Sequence and chromatin determinants of cell-type-specific transcription factor binding Journal Article
| Authors: | Arvey, A.; Agius, P.; Noble, W. S.; Leslie, C. |
| Article Title: | Sequence and chromatin determinants of cell-type-specific transcription factor binding |
| Abstract: | Gene regulatory programs in distinct cell types are maintained in large part through the cell-type-specific binding of transcription factors (TFs). The determinants of TF binding include direct DNA sequence preferences, DNA sequence preferences of cofactors, and the local cell-dependent chromatin context. To explore the contribution of DNA sequence signal, histone modifications, and DNase accessibility to cell-type-specific binding, we analyzed 286 ChIP-seq experiments performed by the ENCODE Consortium. This analysis included experiments for 67 transcriptional regulators, 15 of which were profiled in both the GM12878 (lymphoblastoid) and K562 (erythroleukemic) human hematopoietic cell lines. To model TF-bound regions, we trained support vector machines (SVMs) that use flexible k-mer patterns to capture DNA sequence signals more accurately than traditional motif approaches. In addition, we trained SVM spatial chromatin signatures to model local histone modifications and DNase accessibility, obtaining significantly more accurate TF occupancy predictions than simpler approaches. Consistent with previous studies, we find that DNase accessibility can explain cell-line-specific binding for many factors. However, we also find that of the 10 factors with prominent cell-type-specific binding patterns, four display distinct cell-type-specific DNA sequence preferences according to our models. Moreover, for two factors we identify cell-specific binding sites that are accessible in both cell types but bound only in one. For these sites, cell-type-specific sequence models, rather than DNase accessibility, are better able to explain differential binding. Our results suggest that using a single motif for each TF and filtering for chromatin accessible loci is not always sufficient to accurately account for cell-type-specific binding profiles. © 2012, Published by Cold Spring Harbor Laboratory Press. |
| Keywords: | controlled study; human cell; genetic analysis; computational biology; models, biological; cell line; protein binding; transcription factor; prediction; cell type; transcription factors; gene expression regulation; dna; chromatin; chromatin immunoprecipitation; organ specificity; binding site; dna sequence; binding sites; histones; dna determination; chromatin assembly and disassembly; deoxyribonuclease; regulatory sequences, nucleic acid; histone modification; deoxyribonucleases; high-throughput nucleotide sequencing; proto-oncogene proteins c-jun; nucleotide motifs; yy1 transcription factor |
| Journal Title: | Genome Research |
| Volume: | 22 |
| Issue: | 9 |
| ISSN: | 1088-9051 |
| Publisher: | Cold Spring Harbor Laboratory Press |
| Date Published: | 2012-09-01 |
| Start Page: | 1723 |
| End Page: | 1734 |
| Language: | English |
| DOI: | 10.1101/gr.127712.111 |
| PROVIDER: | scopus |
| PMCID: | PMC3431489 |
| PUBMED: | 22955984 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 3" - "Export Date: 1 October 2012" - "CODEN: GEREF" - "Source: Scopus" |
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