Core transcriptional regulatory circuitries in cancer

Ye Chen,Ruby Yu-Tong Lin,H Phillip Koeffler,Markus Müschen,Liang Xu

doi:10.1038/s41388-020-01459-w

Abstract

Transcription factors (TFs) coordinate the on-and-off states of gene expression typically in a combinatorial fashion. Studies from embryonic stem cells and other cell types have revealed that a clique of self-regulated core TFs control cell identity and cell state. These core TFs form interconnected feed-forward transcriptional loops to establish and reinforce the cell-type-specific gene-expression program; the ensemble of core TFs and their regulatory loops constitutes core transcriptional regulatory circuitry (CRC). Here, we summarize recent progress in computational reconstitution and biologic exploration of CRCs across various human malignancies, and consolidate the strategy and methodology for CRC discovery. We also discuss the genetic basis and therapeutic vulnerability of CRC, and highlight new frontiers and future efforts for the study of CRC in cancer. Knowledge of CRC in cancer is fundamental to understanding cancer-specific transcriptional addiction, and should provide important insight to both pathobiology and therapeutics.

Highlights

Master transcription factors (TFs) are highly expressed in a given cell type
Cancer-specific activation of core TFs and subsequent rewiring of lineage-associated CRC components establish the genetic basis of oncogenic CRCs (Fig. 1b)
The above examples demonstrate the successful application of CRC models to address scientific questions related to cell identity, cancer biology, and therapeutic responses, highlighting the prevalence and importance of CRC in human cancers

Summary

Introduction

Transcriptional regulation is one of the fundamental molecular processes occurring in a cell. Group 1 samples comprised the majority of neuroblastoma cell lines and PDXs, and engaged SE-associated master TFs (e.g., PHOX2B, HAND2 and GATA3) to control sympathetic adrenergic cell identity This module of core TFs showed strong coexpression and constituted a conserved CRC in both group 1 neuroblastoma cell lines and PDXs. In addition to the physical interaction between PHOX2B and GATA3, all three TFs co-localized in the regulatory sequences of their own loci, as well as many other prominent driver genes including MYCN and ALK. Genomic occupancy analysis revealed a substantial binding and co-loading of BRD2, BRD3, BRD4, FOSL2, and RUNX proteins across active enhancers, especially SE regions of core TFs. FOSL2, MYC, and RUNX1 demonstrated interdependent expression in DDLPS cells, which was further supported by their robust co-expression in primary tumor specimens. KLF5 engaged a mutual crosstalk with collaborating factors GATA4 and GATA6 to maintain oncogenic transcriptional regulatory network in gastric cancer [74] These studies suggest that rewiring connectivity of master TFs is fundamental to disease/subtype identity. DbCoRC serves as a valuable database to explore H3K27ac/enhancer-centric core circuitries in over 230 samples including cervical adenocarcinoma, chronic myelogenous leukemia, colorectal cancer, diffuse large B-cell lymphoma, gastric cancer, small cell lung cancer, pancreatic cancer, and prostate cancer

Conclusions

Compliance with ethical standards