MethMotif: an integrative cell specific database of transcription factor binding motifs coupled with DNA methylation profiles

Lin, Quy Xiao Xuan; Sian, Stephanie; An, Ömer; Thieffry, Denis; Jha, Sudhakar; Benoukraf, Touati

doi:10.1093/nar/gky1005

Cited by 57 publications

(39 citation statements)

References 47 publications

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“…The matched included previously confirmed factors to influence methylation levels such as CTCF (2) and PAX5 (50) as well as factors KLF4, SP4 and EGR1 that have been reported to regulate gene expression by binding to CpG rich promoters (51). Furthermore, we also found 22 (24%) top enriched MMs were matched with the 657 reported methyl-specific motifs (52). In addition, we have profiled the binding of 845 known TFs with ChIP-seq experiments documented in the latest GTRD (Gene Transcription Regulation Database) (53) in the motif occurrence sites (Supplementary Figure S2C).…”

Section: Resultsmentioning

confidence: 53%

Identification of DNA motifs that regulate DNA methylation

Wang

Zhang

Ngo

et al. 2019

Nucleic Acids Research

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DNA methylation is an important epigenetic mark but how its locus-specificity is decided in relation to DNA sequence is not fully understood. Here, we have analyzed 34 diverse whole-genome bisulfite sequencing datasets in human and identified 313 motifs, including 92 and 221 associated with methylation (methylation motifs, MMs) and unmethylation (unmethylation motifs, UMs), respectively. The functionality of these motifs is supported by multiple lines of evidence. First, the methylation levels at the MM and UM motifs are respectively higher and lower than the genomic background. Second, these motifs are enriched at the binding sites of methylation modifying enzymes including DNMT3A and TET1, indicating their possible roles of recruiting these enzymes. Third, these motifs significantly overlap with “somatic QTLs” (quantitative trait loci) of methylation and expression. Fourth, disruption of these motifs by mutation is associated with significantly altered methylation level of the CpGs in the neighbor regions. Furthermore, these motifs together with somatic mutations are predictive of cancer subtypes and patient survival. We revealed some of these motifs were also associated with histone modifications, suggesting a possible interplay between the two types of epigenetic modifications. We also found some motifs form feed forward loops to contribute to DNA methylation dynamics.

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Section: Resultsmentioning

confidence: 53%

Identification of DNA motifs that regulate DNA methylation

Wang

Zhang

Ngo

et al. 2019

Nucleic Acids Research

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“…We also plan to integrate data on methylation of DNA into the GTRD. The MethMotif database ( 42 ) demonstrates how ChIP-seq data can be integrated with cell type-specific CpG methylation information.…”

Section: Discussionmentioning

confidence: 99%

GTRD: an integrated view of transcription regulation

Kolmykov

Yevshin

Kulyashov

et al. 2020

Nucleic Acids Research

176

135

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The Gene Transcription Regulation Database (GTRD; http://gtrd.biouml.org/) contains uniformly annotated and processed NGS data related to gene transcription regulation: ChIP-seq, ChIP-exo, DNase-seq, MNase-seq, ATAC-seq and RNA-seq. With the latest release, the database has reached a new level of data integration. All cell types (cell lines and tissues) presented in the GTRD were arranged into a dictionary and linked with different ontologies (BRENDA, Cell Ontology, Uberon, Cellosaurus and Experimental Factor Ontology) and with related experiments in specialized databases on transcription regulation (FANTOM5, ENCODE and GTEx). The updated version of the GTRD provides an integrated view of transcription regulation through a dedicated web interface with advanced browsing and search capabilities, an integrated genome browser, and table reports by cell types, transcription factors, and genes of interest.

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“…RNA-seq expression data of replicated X-linked DMR genes were also derived from this source. Methylation sensitivity data were obtained from MethMotif (v1.3, [ 96 ]), and counts for each motif corresponding to unmethylated (less than 10%), partially methylated (10–90%), and methylated (greater than 90%) loci were summed and divided by the total counts for that motif to determine the proportion of binding sites in each methylation category.…”

Section: Methodsmentioning

confidence: 99%

Cord blood DNA methylome in newborns later diagnosed with autism spectrum disorder reflects early dysregulation of neurodevelopmental and X-linked genes

et al. 2020

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Background Autism spectrum disorder (ASD) is a neurodevelopmental disorder with complex heritability and higher prevalence in males. The neonatal epigenome has the potential to reflect past interactions between genetic and environmental factors during early development and influence future health outcomes. Methods We performed whole-genome bisulfite sequencing of 152 umbilical cord blood samples from the MARBLES and EARLI high-familial risk prospective cohorts to identify an epigenomic signature of ASD at birth. Samples were split into discovery and replication sets and stratified by sex, and their DNA methylation profiles were tested for differentially methylated regions (DMRs) between ASD and typically developing control cord blood samples. DMRs were mapped to genes and assessed for enrichment in gene function, tissue expression, chromosome location, and overlap with prior ASD studies. DMR coordinates were tested for enrichment in chromatin states and transcription factor binding motifs. Results were compared between discovery and replication sets and between males and females. Results We identified DMRs stratified by sex that discriminated ASD from control cord blood samples in discovery and replication sets. At a region level, 7 DMRs in males and 31 DMRs in females replicated across two independent groups of subjects, while 537 DMR genes in males and 1762 DMR genes in females replicated by gene association. These DMR genes were significantly enriched for brain and embryonic expression, X chromosome location, and identification in prior epigenetic studies of ASD in post-mortem brain. In males and females, autosomal ASD DMRs were significantly enriched for promoter and bivalent chromatin states across most cell types, while sex differences were observed for X-linked ASD DMRs. Lastly, these DMRs identified in cord blood were significantly enriched for binding sites of methyl-sensitive transcription factors relevant to fetal brain development. Conclusions At birth, prior to the diagnosis of ASD, a distinct DNA methylation signature was detected in cord blood over regulatory regions and genes relevant to early fetal neurodevelopment. Differential cord methylation in ASD supports the developmental and sex-biased etiology of ASD and provides novel insights for early diagnosis and therapy.

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MethMotif: an integrative cell specific database of transcription factor binding motifs coupled with DNA methylation profiles

Cited by 57 publications

References 47 publications

Identification of DNA motifs that regulate DNA methylation

Identification of DNA motifs that regulate DNA methylation

GTRD: an integrated view of transcription regulation

Cord blood DNA methylome in newborns later diagnosed with autism spectrum disorder reflects early dysregulation of neurodevelopmental and X-linked genes

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