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 D 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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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 - 2014

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Neoplastic Stem Cells
Nucleosomes
Glioblastoma
Tumors
Mi-2 Nucleosome Remodeling and Deacetylase Complex
Gene expression
Cells
Gene Expression
Chromatin Assembly and Disassembly
Internal-External Control
Ports and harbors
Heterografts
Glioma
Chromatin
Transcription Factors
Genes
Maintenance
Phenotype
Survival

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., ... 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

ZFHX4 Interacts with the NuRD core member CHD4 and regulates the glioblastoma tumor-initiating cell state. / Chudnovsky, Yakov; Kim, Dohoon; Zheng, Siyuan; Whyte, Warren A.; Bansal, Mukesh; Bray, Mark Anthony; Gopal, Shuba; Theisen, Matthew A.; Bilodeau, Steve; Thiru, Prathapan; Muffat, Julien; Yilmaz, Omer H.; Mitalipova, Maya; Woolard, Kevin D; Lee, Jeongwu; Nishimura, Riko; Sakata, Nobuo; Fine, Howard A.; Carpenter, Anne E.; Silver, Serena J.; Verhaak, Roel G W; Califano, Andrea; Young, Richard A.; Ligon, Keith L.; Mellinghoff, Ingo K.; Root, David E.; Sabatini, David M.; Hahn, William C.; Chheda, Milan G.

In: Cell Reports, Vol. 6, No. 2, 2014, p. 313-324.

Research output: Contribution to journalArticle

Chudnovsky, Y, Kim, D, Zheng, S, Whyte, WA, Bansal, M, Bray, MA, Gopal, S, Theisen, MA, Bilodeau, S, Thiru, P, Muffat, J, Yilmaz, OH, Mitalipova, M, Woolard, KD, Lee, J, Nishimura, R, Sakata, N, Fine, HA, Carpenter, AE, Silver, SJ, Verhaak, RGW, Califano, A, Young, RA, Ligon, KL, Mellinghoff, IK, Root, DE, Sabatini, DM, Hahn, WC & Chheda, MG 2014, 'ZFHX4 Interacts with the NuRD core member CHD4 and regulates the glioblastoma tumor-initiating cell state', Cell Reports, vol. 6, no. 2, pp. 313-324. https://doi.org/10.1016/j.celrep.2013.12.032
Chudnovsky, Yakov ; Kim, Dohoon ; Zheng, Siyuan ; Whyte, Warren A. ; Bansal, Mukesh ; Bray, Mark Anthony ; Gopal, Shuba ; Theisen, Matthew A. ; Bilodeau, Steve ; Thiru, Prathapan ; Muffat, Julien ; Yilmaz, Omer H. ; Mitalipova, Maya ; Woolard, Kevin D ; Lee, Jeongwu ; Nishimura, Riko ; Sakata, Nobuo ; Fine, Howard A. ; Carpenter, Anne E. ; Silver, Serena J. ; Verhaak, Roel G W ; Califano, Andrea ; Young, Richard A. ; Ligon, Keith L. ; Mellinghoff, Ingo K. ; Root, David E. ; Sabatini, David M. ; Hahn, William C. ; Chheda, Milan G. / ZFHX4 Interacts with the NuRD core member CHD4 and regulates the glioblastoma tumor-initiating cell state. In: Cell Reports. 2014 ; Vol. 6, No. 2. pp. 313-324.
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AU - Chudnovsky, Yakov

AU - Kim, Dohoon

AU - Zheng, Siyuan

AU - Whyte, Warren A.

AU - Bansal, Mukesh

AU - Bray, Mark Anthony

AU - Gopal, Shuba

AU - Theisen, Matthew A.

AU - Bilodeau, Steve

AU - Thiru, Prathapan

AU - Muffat, Julien

AU - Yilmaz, Omer H.

AU - Mitalipova, Maya

AU - Woolard, Kevin D

AU - Lee, Jeongwu

AU - Nishimura, Riko

AU - Sakata, Nobuo

AU - Fine, Howard A.

AU - Carpenter, Anne E.

AU - Silver, Serena J.

AU - Verhaak, Roel G W

AU - Califano, Andrea

AU - Young, Richard A.

AU - Ligon, Keith L.

AU - Mellinghoff, Ingo K.

AU - Root, David E.

AU - Sabatini, David M.

AU - Hahn, William C.

AU - Chheda, Milan G.

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

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