Chromatin accessibility associates with protein-RNA correlation in human cancer

Abstract

Although alterations in chromatin structure are known to exist in tumors, how these alterations relate to molecular phenotypes in cancer remains to be demonstrated. Multi-omics profiling of human tumors can provide insight into how alterations in chromatin structure are propagated through the pathway of gene expression to result in malignant protein expression. We applied multi-omics profiling of chromatin accessibility, RNA abundance, and protein abundance to 36 human thyroid cancer primary tumors, metastases, and patient-match normal tissue. Through quantification of chromatin accessibility associated with active transcription units and global protein expression, we identify a local chromatin structure that is highly correlated with coordinated RNA and protein expression. In particular, we identify enhancers located within gene-bodies as predictive of correlated RNA and protein expression, that is independent of overall transcriptional activity. To demonstrate the generalizability of these findings we also identify similar results in an independent cohort of human breast cancers. Taken together, these analyses suggest that local enhancers, rather than distal enhancers, are likely most predictive of cancer gene expression phenotypes. This allows for identification of potential targets for cancer therapeutic approaches and reinforces the utility of multi-omics profiling as a methodology to understand human disease.

Different genetic landscapes of papillary thyroid carcinoma and paired benign nodules revealed by integrated multi-omics analysis

“…Single-cell chromatin accessibility pro ling was also performed on glioblastoma and an invasive cancer stem cell population associated with lower survival was identi ed [32]. Open chromatin character and identi ed enhancers located within gene bodies could be predictive of correlated RNA and protein expression in TC [25]. The differential expression of genes associated with the differential ATAC-seq peaks was determined.…”

“…Epigenetic pro les, such as DNA methylation [19], histone modi cations [20], and noncoding RNA [21,22] have been characterized in thyroid cancer. Chromosomal accessibility is a powerful method for mapping genome-wide open chromatin patterns in multiple tumors [23,24] and provides valuable insights into the regulatory mechanisms of TC [25]. However, there was no association between chromosomal accessibility and genomic alterations among patients with paired benign/malignant thyroid nodules.…”

Emergence of new enhancers at late DNA replicating regions

“…For AML and thyroid cancer, enhancers were defined as distal chromatin accessible regions (± 1kb from TSS). We used ATAC-seq data for matched cancer and normal thyroid samples from three individuals (Acc: GSE162515; C1, C7, C8) [39], and ATAC-seq files for the matched pre-leukemic and blast cells from three individuals (Acc: GSE74912; SU484, SU501, SU654) [38]. ATAC-seq processing and peak calling are described in Supplemental Methods .…”

“…Enhancers, based on distal chromatin accessible regions, were identified in matched patient primary cancer and healthy samples in six individuals (n = 3 for each cancer type) for thyroid cancer and acute myeloid leukemia (AML) where preleukemic cells were considered as the healthy counterpart in AML. We also identified enhancers in both normal breast and prostate and in their diseased states based on the presence/absence of histone modifications denoting active enhancers [38][39][40][41][42] (Fig. 1A, Fig.…”

Advanced image-free analysis of the nano-organization of chromatin and other biomolecules by Single Molecule Localization Microscopy (SMLM)

“…In addition to changes at the level of the chromatin network as a whole [34] , [45] , specific rearrangements take place at individual DSB sites [38] , [44] , [46] , [47] , [48] , [49] . This affects the accessibility of chromatin to specific proteins and RNAs [50] , [51] , [52] , governs the formation of IRIFs (ionizing radiation induced foci), and presumably also the choice of the specific repair mechanism at the sites of individual DSBs [53] , [54] , [55] ; etc. (see Section 2.2 ).…”