Abstract
To better understand the impact of chromatin structure on regulation of the prostate cancer transcriptome, we develop high-resolution chromatin interaction maps in normal and prostate cancer cells using in situ Hi-C. By combining the in situ Hi-C data with active and repressive histone marks, CTCF binding sites, nucleosome-depleted regions, and transcriptome profiling, we identify topologically associating domains (TADs) that change in size and epigenetic states between normal and prostate cancer cells. Moreover, we identify normal and prostate cancer-specific enhancer-promoter loops and involved transcription factors. For example, we show that FOXA1 is enriched in prostate cancer-specific enhancer-promoter loop anchors. We also find that the chromatin structure surrounding the androgen receptor (AR) locus is altered in the prostate cancer cells with many cancer-specific enhancer-promoter loops. This creation of 3D epigenomic maps enables a better understanding of prostate cancer biology and mechanisms of gene regulation.
Highlights
To better understand the impact of chromatin structure on regulation of the prostate cancer transcriptome, we develop high-resolution chromatin interaction maps in normal and prostate cancer cells using in situ Hi-C
Transcription factors (TFs) that are involved in the chromatin interactions can be inferred from motif analyses using methods such as DNase-seq, ATAC-seq, or NOMe-seq (Nucleosome Occupancy and Methylome sequencing), which define nucleosome-depleted regions (NDRs) that correspond to TFbinding platforms, and the binding sites of TFs can be further identified by ChIP-seq
Using our in situ Hi-C and epigenomic data, we identified two strong cancer-specific H3K27ac peaks located at ~350 and ~180 kb upstream of the transcription start site of FOXA1 that are looped to the FOXA1 promoter region in C42B prostate cancer cells (Fig. 5c); the interaction of each loop was more frequent in cancer cells compared to normal cells
Summary
To better understand the impact of chromatin structure on regulation of the prostate cancer transcriptome, we develop high-resolution chromatin interaction maps in normal and prostate cancer cells using in situ Hi-C. Cancer-specific changes in the activity of regulatory elements such as enhancers (caused by the gain or loss of TFs) can cause alterations in expression of specific genes due to changes in long-range enhancer–promoter loops[9,10] To study these chromatin interactions, various chromatin conformation capture assays have been developed. To better understand the mechanisms by which the prostate cancer transcriptome is controlled, we have used a combination of these methods in normal prostate and prostate cancer cells to (a) map TAD boundaries, (b) investigate the epigenetic state of the TADs, and (c) identify and characterize normaland cancer-specific enhancer–promoter loops. We performed ChIP-seq for modified histones and CTCF, NOMe-seq, and RNA-seq in normal and prostate cancer cells This characterization of TADs and chromatin loops provides more detailed epigenetic mechanisms of prostate tumorigenesis
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