RESUMEN
We present a major update of the HOCOMOCO collection that provides DNA binding specificity patterns of 949 human transcription factors and 720 mouse orthologs. To make this release, we performed motif discovery in peak sets that originated from 14 183 ChIP-Seq experiments and reads from 2554 HT-SELEX experiments yielding more than 400 thousand candidate motifs. The candidate motifs were annotated according to their similarity to known motifs and the hierarchy of DNA-binding domains of the respective transcription factors. Next, the motifs underwent human expert curation to stratify distinct motif subtypes and remove non-informative patterns and common artifacts. Finally, the curated subset of 100 thousand motifs was supplied to the automated benchmarking to select the best-performing motifs for each transcription factor. The resulting HOCOMOCO v12 core collection contains 1443 verified position weight matrices, including distinct subtypes of DNA binding motifs for particular transcription factors. In addition to the core collection, HOCOMOCO v12 provides motif sets optimized for the recognition of binding sites in vivo and in vitro, and for annotation of regulatory sequence variants. HOCOMOCO is available at https://hocomoco12.autosome.org and https://hocomoco.autosome.org.
Asunto(s)
Bases de Datos Genéticas , Regulación de la Expresión Génica , Dominios y Motivos de Interacción de Proteínas , Factores de Transcripción , Animales , Humanos , Ratones , Sitios de Unión/genética , Motivos de Nucleótidos , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Internet , Dominios y Motivos de Interacción de Proteínas/genéticaRESUMEN
We present ANANASTRA, https://ananastra.autosome.org, a web server for the identification and annotation of regulatory single-nucleotide polymorphisms (SNPs) with allele-specific binding events. ANANASTRA accepts a list of dbSNP IDs or a VCF file and reports allele-specific binding (ASB) sites of particular transcription factors or in specific cell types, highlighting those with ASBs significantly enriched at SNPs in the query list. ANANASTRA is built on top of a systematic analysis of allelic imbalance in ChIP-Seq experiments and performs the ASB enrichment test against background sets of SNPs found in the same source experiments as ASB sites but not displaying significant allelic imbalance. We illustrate ANANASTRA usage with selected case studies and expect that ANANASTRA will help to conduct the follow-up of GWAS in terms of establishing functional hypotheses and designing experimental verification.
Asunto(s)
Polimorfismo de Nucleótido Simple , Factores de Transcripción , Alelos , Sitios de Unión , Estudio de Asociación del Genoma Completo , Unión Proteica , Factores de Transcripción/química , Factores de Transcripción/metabolismo , Proteínas de Unión al ADNRESUMEN
The position weight matrix, also called the position-specific scoring matrix, is the commonly accepted model to quantify the specificity of transcription factor binding to DNA. Position weight matrices are used in thousands of projects and software tools in regulatory genomics, including computational prediction of the regulatory impact of single-nucleotide variants. Yet, recently Yan et al. reported that "the position weight matrices of most transcription factors lack sufficient predictive power" if applied to the analysis of regulatory variants studied with a newly developed experimental method, SNP-SELEX. Here, we re-analyze the rich experimental dataset obtained by Yan et al. and show that appropriately selected position weight matrices in fact can adequately quantify transcription factor binding to alternative alleles.
Asunto(s)
Programas Informáticos , Factores de Transcripción , Sitios de Unión/genética , Posición Específica de Matrices de Puntuación , Unión Proteica , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
Sequence variants in gene regulatory regions alter gene expression and contribute to phenotypes of individual cells and the whole organism, including disease susceptibility and progression. Single-nucleotide variants in enhancers or promoters may affect gene transcription by altering transcription factor binding sites. Differential transcription factor binding in heterozygous genomic loci provides a natural source of information on such regulatory variants. We present a novel approach to call the allele-specific transcription factor binding events at single-nucleotide variants in ChIP-Seq data, taking into account the joint contribution of aneuploidy and local copy number variation, that is estimated directly from variant calls. We have conducted a meta-analysis of more than 7 thousand ChIP-Seq experiments and assembled the database of allele-specific binding events listing more than half a million entries at nearly 270 thousand single-nucleotide polymorphisms for several hundred human transcription factors and cell types. These polymorphisms are enriched for associations with phenotypes of medical relevance and often overlap eQTLs, making candidates for causality by linking variants with molecular mechanisms. Specifically, there is a special class of switching sites, where different transcription factors preferably bind alternative alleles, thus revealing allele-specific rewiring of molecular circuitry.