATAC-seq peaks suggest altered transcription factor-binding. Conclusion: CPSP-associated meQTLs indicate epigenetic mechanisms mediate genetic risk. Clinical trial registration: NCT01839461 , NCT01731873 (ClinicalTrials.gov).

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DNA methylation changes are a late event in acute promyelocytic leukemia and coincide with loss of transcription factor binding

Blood ◽

10.1182/blood-2012-08-448860 ◽

2013 ◽

Vol 121 (1) ◽

pp. 178-187 ◽

Cited By ~ 48

Author(s):

Till Schoofs ◽

Christian Rohde ◽

Katja Hebestreit ◽

Hans-Ulrich Klein ◽

Stefanie Göllner ◽

...

Keyword(s):

Dna Methylation ◽

Transcription Factor ◽

Retinoic Acid ◽

Acute Promyelocytic Leukemia ◽

Binding Sites ◽

Embryonic Stem ◽

Transcription Factor Binding ◽

Promyelocytic Leukemia ◽

Factor Binding ◽

Aberrant Dna Methylation

Abstract The origin of aberrant DNA methylation in cancer remains largely unknown. In the present study, we elucidated the DNA methylome in primary acute promyelocytic leukemia (APL) and the role of promyelocytic leukemia–retinoic acid receptor α (PML-RARα) in establishing these patterns. Cells from APL patients showed increased genome-wide DNA methylation with higher variability than healthy CD34+ cells, promyelocytes, and remission BM cells. A core set of differentially methylated regions in APL was identified. Age at diagnosis, Sanz score, and Flt3-mutation status characterized methylation subtypes. Transcription factor–binding sites (eg, the c-myc–binding sites) were associated with low methylation. However, SUZ12- and REST-binding sites identified in embryonic stem cells were preferentially DNA hypermethylated in APL cells. Unexpectedly, PML-RARα–binding sites were also protected from aberrant DNA methylation in APL cells. Consistent with this, myeloid cells from preleukemic PML-RARα knock-in mice did not show altered DNA methylation and the expression of PML-RARα in hematopoietic progenitor cells prevented differentiation without affecting DNA methylation. Treatment of APL blasts with all-trans retinoic acid also did not result in immediate DNA methylation changes. The results of the present study suggest that aberrant DNA methylation is associated with leukemia phenotype but is not required for PML-RARα–mediated initiation of leukemogenesis.

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

10.1101/015966 ◽

2015 ◽

Cited By ~ 1

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.

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DNA methylation alone does not cause most cell-type selective transcription factor binding

Epigenetics & Chromatin ◽

10.1186/1756-8935-6-s1-p103 ◽

2013 ◽

Vol 6 (S1) ◽

Cited By ~ 3

Author(s):

Matthew T Maurano ◽

Hao Wang ◽

Anthony Shafer ◽

Sam John ◽

John A Stamatoyannopoulos

Keyword(s):

Dna Methylation ◽

Transcription Factor ◽

Transcription Factor Binding ◽

Cell Type ◽

Factor Binding

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Widespread effects of DNA methylation and intra-motif dependencies revealed by novel transcription factor binding models

10.1101/2020.10.21.348193 ◽

2020 ◽

Author(s):

Jan Grau ◽

Florian Schmidt ◽

Marcel H. Schulz

Keyword(s):

Dna Methylation ◽

Transcription Factor ◽

Large Scale ◽

Transcription Factor Binding ◽

Cpg Methylation ◽

Motif Analysis ◽

Factor Binding ◽

Large Scale Study ◽

Binding Models ◽

The Impact

AbstractSeveral studies suggested that transcription factor (TF) binding to DNA may be impaired or enhanced by DNA methylation. We present MeDeMo, a toolbox for TF motif analysis that combines information about DNA methylation with models capturing intra-motif dependencies. In a large-scale study using ChIP-seq data for 335 TFs, we identify novel TFs that are affected by DNA methylation. Overall, we find that CpG methylation decreases the likelihood of binding for the majority of TFs. For a considerable subset of TFs, we show that intra-motif dependencies are pivotal for accurately modelling the impact of DNA methylation on TF binding.

