ZFHX4 Interacts with the NuRD core member CHD4 and regulates the glioblastoma tumor-initiating cell state

Yakov Chudnovsky, Dohoon Kim, Siyuan Zheng, Warren A. Whyte, Mukesh Bansal, Mark Anthony Bray, Shuba Gopal, Matthew A. Theisen, Steve Bilodeau, Prathapan Thiru, Julien Muffat, Omer H. Yilmaz, Maya Mitalipova, Kevin Woolard, Jeongwu Lee, Riko Nishimura, Nobuo Sakata, Howard A. Fine, Anne E. Carpenter, Serena J. SilverRoel G.W. Verhaak, Andrea Califano, Richard A. Young, Keith L. Ligon, Ingo K. Mellinghoff, David E. Root, David M. Sabatini, William C. Hahn, Milan G. Chheda

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60 Scopus citations

Abstract

Glioblastoma (GBM) harbors subpopulations of therapy-resistant tumor-initiating cells (TICs) that are self-renewing and multipotent. To understand the regulation of the TIC state, we performed an image-based screen for genes regulating GBM TIC maintenance and identified ZFHX4, a 397kDa transcription factor. ZFHX4 is required to maintain TIC-associated and normal human neural precursor cell phenotypes invitro, suggesting that ZFHX4 regulates differentiation, and its suppression increases glioma-free survival in intracranial xenografts. ZFHX4 interacts with CHD4, a core member of the nucleosome remodeling and deacetylase (NuRD) complex. ZFHX4 and CHD4 bind to overlapping sets of genomic loci and control similar gene expression programs. Using expression data derived from GBM patients, we found that ZFHX4 significantly affects CHD4-mediated gene expression perturbations, which defines ZFHX4 as a master regulator of CHD4. These observations define ZFHX4 as a regulatory factor that links the chromatin-remodeling NuRD complex and the GBM TIC state.

Original languageEnglish (US)
Pages (from-to)313-324
Number of pages12
JournalCell Reports
Volume6
Issue number2
DOIs
StatePublished - Jan 17 2014

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Chudnovsky, Y., Kim, D., Zheng, S., Whyte, W. A., Bansal, M., Bray, M. A., Gopal, S., Theisen, M. A., Bilodeau, S., Thiru, P., Muffat, J., Yilmaz, O. H., Mitalipova, M., Woolard, K., Lee, J., Nishimura, R., Sakata, N., Fine, H. A., Carpenter, A. E., ... Chheda, M. G. (2014). ZFHX4 Interacts with the NuRD core member CHD4 and regulates the glioblastoma tumor-initiating cell state. Cell Reports, 6(2), 313-324. https://doi.org/10.1016/j.celrep.2013.12.032