A Structural Model of the Endogenous Human BAF Complex Informs Disease Mechanisms

Mashtalir, Nazar; Suzuki, Hiroshi; Farrell, Daniel P.; Sankar, Akshay; Luo, Jie; Filipovski, Martin; D’Avino, Andrew R.; Pierre, Roodolph St.; Valencia, Alfredo M.; Onikubo, Takashi; Roeder, Robert G.; Han, Yanping; Ranish, Jeffrey A.; DiMaio, Frank; Walz, Thomas; Kadoch, Cigall

doi:10.1016/j.cell.2020.09.051

Cited by 122 publications

(151 citation statements)

References 75 publications

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“…Recent structural studies (He et al, 2020;Mashtalir et al, 2020) suggest that this specificity emerges from combinatorial assembly of the products of 29 genes encoding the 15 subunits creating composite surfaces at their interfaces available to interact with proteins such as TEADs and YAP.…”

Section: Discussionmentioning

confidence: 99%

“…Mammalian SWI/SNF (also known as BAF) complexes belong to a family of ATP-dependent chromatin remodelers, which contain an ATPase motor that binds nucleosomes and acts to distort or disrupt DNA-histone contacts (Clapier et al, 2017; He et al, 2020; Mashtalir et al, 2020). The enzymatic remodeling activity of the BAF complex is critical for gene regulation allowing specific transcription factors to access their recognition sites (Barisic et al, 2019; Clapier et al, 2017; Kadoch and Crabtree, 2015).…”

Section: Introductionmentioning

confidence: 99%

“…Meanwhile, it also facilitates chromatin access for machinery regulating DNA repair, DNA decatenation, and other nuclear processes (Clapier et al, 2017; Kadoch and Crabtree, 2015). BAF complexes are combinatorially assembled from 15 different subunits encoded by 29 genes (He et al, 2020; Kadoch et al, 2013; Mashtalir et al, 2020). They lack sequence-specific DNA recognition; however, subunits of BAF complexes contain domains involved in binding to diverse histone modifications, AT-rich sequences, cruciform DNA structures as well as chromatin and transcriptional regulators that act in concert to guide BAF complex targeting over the genome (Kadoch and Crabtree, 2015).…”

Section: Introductionmentioning

confidence: 99%

“…This fusion retargets BAF across the genome to reverse polycomb-mediated repression and activate oncogenes including SOX2 (Kadoch and Crabtree, 2013). Thus, alterations in individual subunits compromise specific biologic actions of BAF complexes, and identifying the underpinning mechanisms holds potential for development of targeted therapy (Kadoch and Crabtree, 2015; Mashtalir et al, 2020; Wilson and Roberts, 2011).…”

Section: Introductionmentioning

confidence: 99%

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Increased ACTL6A Occupancy Within mSWI/SNF Chromatin Remodelers Drives Human Squamous Cell Carcinoma

Chang

Shipony

Kuo

et al. 2021

Preprint

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Mammalian SWI/SNF (BAF) chromatin remodelers play dosage-sensitive roles in many human malignancies and neurologic disorders. The gene encoding the BAF subunit, ACTL6A, is amplified at an early stage in the development of squamous cell carcinomas (SCCs), but its oncogenic role remains unclear. Here we demonstrate that ACTL6A overexpression leads to its stoichiometric assembly into BAF complexes and drives its interaction and engagement with specific regulatory regions in the genome. In normal epithelial cells, ACTL6A was sub-stoichiometric to other BAF subunits. However, increased ACTL6A levels by ectopic expression or in SCC cells led to near-saturation of ACTL6A within BAF complexes. Increased ACTL6A occupancy enhanced polycomb opposition over the genome activating SCC genes and also enhanced the recruitment of transcription factor TEAD with its co-activator YAP, promoting their chromatin binding and enhancer accessibility. Both of these mechanisms appeared to be critical and function as a molecular AND gate for SCC initiation and maintenance, thereby explaining the specificity of the role of ACTL6A amplification in SCCs.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Increased ACTL6A Occupancy Within mSWI/SNF Chromatin Remodelers Drives Human Squamous Cell Carcinoma

Chang

Shipony

Kuo

et al. 2021

Preprint

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“…As opposed to BRD4, BRD9 is a selective dependency in certain cancer types, including AML and synovial sarcoma [ 238 , 239 , 240 ]. BRD9 is a part of the mammalian SWI/SNF chromatin remodeling complex, more specifically the ncBAF complex [ 241 , 242 ]. Dysfunctional BAF-complexes have a specific relevance in synovial sarcoma, since the disease is driven by SS18-SSX fusion oncogenes.…”

