TP63, SOX2 and KLF5 Establish Core Regulatory Circuitry and Construct Cancer Specific Epigenome in Esophageal Squamous Cell Carcinoma

Jiang, Yan‐Yi; Jiang, Yuan; Li, Chunquan; Zhang, Ying; Dakle, Pushkar; Kaur, Harvinder; Deng, Jianwen; Lin, Ruby Yu-Tong; Lin, Han; Xie, Jian‐Jun; Mayakonda, Anand; Hazawa, Masaharu; Xu, Liang; Li, Yanyu; Aswad, Luay; Jeitany, Maya; Kanojia, Deepika; Guan, Xin‐Yuan; Fullwood, Melissa J.; Lin, De–Chen; Koeffler, H. Phillip

doi:10.1101/825372

Cited by 4 publications

(5 citation statements)

References 65 publications

(69 reference statements)

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“…Notably, compared with PPARG solo-binding regions, these co-binding regions were significantly more enriched in super-enhancers (13.4% vs 8.1%, P value = 1.6e-14, Fig. 6D), congruent with our previous finding that MRTFs favor binding to super-enhancers over typical-enhancers (5,44,45). Super-enhancers of several known tumor-promoting genes, such as CDX2, FOSL2, MCL1 and HES1, were all highly ranked in PPARG/ELF3 co-binding regions ( Fig.…”

Section: Pparg Cooperates With Elf3 and Directly Activates Elf3 Supersupporting

confidence: 89%

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A Transcriptional Regulatory Loop of Master Regulator Transcription Factors, PPARG, and Fatty Acid Synthesis Promotes Esophageal Adenocarcinoma

Zhou

Yang

et al. 2021

Cancer Research

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Although obesity is one of the strongest risk factors for esophageal adenocarcinoma, the molecular mechanisms underlying this association remain unclear. We recently identified four esophageal adenocarcinoma–specific master regulator transcription factors (MRTF) ELF3, KLF5, GATA6, and EHF. In this study, gene-set enrichment analysis of both esophageal adenocarcinoma patient samples and cell line models unbiasedly underscores fatty acid synthesis as the central pathway downstream of three MRTFs (ELF3, KLF5, GATA6). Further characterizations unexpectedly identified a transcriptional feedback loop between MRTF and fatty acid synthesis, which mutually activated each other through the nuclear receptor, PPARG. MRTFs cooperatively promoted PPARG transcription by directly regulating its promoter and a distal esophageal adenocarcinoma–specific enhancer, leading to PPARG overexpression in esophageal adenocarcinoma. PPARG was also elevated in Barrett’s esophagus, a recognized precursor to esophageal adenocarcinoma, implying that PPARG might play a role in the intestinal metaplasia of esophageal squamous epithelium. Upregulation of PPARG increased de novo synthesis of fatty acids, phospholipids, and sphingolipids as revealed by mass spectrometry–based lipidomics. Moreover, ChIP-seq, 4C-seq, and a high-fat diet murine model together characterized a novel, noncanonical, and cancer-specific function of PPARG in esophageal adenocarcinoma. PPARG directly regulated the ELF3 super-enhancer, subsequently activating the transcription of other MRTFs through an interconnected regulatory circuitry. Together, elucidation of this novel transcriptional feedback loop of MRTF/PPARG/fatty acid synthesis advances our understanding of the mechanistic foundation for epigenomic dysregulation and metabolic alterations in esophageal adenocarcinoma. More importantly, this work identifies a potential avenue for prevention and early intervention of esophageal adenocarcinoma by blocking this feedback loop. Significance: These findings elucidate a transcriptional feedback loop linking epigenomic dysregulation and metabolic alterations in esophageal adenocarcinoma, indicating that blocking this feedback loop could be a potential therapeutic strategy in high-risk individuals.

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Section: Pparg Cooperates With Elf3 and Directly Activates Elf3 Supersupporting

confidence: 89%

“…One of the most important characteristics of EAC-specific MRTFs is their unique capability of forming an inter-connected regulatory circuitry by binding to each other's super-enhancers(5), a transcriptional paradigm also observed in other cell types (3,(45)(46)(47).…”

Section: Pparg Cooperates With Elf3 and Directly Activates Elf3 Supermentioning

confidence: 99%

A Transcriptional Regulatory Loop of Master Regulator Transcription Factors, PPARG, and Fatty Acid Synthesis Promotes Esophageal Adenocarcinoma

Zhou

Yang

et al. 2021

Cancer Research

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“…To provide a measure of confidence in our CaCTS predictions, we tested for SE association in a few systems where the relevant data were publicly available. We curated a list of 17 experimentally validated MTFs in B cell lymphoma [lymphoid neoplasm diffuse large B cell lymphoma (DLBC)] ( 8 ), melanoma [skin cutaneous melanoma (SKCM)] ( 20 ), esophageal squamous carcinoma (ESSC) ( 19 ), esophageal adenocarcinoma (ESAD) ( 22 ), and breast cancer (BRCA) ( 23 , 24 ) (table S4), which served as positive controls in the development of our algorithm. By analyzing publicly available H3K27ac ChIP-seq data, we confirmed that 15 (of 17) positive controls are associated with SEs in the relevant tissue types ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Predicting master transcription factors from pan-cancer expression data

et al. 2021

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“…ChIP assay was performed as previously described (42). Briefly, cells were cultured ~1 × 10 7 cells in 10 cm dishes.…”

Section: Chromatin Immunoprecipitation (Chip)mentioning

confidence: 99%

Epigenomic Analyses Identify FOXM1 As a Key Regulator of Anti-Tumor Immune Response in Esophageal Adenocarcinoma

Ziman¹,

Yang

Zheng

et al. 2023

Preprint

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Unlike most cancer types, the incidence of esophageal adenocarcinoma (EAC) has rapidly escalated in the western world over recent decades. Using whole genome bisulfite sequencing (WGBS), we identify the transcription factor (TF) FOXM1 as an important epigenetic regulator of EAC. FOXM1 plays a critical role in cellular proliferation and tumor growth in EAC patient-derived organoids and cell line models. We identify ERBB2 as an upstream regulator of the expression and transcriptional activity of FOXM1. Unexpectedly, Gene Set Enrichment Analysis (GSEA) unbiased screen reveals a prominent anti-correlation between FOXM1 and immune response pathways. Indeed, syngeneic mouse models show that FOXM1 inhibits the infiltration of CD8+ T cells into the tumor microenvironment. Consistently, FOXM1 suppresses CD8+ T cell chemotaxis in vitro and antigen-dependent CD8+ T cell killing. This study characterizes FOXM1 as a significant EAC-promoting TF and elucidates its novel function in regulating anti-tumor immune response.

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TP63, SOX2 and KLF5 Establish Core Regulatory Circuitry and Construct Cancer Specific Epigenome in Esophageal Squamous Cell Carcinoma

Cited by 4 publications

References 65 publications

A Transcriptional Regulatory Loop of Master Regulator Transcription Factors, PPARG, and Fatty Acid Synthesis Promotes Esophageal Adenocarcinoma

A Transcriptional Regulatory Loop of Master Regulator Transcription Factors, PPARG, and Fatty Acid Synthesis Promotes Esophageal Adenocarcinoma

Predicting master transcription factors from pan-cancer expression data

Epigenomic Analyses Identify FOXM1 As a Key Regulator of Anti-Tumor Immune Response in Esophageal Adenocarcinoma

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