Nucleosome eviction and multiple co-factor binding predict estrogen-receptor-alpha-associated long-range interactions.
Bottom Line: We found characteristic distance features related to promoter-promoter, enhancer-enhancer and insulator-insulator interactions.We further applied the classifier to generate additional novel interactions, which were undetected in the original ChIA-PET paper but were validated by other independent experiments.Our work provides a new insight into the long-range chromatin interactions through deeper and integrative ChIA-PET data analysis and demonstrates DNA looping predictability from ordinary ChIP-seq data.
Affiliation: MOE Key Laboratory of Bioinformatics and Bioinformatics Division, Center for Synthetic and System Biology, TNLIST/Department of Automation, Tsinghua University, Beijing 100084, China.Show MeSH
Mentions: To test this hypothesis, we conducted an enrichment analysis against the ChIP-seq data ofthree known ERα's co-factors, and the general co-activator p300. More than80% laERBSs (either with an ERE or not) overlapped with FoxA1, GATA3 and AP2γbinding sites (Figure 3). The percentages weresignificantly higher than those of nlaERBSs (P < 2.2e−16;Supplementary Table S2), indicating that these three TFs are likely in the complexmediating ERα-associated long-range interactions. Reported RNAi knock-downexperiments also support the notion that these three co-factors are important forERα loop formation (23,24). Thus they might be associated with nucleosome eviction in laERBSs.For p300, the percentage of overlapping with laERBSs was not as high as that of thosethree co-factors. However, interestingly, p300 was significantly enriched in laERBSs withan ERE in comparison with laERBSs without an ERE (P =7.59e−4), but showed no difference between nlaERBSs with an ERE and nlaERBSs withoutan ERE (P = 0.72), while none of the three co-factors have asimilar pattern. A previous study (36) showed thatp300 is a component of an estrogen receptor co-activator complex and the formation of thep300 complex is associated with nucleosome eviction (37). This indicated that p300 might be more frequently recruited to laERBSs withan ERE for higher level of nucleosome depletion. In addition, with the GRO-seq data (GEOaccession numbers GSM678539 and GSM678540) we found that laERBSs showed strongerbidirectional transcription of small RNAs (smRNAs) compared to nlaERBSs (SupplementaryFigure S7), with the highest transcription level occurring in laERBSs with an ERE(Supplementary Figure S7A). This is consistent with the notion that the bidirectionalsmRNAs transcription may help maintain the open chromatin structure in these regions(38). Taken together, these observations suggestthat laERBSs, especially those with canonical EREs, are often associated with an openchromatin structure, which is likely resulted by the formation of the looping-specificprotein complex of ERα, its co-factors and p300, and associated with thebidirectional transcription of smRNAs.
Affiliation: MOE Key Laboratory of Bioinformatics and Bioinformatics Division, Center for Synthetic and System Biology, TNLIST/Department of Automation, Tsinghua University, Beijing 100084, China.