Section: Hijacking the Proteasome For Targeted Protein Degradationmentioning

confidence: 99%

Targeting Chromatin Complexes in Myeloid Malignancies and Beyond: From Basic Mechanisms to Clinical Innovation

Perner

Armstrong

2020

Cells

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The aberrant function of chromatin regulatory networks (epigenetics) is a hallmark of cancer promoting oncogenic gene expression. A growing body of evidence suggests that the disruption of specific chromatin-associated protein complexes has therapeutic potential in malignant conditions, particularly those that are driven by aberrant chromatin modifiers. Of note, a number of enzymatic inhibitors that block the catalytic function of histone modifying enzymes have been established and entered clinical trials. Unfortunately, many of these molecules do not have potent single-agent activity. One potential explanation for this phenomenon is the fact that those drugs do not profoundly disrupt the integrity of the aberrant network of multiprotein complexes on chromatin. Recent advances in drug development have led to the establishment of novel inhibitors of protein–protein interactions as well as targeted protein degraders that may provide inroads to longstanding effort to physically disrupt oncogenic multiprotein complexes on chromatin. In this review, we summarize some of the current concepts on the role epigenetic modifiers in malignant chromatin states with a specific focus on myeloid malignancies and recent advances in early-phase clinical trials.

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Resolving the Amino Acid Sequence of Aβ_1‐42 at the Single‐Residue Level Using Subnanopores in Ultrathin Films

Chen,

Meng,

Xie

et al. 2024

Adv Funct Materials

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Proteoforms are proteins derived from highly related genes or post translational modifications (PTMs) of the same protein. They share extremely similar primary structures but have varying functions. Unfortunately, protein de novo sequencing including specific PTM/mutation detection is still challenging. Herein, a nanopore‐based technique is reported to resolve the amino acid order of amyloid‐β (Aβ1‐42) with site specificity. Subnanopores are sputtered in 5 nm‐thick inorganic membranes with a sensing depth of 0.66 nm inferred by finite element analysis. Denatured molecules at 0.45 ng mL−1 translocate through subnanopores while the current traces are sampled at 500 kHz with rms noise <15 pA. Hundreds of blockades are clustered using machine learning, and multiple blockades are averaged to establish current consensus. Consensus traces strongly correlate with a linear model of amino acid volume of Aβ1‐42 at single residue resolution, with Pearson Correlation Coefficients (PCCs) of 0.81 ± 0.03 and 0.92 ± 0.03 before and after dynamic time warping (DTW). A scrambled version of Aβ1‐42 is tested for validation purposes. Deep learning classification reveals that different polypeptides generate distinct translocation fluctuating patterns, but variations become imperceptible for the same species measured across nanopores (Area Under the Curve, AUC 0.93 ± 0.05 vs 0.64 ± 0.12). Lastly, important PTMs and mutations are site‐specifically located along the primary structure, implying new potential clinical applications.

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A Structural Model of the Endogenous Human BAF Complex Informs Disease Mechanisms

Cited by 122 publications

References 75 publications

Increased ACTL6A Occupancy Within mSWI/SNF Chromatin Remodelers Drives Human Squamous Cell Carcinoma

Increased ACTL6A Occupancy Within mSWI/SNF Chromatin Remodelers Drives Human Squamous Cell Carcinoma

Targeting Chromatin Complexes in Myeloid Malignancies and Beyond: From Basic Mechanisms to Clinical Innovation

Resolving the Amino Acid Sequence of Aβ_1‐42 at the Single‐Residue Level Using Subnanopores in Ultrathin Films

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A Structural Model of the Endogenous Human BAF Complex Informs Disease Mechanisms

Cited by 122 publications

References 75 publications

Increased ACTL6A Occupancy Within mSWI/SNF Chromatin Remodelers Drives Human Squamous Cell Carcinoma

Increased ACTL6A Occupancy Within mSWI/SNF Chromatin Remodelers Drives Human Squamous Cell Carcinoma

Targeting Chromatin Complexes in Myeloid Malignancies and Beyond: From Basic Mechanisms to Clinical Innovation

Resolving the Amino Acid Sequence of Aβ1‐42 at the Single‐Residue Level Using Subnanopores in Ultrathin Films

Contact Info

Product

Resources

About

Resolving the Amino Acid Sequence of Aβ_1‐42 at the Single‐Residue Level Using Subnanopores in Ultrathin Films