A framework for identifying dysregulated chromatin regulators as master regulators in human cancer

Chromatin regulators (CRs) are frequently dysregulated to reprogram the epigenetic landscape of the cancer genome. However, the underpinnings of the dysregulation of CRs and their downstream effectors remain to be elucidated.

Here, we designed an integrated framework based on multi-omics data to identify candidate master regulatory CRs affected by genomic alterations across eight cancer types in The Cancer Genome Atlas. Most of them showed consistent activated or repressed (i.e. oncogenic or tumor-suppressive) roles in cancer initiation and progression. In order to further explore the insight mechanism of the dysregulated CRs, we developed an R package ModReg based on differential connectivity to identify CRs as modulators of transcription factors (TFs) involved in tumorigenesis. Our analysis revealed that the connectivity between TFs and their target genes (TGs) tended to be disrupted in the patients who had a high expression of oncogenic CRs or low-expression of tumor-suppressive CRs. As a proof-of-principle study, 14 (82.4%) of the top-ranked 17 driver CRs in liver cancer were able to be validated by literature mining or experiments including shRNA knockdown and dCas9-based epigenetic editing. Moreover, we confirmed that CR SIRT7 physically interacted with TF NFE2L2, and positively modulated the transcriptional program of NFE2L2 by affecting ∼64% of its TGs.

ModReg is freely accessible at http://cis.hku.hk/software/ModReg.tar.gz.

Supplementary data are available at Bioinformatics online.