Saba Ghaffari1, Casey Hanson2, Remington E Schmidt3, Kelly J Bouchonville3, Steven M Offer4, Saurabh Sinha5. 1. Department of Computer Science, University of Illinois at Urbana-Champaign, Urbana, USA. 2. Department of Genetics, Stanford University, Stanford, USA. 3. Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Gonda 19-476, 200 First St SW, Rochester, MN, 55905, USA. 4. Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Gonda 19-476, 200 First St SW, Rochester, MN, 55905, USA. Offer.Steven1@mayo.edu. 5. Department of Computer Science, Carl R. Woese Institute of Genomic Biology, and Cancer Center of Illinois, University of Illinois at Urbana-Champaign, 2122, Siebel Center, 201 N. Goodwin Ave., Urbana, IL, 61801, USA. sinhas@illinois.edu.
Abstract
BACKGROUND: Metastatic progress is the primary cause of death in most cancers, yet the regulatory dynamics driving the cellular changes necessary for metastasis remain poorly understood. Multi-omics approaches hold great promise for addressing this challenge; however, current analysis tools have limited capabilities to systematically integrate transcriptomic, epigenomic, and cistromic information to accurately define the regulatory networks critical for metastasis. RESULTS: To address this limitation, we use a purposefully generated cellular model of colon cancer invasiveness to generate multi-omics data, including expression, accessibility, and selected histone modification profiles, for increasing levels of invasiveness. We then adopt a rigorous probabilistic framework for joint inference from the resulting heterogeneous data, along with transcription factor binding profiles. Our approach uses probabilistic graphical models to leverage the functional information provided by specific epigenomic changes, models the influence of multiple transcription factors simultaneously, and automatically learns the activating or repressive roles of cis-regulatory events. Global analysis of these relationships reveals key transcription factors driving invasiveness, as well as their likely target genes. Disrupting the expression of one of the highly ranked transcription factors JunD, an AP-1 complex protein, confirms functional relevance to colon cancer cell migration and invasion. Transcriptomic profiling confirms key regulatory targets of JunD, and a gene signature derived from the model demonstrates strong prognostic potential in TCGA colorectal cancer data. CONCLUSIONS: Our work sheds new light into the complex molecular processes driving colon cancer metastasis and presents a statistically sound integrative approach to analyze multi-omics profiles of a dynamic biological process.
BACKGROUND: Metastatic progress is the primary cause of death in most cancers, yet the regulatory dynamics driving the cellular changes necessary for metastasis remain poorly understood. Multi-omics approaches hold great promise for addressing this challenge; however, current analysis tools have limited capabilities to systematically integrate transcriptomic, epigenomic, and cistromic information to accurately define the regulatory networks critical for metastasis. RESULTS: To address this limitation, we use a purposefully generated cellular model of colon cancer invasiveness to generate multi-omics data, including expression, accessibility, and selected histone modification profiles, for increasing levels of invasiveness. We then adopt a rigorous probabilistic framework for joint inference from the resulting heterogeneous data, along with transcription factor binding profiles. Our approach uses probabilistic graphical models to leverage the functional information provided by specific epigenomic changes, models the influence of multiple transcription factors simultaneously, and automatically learns the activating or repressive roles of cis-regulatory events. Global analysis of these relationships reveals key transcription factors driving invasiveness, as well as their likely target genes. Disrupting the expression of one of the highly ranked transcription factors JunD, an AP-1 complex protein, confirms functional relevance to colon cancer cell migration and invasion. Transcriptomic profiling confirms key regulatory targets of JunD, and a gene signature derived from the model demonstrates strong prognostic potential in TCGA colorectal cancer data. CONCLUSIONS: Our work sheds new light into the complex molecular processes driving colon cancer metastasis and presents a statistically sound integrative approach to analyze multi-omics profiles of a dynamic biological process.
Authors: Andrea J Cohen; Alina Saiakhova; Olivia Corradin; Jennifer M Luppino; Katreya Lovrenert; Cynthia F Bartels; James J Morrow; Stephen C Mack; Gursimran Dhillon; Lydia Beard; Lois Myeroff; Matthew F Kalady; Joseph Willis; James E Bradner; Ruth A Keri; Nathan A Berger; Shondra M Pruett-Miller; Sanford D Markowitz; Peter C Scacheri Journal: Nat Commun Date: 2017-02-07 Impact factor: 14.919
Authors: Charles Blatti; Amin Emad; Matthew J Berry; Lisa Gatzke; Milt Epstein; Daniel Lanier; Pramod Rizal; Jing Ge; Xiaoxia Liao; Omar Sobh; Mike Lambert; Corey S Post; Jinfeng Xiao; Peter Groves; Aidan T Epstein; Xi Chen; Subhashini Srinivasan; Erik Lehnert; Krishna R Kalari; Liewei Wang; Richard M Weinshilboum; Jun S Song; C Victor Jongeneel; Jiawei Han; Umberto Ravaioli; Nahil Sobh; Colleen B Bushell; Saurabh Sinha Journal: PLoS Biol Date: 2020-01-23 Impact factor: 8.029