Abstract
BackgroundInteractions among transcription factors (TFs) and histone modifications (HMs) play an important role in the precise regulation of gene expression. The context specificity of those interactions and further its dynamics in normal and disease remains largely unknown. Recent development in genomics technology enables transcription profiling by RNA-seq and protein’s binding profiling by ChIP-seq. Integrative analysis of the two types of data allows us to investigate TFs and HMs interactions both from the genome co-localization and downstream target gene expression.ResultsWe propose a integrative pipeline to explore the co-localization of 55 TFs and 11 HMs and its dynamics in human GM12878 and K562 by matched ChIP-seq and RNA-seq data from ENCODE. We classify TFs and HMs into three types based on their binding enrichment around transcription start site (TSS). Then a set of statistical indexes are proposed to characterize the TF-TF and TF-HM co-localizations. We found that Rad21, SMC3, and CTCF co-localized across five cell lines. High resolution Hi-C data in GM12878 shows that they associate most of the Hi-C peak loci with a specific CTCF-motif “anchor” and supports that CTCF, SMC3, and RAD2 co-localization serves important role in 3D chromatin structure. Meanwhile, 17 TF-TF pairs are highly dynamic between GM12878 and K562. We then build SVM models to correlate high and low expression level of target genes with TF binding and HM strength. We found that H3k9ac, H3k27ac, and three TFs (ELF1, TAF1, and POL2) are predictive with the accuracy about 85~92%.ConclusionWe propose a pipeline to analyze the co-localization of TF and HM and their dynamics across cell lines from ChIP-seq, and investigate their regulatory potency by RNA-seq. The integrative analysis of two level data reveals new insight for the cooperation of TFs and HMs and is helpful in understanding cell line specificity of TF/HM interactions.
Highlights
Interactions among transcription factors (TFs) and histone modifications (HMs) play an important role in the precise regulation of gene expression
The dynamics of TF and HM localization We develop a two-step analysis pipeline (Fig. 1) to integrate ChIP-seq, RNA-seq, and genome annotation to pinpoint the unique roles of transcription factor and histone modification in biological processes and their location at specific DNA region
We correlate TFs binding and HMs with gene expression level to detect reliable co-operations related with downstream effects
Summary
Interactions among transcription factors (TFs) and histone modifications (HMs) play an important role in the precise regulation of gene expression. TFs and HMs tend to localize together at regulatory elements (promoter, enhancer, or insulator) in genome to achieve complex and accurate regulation of target genes [1,2,3,4]. The initiation of transcription involves many protein-protein interactions among transcription factors, which bind to the promoter or enhancer and stabilize RNA polymerase [5,6,7]. Recent studies have shown that histone modifications play significant regulation roles in the process of transcriptional initiation and elongation by interacting with transcription factors [8, 9]. Co-localization among TFs binding and HMs is critically important for understanding the precise control of gene expression [10, 11]
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