Mammalian SWI/SNF complexes are ATP-dependent chromatin remodeling complexes that regulate genomic architecture. Here, we present a structural model of the endogenously purified human canonical BAF complex bound to the nucleosome, generated using cryoelectron microscopy (cryo-EM), cross-linking mass spectrometry, and homology modeling. BAF complexes bilaterally engage the nucleosome H2A/H2B acidic patch regions through the SMARCB1 C-terminal α-helix and the SMARCA4/2 C-terminal SnAc/post-SnAc regions, with disease-associated mutations in either causing attenuated chromatin remodeling activities. Further, we define changes in BAF complex architecture upon nucleosome engagement and compare the structural model of endogenous BAF to those of related SWI/SNF-family complexes. Finally, we assign and experimentally interrogate cancer-associated hot-spot mutations localizing within the endogenous human BAF complex, identifying those that disrupt BAF subunit-subunit and subunit-nucleosome interfaces in the nucleosome-bound conformation. Taken together, this integrative structural approach provides important biophysical foundations for understanding the mechanisms of BAF complex function in normal and disease states.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7717177 | PMC |
| http://dx.doi.org/10.1016/j.cell.2020.09.051 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Differentiation therapy targeting the stalled epigenetic developmental programs in pediatric high-grade gliomas.
Pharmacol Res
January 2025
Department of Physiology, Tongji Medical College of Huazhong University of Science & Technology, Wuhan, 430030, PR China. Electronic address:
Pediatric high-grade gliomas (pHGGs) are the most common brain malignancies in children and are characterized by blocked differentiation. The epigenetic landscape of pHGGs, particularly the H3K27-altered and H3G34-mutant subtypes, suggests these tumors may be particularly susceptible to strategies that target blocked differentiation. Differentiation therapy aims to overcome this differentiation blockade by promoting glioma cell differentiation into more mature and less malignant cells.
View Article and Find Full Text PDFArgonaute proteins are best known for their role in microRNA-mediated post-transcriptional gene silencing. Here, we show that AGO3 and AGO4, but not AGO2, localize to the sex chromatin of pachytene spermatocytes where they are required for transcriptional silencing of XY-linked genes, known as Meiotic Sex Chromosome Inactivation (MSCI). Using an mouse, we show that AGO3 and AGO4 are key regulators of spermatogenesis, orchestrating expression of meiosis-related genes during prophase I while maintaining silencing of spermiogenesis genes.
View Article and Find Full Text PDFDiscovery of FHD-286, a First-in-Class, Orally Bioavailable, Allosteric Dual Inhibitor of the Brahma Homologue (BRM) and Brahma-Related Gene 1 (BRG1) ATPase Activity for the Treatment of SWItch/Sucrose Non-Fermentable (SWI/SNF) Dependent Cancers.
J Med Chem
January 2025
Foghorn Therapeutics, 500 Technology Square, Suite 700, Cambridge, Massachusetts 02139, United States.
BRM (SMARCA2) and BRG1 (SMARCA4) are mutually exclusive ATPase subunits of the mSWI/SNF (BAF) chromatin remodeling complex. BAF is an attractive therapeutic target because of its role in transcription, and mutations in the subunits of BAF are common in cancer and neurological disorders. Herein, we report the discovery of compound () as a potent allosteric inhibitor of the dual ATPase subunits from a high-throughput screening hit with a BRM IC of ∼27 μM.
View Article and Find Full Text PDFPIKFYVE deficiency induces vacuole-like cataract via perturbing late endosome homeostasis.
Biochem Biophys Res Commun
February 2025
Department of Ophthalmology, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, China. Electronic address:
Phosphoinositide kinase, FYVE-type zinc finger containing (PIKFYVE) was recently identified as a causative gene for cataract. Pikfyve phosphatidylinositol phosphate kinase domain-deficient (pikfyve) zebrafish lens and PIKFYVE-inhibited human lens epithelial cells developed vacuoles, colocalized with late endosome marker RAB7. In this study, the pikfyvezebrafish with vacuole-like cataract underwent transcriptomic and proteomic analyses to explore the underlying mechanisms of vacuole formation.
View Article and Find Full Text PDFHuntingtin interactome reveals huntingtin role in regulation of double strand break DNA damage response (DSB/DDR), chromatin remodeling and RNA processing pathways.
bioRxiv
December 2024
Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, 600 North Wolfe Street, CMSC 5 South, Baltimore, MD21287.
Huntington's Disease (HD), a progressive neurodegenerative disorder with no disease-modifying therapies, is caused by a CAG repeat expansion in the HD gene encoding polyglutamine-expanded huntingtin (HTT) protein. Mechanisms of HD cellular pathogenesis and cellular functions of the normal and mutant HTT proteins are still not completely understood. HTT protein has numerous interaction partners, and it likely provides a scaffold for assembly of multiprotein complexes many of which may be altered in HD.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!