Nfib Promotes Metastasis through a Widespread Increase in Chromatin Accessibility

Sarah K. Denny, Dian Yang, Chen Hua Chuang, Jennifer J. Brady, Jing Shan S. 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

Research output: Contribution to journalArticlepeer-review

157 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)328-342
Number of pages15
Issue number2
StatePublished - Jul 14 2016
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)


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