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Microglia from offspring of dams with allergic asthma exhibit epigenomic alterations in genes dysregulated in autism

10.1101/192997 ◽

2017 ◽

Cited By ~ 2

Author(s):

Annie Vogel Ciernia ◽

Milo Careaga ◽

Janine LaSalle ◽

Paul Ashwood

Keyword(s):

Dna Methylation ◽

Transcription Factor ◽

Allergic Asthma ◽

Transcription Factor Binding ◽

Autism Spectrum ◽

Differentially Expressed ◽

Differentially Methylated Regions ◽

Binding Motifs ◽

Factor Binding ◽

Transcription Factor Binding Motifs

AbstractDysregulation in immune responses during pregnancy increase the risk of a having a child with an autism spectrum disorder (ASD). Asthma is one of the most common chronic diseases among pregnant women, and symptoms often worsen during pregnancy. We recently developed a mouse model of maternal allergic asthma (MAA) that induces changes in sociability, repetitive and perseverative behaviors in the offspring. Since epigenetic changes help a static genome adapt to the maternal environment, activation of the immune system may epigenetically alter fetal microglia, the brain’s resident immune cells. We therefore tested the hypothesis that epigenomic alterations to microglia may be involved in behavioral abnormalities observed in MAA offspring. We used the genome-wide approaches of whole genome bisulfite sequencing to examine DNA methylation and RNA sequencing to examine gene expression in microglia from juvenile MAA offspring. Differentially methylated regions (DMRs) were enriched for immune signaling pathways and important microglial developmental transcription factor binding motifs. Differential expression analysis identified genes involved in controlling microglial sensitivity to the environment and shaping neuronal connections in the developing brain. Differentially expressed associated genes significantly overlapped genes with altered expression in human ASD cortex, supporting a role for microglia in the pathogenesis of ASD.Main Points:Maternal allergic asthma induces changes in DNA methylation and transcription in juvenile offspring microgliaDifferentially methylated regions are enriched for functions and transcription factor binding motifs involved in inflammation and microglial developmentDifferentially expressed genes and differentially methylated regions are enriched for genes dysregulated in Autism Spectrum Disorders

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

PLoS Genetics ◽

10.1371/journal.pgen.1009189 ◽

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.

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Predicting the effects of SNPs on transcription factor binding affinity

Bioinformatics ◽

10.1093/bioinformatics/btz612 ◽

2019 ◽

Author(s):

Sierra S Nishizaki ◽

Natalie Ng ◽

Shengcheng Dong ◽

Robert S Porter ◽

Cody Morterud ◽

...

Keyword(s):

Transcription Factor ◽

Binding Affinity ◽

Association Studies ◽

Transcription Factor Binding ◽

Supplementary Information ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Factor Binding ◽

Genome Wide

Abstract Motivation Genome-wide association studies have revealed that 88% of disease-associated single-nucleotide polymorphisms (SNPs) reside in noncoding regions. However, noncoding SNPs remain understudied, partly because they are challenging to prioritize for experimental validation. To address this deficiency, we developed the SNP effect matrix pipeline (SEMpl). Results SEMpl estimates transcription factor-binding affinity by observing differences in chromatin immunoprecipitation followed by deep sequencing signal intensity for SNPs within functional transcription factor-binding sites (TFBSs) genome-wide. By cataloging the effects of every possible mutation within the TFBS motif, SEMpl can predict the consequences of SNPs to transcription factor binding. This knowledge can be used to identify potential disease-causing regulatory loci. Availability and implementation SEMpl is available from https://github.com/Boyle-Lab/SEM_CPP. Supplementary information Supplementary data are available at Bioinformatics online.

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