PHF6 cooperates with SWI/SNF complexes to facilitate transcriptional progression

Priya Mittal, Jacquelyn A. Myers, Raymond D. Carter, Sandi Radko-Juettner, Hayden A. Malone, Wojciech Rosikiewicz, Alexis N. Robertson, Zhexin Zhu, Ishwarya V. Narayanan, Baranda S. Hansen, Meadow Parrish, Natarajan V. Bhanu, Robert J. Mobley, Jerold E. Rehg, Beisi Xu, Yiannis Drosos, Shondra M. Pruett-Miller, Mats Ljungman, Benjamin A. Garcia, Gang Wu, Janet F. Partridge and Charles W. M. Roberts ()
Additional contact information
Priya Mittal: St. Jude Children’s Research Hospital
Jacquelyn A. Myers: St. Jude Children’s Research Hospital
Raymond D. Carter: St. Jude Children’s Research Hospital
Sandi Radko-Juettner: St. Jude Children’s Research Hospital
Hayden A. Malone: St. Jude Children’s Research Hospital
Wojciech Rosikiewicz: St. Jude Children’s Research Hospital
Alexis N. Robertson: St. Jude Children’s Research Hospital
Zhexin Zhu: St. Jude Children’s Research Hospital
Ishwarya V. Narayanan: University of Michigan
Baranda S. Hansen: St. Jude Children’s Research Hospital
Meadow Parrish: St. Jude Children’s Research Hospital
Natarajan V. Bhanu: Smilow Center for Translational Research, Perelman School of Medicine, University of Pennsylvania
Robert J. Mobley: St. Jude Children’s Research Hospital
Jerold E. Rehg: St. Jude Children’s Research Hospital
Beisi Xu: St. Jude Children’s Research Hospital
Yiannis Drosos: St. Jude Children’s Research Hospital
Shondra M. Pruett-Miller: St. Jude Children’s Research Hospital
Mats Ljungman: University of Michigan
Benjamin A. Garcia: Smilow Center for Translational Research, Perelman School of Medicine, University of Pennsylvania
Gang Wu: St. Jude Children’s Research Hospital
Janet F. Partridge: St. Jude Children’s Research Hospital
Charles W. M. Roberts: St. Jude Children’s Research Hospital

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract Genes encoding subunits of SWI/SNF (BAF) chromatin remodeling complexes are mutated in nearly 25% of cancers. To gain insight into the mechanisms by which SWI/SNF mutations drive cancer, we contributed ten rhabdoid tumor (RT) cell lines mutant for SWI/SNF subunit SMARCB1 to a genome-scale CRISPR–Cas9 depletion screen performed across 896 cell lines. We identify PHF6 as specifically essential for RT cell survival and demonstrate that dependency on Phf6 extends to Smarcb1-deficient cancers in vivo. As mutations in either SWI/SNF or PHF6 can cause the neurodevelopmental disorder Coffin-Siris syndrome, our findings of a dependency suggest a previously unrecognized functional link. We demonstrate that PHF6 co-localizes with SWI/SNF complexes at promoters, where it is essential for maintenance of an active chromatin state. We show that in the absence of SMARCB1, PHF6 loss disrupts the recruitment and stability of residual SWI/SNF complex members, collectively resulting in the loss of active chromatin at promoters and stalling of RNA Polymerase II progression. Our work establishes a mechanistic basis for the shared syndromic features of SWI/SNF and PHF6 mutations in CSS and the basis for selective dependency on PHF6 in SMARCB1-mutant cancers.

Date: 2024
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DOI: 10.1038/s41467-024-51566-5

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