PHF6 cooperates with SWI/SNF complexes to facilitate transcriptional progression

Sep 21, 2026

Uploaded by Oliver

SWI/SNF (BAF) chromatin remodeling complex subunits are mutated in nearly 25% of cancers, including rhabdoid tumors (RTs) driven by SMARCB1 loss. Using a genome-scale CRISPR–Cas9 depletion screen across 896 cell lines, PHF6 is identified as specifically essential for RT survival. This dependency extends to SMARCB1-deficient cancers in vivo, with PHF6 co-localizing with SWI/SNF at promoters to maintain an active chromatin state. In the absence of SMARCB1, PHF6 loss disrupts recruitment and stability of residual SWI/SNF members, leading to reduced promoter activity and stalled RNA Polymerase II progression, providing a mechanistic link to Cofﬁn-Siris syndrome.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages17

Reading Time43 min

AccessFree to download

Background

SWI/SNF complexes and disease relevance

Rhabdoid tumors and SMARCB1 loss

Study design

CRISPR–Cas9 depletion screen across cancer cell lines

Findings

PHF6 is essential for RT survival

PHF6 dependency in vivo and syndromic link

PHF6–SWI/SNF promoter co-localization and transcriptional effects

Article [https://doi.org/10.1038/s41467-024-51566-5](https://doi.org/10.1038/s41467-024-51566-5) PHF6cooperateswith SWI/SNF complexesto facilitate transcriptional progression Received: 27 September 2023 | Accepted: 7 August 2024 | | --- | | | | Check for updates | Priya Mittal1, JacquelynA. Myers1, Raymond D. Carter 1, Sandi Radko-Juettner1,2, Hayden A. Malone 1,2, Wojciech Rosikiewicz 3, Alexis N. Robertson1, Zhexin Zhu1, Ishwarya V. Narayanan4, Baranda S. Hansen 5, Meadow Parrish1, Natarajan V. Bhanu6, Robert J. Mobley 1, Jerold E. Rehg7, Beisi Xu 3,7, Yiannis Drosos 1, Shondra M. Pruett-Miller 5, Mats Ljungman 4, Benjamin A. Garcia 6, Gang Wu 3,7, Janet F. Partridge 1 & Charles W. M. Roberts 1 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. Chromatin regulators function in part to facilitate the precise spatiotemporal gene regulation that underlies cell fate speciﬁcation. The importance of this function is exempliﬁed by the recurrent mutations observed in genes encoding subunits of the SWI/SNF chromatin remodeler, manifesting in both developmental disordersand cancers1–3. The discovery of bi-allelic inactivating mutations in the gene encoding the SWI/SNF subunit SMARCB1 in nearly all cases of rhabdoid tumor (RT) provided the ﬁrst link between SWI/SNF complexes and cancer4,5. RTs are highly aggressive cancers that typically develop in young children. They arise most frequently in the kidneys, brain, and liver and have poor survival outcomes6. Aside from SMARCB1 inactivation, RTshave remarkably simple diploid genomes, making them an ideal model 1Division of Molecular Oncology, Department of Oncology, St. Jude Children’s Research Hospital, Memphis, TN, USA. 2St. Jude Graduate School of Biomedical Sciences, St. Jude Children’s Research Hospital, Memphis, TN, USA. 3Center for Applied Bioinformatics, St. Jude Children’s Research Hospital, Memphis, TN, USA. 4Department of Radiation Oncology, Rogel Cancer Center and Center for RNA Biomedicine, University of Michigan, Ann Arbor, MI, USA. 5Center for Advanced Genome Engineering, Department of Cell and Molecular Biology, St. Jude Children’s Research Hospital, Memphis, TN, USA. 6Department of Biochemistry and Biophysics, Smilow Center for Translational Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. 7Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN, USA. [e-mail:](e-mail: Charles.roberts@stjude.org)[ Charles.roberts@stjude.org](e-mail: Charles.roberts@stjude.org) to gain mechanistic insights into the functional consequences of SWI/ SNF mutations in cancer7. SWI/SNF complexes are multi-protein assemblies that hydrolyze ATP to mobilize nucleosomes. There are three families of SWI/SNF complexes, cBAF, PBAF, and

FAQs

What role does PHF6 play in rhabdoid tumor survival?

PHF6 is specifically essential for RT cell survival as identified by a genome-scale CRISPR–Cas9 depletion screen.

Does PHF6 dependency occur beyond cell culture?

Yes. Dependency on PHF6 extends to Smarcb1-deficient cancers in vivo.

How does loss of SMARCB1 affect PHF6 and SWI/SNF function at promoters?

In the absence of SMARCB1, PHF6 loss disrupts recruitment and stability of residual SWI/SNF complex members, resulting in loss of active chromatin at promoters and stalling of RNA Polymerase II progression.

Sep 21, 2026

Uploaded by Oliver