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Distinct epigenetic landscapes underlie the pathobiology of pancreatic cancer subtypes

Gwen Lomberk 1 Yuna Blum 2 Remy Nicolle 2, 3, 4 Asha Nair 5 Krutika Satish Gaonkar 5 Laetitia Marisa 2 Angela Mathison 6 Zhifu Sun 5 Huihuang Yan 5 Nabila Elarouci 2 Lucile Armenoult 2 Mira Ayadi 2 Tamas Ordog 7 Jeong-Heon Lee 8 Gavin Oliver 5 Eric Klee 5 Vincent Moutardier 9 Odile Gayet 9 Benjamin Bian 9 Pauline Duconseil 9 Marine Gilabert 9 Martin Bigonnet 9 Stephane Garcia 9 Olivier Turrini 9 Jean-Robert Delpero 10 Marc Giovannini 10 Philippe Grandval 11 Mohamed Gasmi 12 Veronique Secq 12 Aurelien de Reynies 2 Nelson Dusetti 9 Juan Iovanna 9 Raul Urrutia 13, 6
1 Medical College of Wisconsin
2 Ligue Nationale Contre le Cancer - Paris
3 CDC - Compartimentation et dynamique cellulaires
4 PSL - Université Paris sciences et lettres
5 HSR - Department of Health Sciences Research [Mayo Clinic]
6 Medical College of Wisconsin
7 Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine
8 Translational Epigenomics Program
9 CRCM - Centre de Recherche en Cancérologie de Marseille
10 Institut Paoli-Calmettes
11 Département de Gastro-Entérologie [Hôpital de La Timone - APHM]
12 Service De Gastroenterologie, Hôpital Nord, Assistance Publique-Hôpitaux de Marseille
13 Mayo Clinic
Abstract : Recent studies have offered ample insight into genome-wide expression patterns to define pancreatic ductal adenocarcinoma (PDAC) subtypes, although there remains a lack of knowledge regarding the underlying epigenomics of PDAC. Here we perform multiparametric integrative analyses of chromatin immunoprecipitation-sequencing (ChIP-seq) on multiple histone modifications, RNA-sequencing (RNA-seq), and DNA methylation to define epigenomic landscapes for PDAC subtypes, which can predict their relative aggressiveness and survival. Moreover, we describe the state of promoters, enhancers, super-enhancers, euchromatic, and heterochromatic regions for each subtype. Further analyses indicate that the distinct epigenomic landscapes are regulated by different membrane-to-nucleus pathways. Inactivation of a basal-specific super-enhancer associated pathway reveals the existence of plasticity between subtypes. Thus, our study provides new insight into the epigenetic landscapes associated with the heterogeneity of PDAC, thereby increasing our mechanistic understanding of this disease, as well as offering potential new markers and therapeutic targets.
Keywords : Epigenomics Cancer
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UNIV-AMU | UMR144 | SORBONNE-UNIVERSITE | CRCM | SU-SCIENCES | PAOLI_CALMETTES | CURIE | FNCLCC | CNRS | PSL

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Gwen Lomberk, Yuna Blum, Remy Nicolle, Asha Nair, Krutika Satish Gaonkar, et al.. Distinct epigenetic landscapes underlie the pathobiology of pancreatic cancer subtypes. Nature Communications, Nature Publishing Group, 2018, 9 (1), pp.1978. ⟨10.1038/s41467-018-04383-6⟩. ⟨hal-02143535⟩

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