PT  - JOURNAL ARTICLE
AU  - Yan-Yi Jiang
AU  - Yuan Jiang
AU  - Chun-Quan Li
AU  - Ying Zhang
AU  - Pushkar Dakle
AU  - Harvinder Kaur
AU  - Jian-Wen Deng
AU  - Ruby Yu-Tong Lin
AU  - Lin Han
AU  - Jian-Jun Xie
AU  - Anand Mayakonda
AU  - Masaharu Hazawa
AU  - Liang Xu
AU  - YanYu Li
AU  - Luay Aswad
AU  - Maya Jeitany
AU  - Deepika Kanojia
AU  - Xin-Yuan Guan
AU  - Melissa J. Fullwood
AU  - De-Chen Lin
AU  - H. Phillip Koeffler
TI  - TP63, SOX2 and KLF5 Establish Core Regulatory Circuitry and Construct Cancer Specific Epigenome in Esophageal Squamous Cell Carcinoma
AID  - 10.1101/825372
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 825372
4099  - http://biorxiv.org/content/early/2019/11/06/825372.short
4100  - http://biorxiv.org/content/early/2019/11/06/825372.full
AB  - Transcriptional network is controlled by master transcription factors (TFs) and cis-regulatory elements through interacting with target sequences and recruiting epigenetic regulators. By integration of enhancer profiling and chromatin accessibility, we establish super-enhancer (SE) mediated core regulatory circuitry (CRC) for esophageal squamous cell carcinoma (ESCC) and identify tumor cells-dependent CRC TFs-TP63, SOX2 and KLF5. They preferentially co-occupy SE loci and form a positive interconnected auto-regulatory loop through SEs to orchestrate chromatin and transcriptional programming. SE-associated oncogene-ALDH3A1 is identified as a novel CRC target contributing to ESCC viability. Using circular chromosome conformation capture sequencing (4C-seq) and CRISPR/Cas9 genome editing, the direct interaction between TP63 promoter and functional enhancers which is mediated by CRC TFs is identified. Deletion of each enhancer decreases expression of CRC TFs and impairs cell viability, phenocopying the knockdown of each CRC TF. Targeting epigenetic regulation by inhibition of either the BET bromodomain or HDAC disrupts the CRC program and its dependent global epigenetic modification, consequently suppressing ESCC tumor growth. Importantly, combination of both compounds result in synergistic anti-tumor effect.Graphical Abstract HIGHLIGHTSSuper-enhancers mediated transcriptional regulatory circuitry is established for ESCCTP63, SOX2 and KLF5 as CRC TFs co-localize super-enhancer loci to orchestrate chromatin accessibility and transcriptional dysregulationComplex interaction between functional enhancers and TP63 promoter is mediated by CRC TFsALDH3A1 is a key downstream target of ESCC CRC and is essential for ESCC cell survivalBET degrader-ARV-771 and HDAC inhibitor-Romidepsin synergistically inhibit ESCC tumor growth