Nfib Promotes Metastasis through a Widespread Increase in Chromatin Accessibility

Sarah K Denny; Dian Yang; Chen-Hua Chuang; Jennifer J Brady; Jing Shan Lim; Barbara M Grüner; Shin-Heng Chiou; Alicia N Schep; Jessika Baral; Cécile Hamard; Martine Antoine; Marie Wislez; Christina S Kong; Andrew J Connolly; Kwon-Sik Park; Julien Sage; William J Greenleaf; Monte M Winslow

doi:10.1016/j.cell.2016.05.052

Nfib Promotes Metastasis through a Widespread Increase in Chromatin Accessibility

Cell. 2016 Jul 14;166(2):328-342. doi: 10.1016/j.cell.2016.05.052. Epub 2016 Jun 30.

Authors

Sarah K Denny¹, Dian Yang², Chen-Hua Chuang³, Jennifer J Brady³, Jing Shan Lim², Barbara M Grüner³, Shin-Heng Chiou³, Alicia N Schep³, Jessika Baral³, Cécile Hamard⁴, Martine Antoine⁴, Marie Wislez⁴, Christina S Kong⁵, Andrew J Connolly⁵, Kwon-Sik Park⁶, Julien Sage⁷, William J Greenleaf⁸, Monte M Winslow⁹

Affiliations

¹ Biophysics Program, Stanford University School of Medicine, Stanford, CA 94305, USA.
² Cancer Biology Program, Stanford University School of Medicine, Stanford, CA 94305, USA.
³ Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁴ Service de Pneumologie, Hôpital Tenon-APHP, Université Paris 6 Pierre et Marie Curie, 75020 Paris, France.
⁵ Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁶ Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
⁷ Cancer Biology Program, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁸ Biophysics Program, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Applied Physics, Stanford University, Stanford, CA 94305, USA. Electronic address: wjg@stanford.edu.
⁹ Cancer Biology Program, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: mwinslow@stanford.edu.

Abstract

Metastases are the main cause of cancer deaths, but the mechanisms underlying metastatic progression remain poorly understood. We isolated pure populations of cancer cells from primary tumors and metastases from a genetically engineered mouse model of human small cell lung cancer (SCLC) to investigate the mechanisms that drive the metastatic spread of this lethal cancer. Genome-wide characterization of chromatin accessibility revealed the opening of large numbers of distal regulatory elements across the genome during metastatic progression. These changes correlate with copy number amplification of the Nfib locus, and differentially accessible sites were highly enriched for Nfib transcription factor binding sites. Nfib is necessary and sufficient to increase chromatin accessibility at a large subset of the intergenic regions. Nfib promotes pro-metastatic neuronal gene expression programs and drives the metastatic ability of SCLC cells. The identification of widespread chromatin changes during SCLC progression reveals an unexpected global reprogramming during metastatic progression.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Motifs
Animals
Cell Line, Tumor
Cells, Cultured
Disease Models, Animal
Gene Expression Regulation, Neoplastic
Gene Knockdown Techniques
Humans
Lung Neoplasms / genetics
Lung Neoplasms / metabolism
Lung Neoplasms / pathology*
Mice
NFI Transcription Factors / genetics
NFI Transcription Factors / metabolism*
Neoplasm Metastasis / pathology*
Promoter Regions, Genetic
Small Cell Lung Carcinoma / genetics
Small Cell Lung Carcinoma / metabolism
Small Cell Lung Carcinoma / pathology*
Up-Regulation

Substances

NFI Transcription Factors
Nfib protein, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding