BackgroundThe binding of transcription factors (TFs) to specific DNA sequences is an initial and crucial step of transcription. In eukaryotes, this process is highly dependent on the local chromatin state, which can be modified by recruiting chromatin remodelers. However, previous studies have focused mainly on nucleosome occupancy around the TF binding sites (TFBSs) of a few specific TFs. Here, we investigated the nucleosome occupancy profiles around computationally inferred binding sites, based on 519 TF binding motifs, in human GM12878 and K562 cells.ResultsAlthough high nucleosome occupancy is intrinsically encoded at TFBSs in vitro, nucleosomes are generally depleted at TFBSs in vivo, and approximately a quarter of TFBSs showed well-positioned in vivo nucleosomes on both sides. RNA polymerase near the transcription start site (TSS) has a large effect on the nucleosome occupancy distribution around the binding sites located within one kilobase to the nearest TSS; fuzzier nucleosome positioning was thus observed around these sites. In addition, in contrast to yeast, repressors, rather than activators, were more likely to bind to nucleosomal DNA in the human cells, and nucleosomes around repressor sites were better positioned in vivo. Genes with repressor sites exhibiting well-positioned nucleosomes on both sides, and genes with activator sites occupied by nucleosomes had significantly lower expression, suggesting that actions of activators and repressors are associated with the nucleosome occupancy around their binding sites. It was also interesting to note that most of the binding sites, which were not in the DNase I-hypersensitive regions, were cell-type specific, and higher in vivo nucleosome occupancy were observed at these binding sites.ConclusionsThis study demonstrated that RNA polymerase and the functions of bound TFs affected the local nucleosome occupancy around TFBSs, and nucleosome occupancy patterns around TFBSs were associated with the expression levels of target genes.Electronic supplementary materialThe online version of this article (doi: 10.1186/1471-2164-15-493) contains supplementary material, which is available to authorized users.

Transcription factor (TF) binding at specific DNA sequences is the fundamental step in transcriptional regulation and is highly dependent on the chromatin structure context, which may be affected by specific histone modifications and variants, known as histone marks. The lack of a global binding map for hundreds of TFs means that previous studies have focused mainly on histone marks at binding sites for several specific TFs. We therefore studied 11 histone marks around computationally-inferred and experimentally-determined TF binding sites (TFBSs), based on 164 and 34 TFs, respectively, in human lymphoblastoid cell lines. For H2A.Z, methylation of H3K4, and acetylation of H3K27 and H3K9, the mark patterns exhibited bimodal distributions and strong pairwise correlations in the 600-bp region around enriched TFBSs, suggesting that these marks mainly coexist within the two nucleosomes proximal to the TF sites. TFs competing with nucleosomes to access DNA at most binding sites, contributes to the bimodal distribution, which is a common feature of histone marks for TF binding. Mark H3K79me2 showed a unimodal distribution on one side of TFBSs and the signals extended up to 4000 bp, indicating a longer-distance pattern. Interestingly, H4K20me1, H3K27me3, H3K36me3 and H3K9me3, which were more diffuse and less enriched surrounding TFBSs, showed unimodal distributions around the enriched TFBSs, suggesting that some TFs may bind to nucleosomal DNA. Besides, asymmetrical distributions of H3K36me3 and H3K9me3 indicated that repressors might establish a repressive chromatin structure in one direction to repress gene expression. In conclusion, this study demonstrated the ranges of histone marks associated with TF binding, and the common features of these marks around the binding sites. These findings have epigenetic implications for future analysis of regulatory elements.

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Obesity is directly associated with the risk of cancer in different organs, including breast, colon, and kidney. However, adipocytes could be utilized to control progression for some types of cancer, such as leukemia and breast cancer. To explore the potential correlation between adipocytes and cancer, the combined effect of expression levels of obesity-related genes and clinical factors (i.e., gender, race, menopausal status, history of smoking, tumor grade, body mass index (BMI), and history of drinking) on cancer survival rate was systemically studied. The expression levels of obesity-related genes in cancer tissues and normal tissues were downloaded from The Cancer Genome Atlas (TCGA). Kaplan–Meier curves were plotted using R programming language. The log-rank test was applied to explore the correlation between different clinical subgroups. The overexpression of the nine obesity-related genes (MC4R, TMEM18, KCTD15, GNPDA2, SH2B1, MTCH2, FTO, PCSK1, and GPR120) may associate with tumor-promoting factors in some organs (head and neck, gastrointestinal tract, liver, and gallbladder). Underexpressed LEPR, NEGR1, TMEM18, and SH2B1 genes prevented the progression and metastasis of kidney cancer. The combined effect of clinical factors and the expression levels of obesity-related genes on patients’ survival was found to be significant. Our outcomes suggested that the alternations of DNA methylation patterns could result in the changes of expression levels of obesity-related genes, playing a critical role in tumor progression. The results of the current study may be utilized to supplement precision and personalized medicine, as well as provide novel insights for the development of treatment approaches for cancer.

Somatic mutations in 3′-untranslated regions (3′UTR) do not alter amino acids and are considered to be silent in cancers. We found that such mutations can promote tumor progression by altering microRNA (miRNA) targeting efficiency and consequently affecting miRNA–mRNA interactions. We identified 67,159 somatic mutations located in the 3′UTRs of messenger RNAs (mRNAs) which can alter miRNA–mRNA interactions (functional somatic mutations, funcMutations), and 69.3% of these funcMutations (the degree of energy change > 12 kcal/mol) were identified to significantly promote loss of miRNA-mRNA binding. By integrating mRNA expression profiles of 21 cancer types, we found that the expression of target genes was positively correlated with the loss of absolute affinity level and negatively correlated with the gain of absolute affinity level. Functional enrichment analysis revealed that genes carrying funcMutations were significantly enriched in the MAPK and WNT signaling pathways, and analysis of regulatory modules identified eighteen miRNA modules involved with similar cellular functions. Our findings elucidate a complex relationship between miRNA, mRNA, and mutations, and suggest that 3′UTR mutations may play an important role in tumor development.