HMS Virology

Virology Faculty Member - Cigall Kadoch

Cigall Kadoch

Associate Professor of Pediatric Oncology

Dana Farber Cancer Institute
Dana Building, Room 620
450 Brookline Avenue
Boston, MA 02115
Tel: 617-632-3789
Email: cigall_kadoch@dfci.harvard.edu
Visit my lab page here.



Our laboratory research program is centered in understanding the structure and function of ATP-dependent chromatin remodeling complexes, with emphasis on the mammalian SWI/SNF (mSWI/SNF or BAF) family of assemblies. Using a multidisciplinary set of approaches ranging from protein biochemistry and structural biology to functional genomics and systems biology, we aim to understand the mechanisms governing mSWI/SNF complex activity and genomic targeting in both normal and disease states. Human genetic sequencing efforts performed over the past several years have unmasked the major contributions of these chromatin regulators to human disease. Indeed, mutations in mSWI/SNF complex genes are present in over 20% of human cancers, including several rare cancers in which mSWI/SNF subunit perturbation is the hallmark and driving feature, occurring in 100% of cases. In addition, mSWI/SNF genes are frequently mutated in neurodevelopmental and intellectual disability syndromes, including autism, as well as immune conditions. Functional studies have revealed the essential roles of these complexes in biologic processes such as viral infection, T cell activation and specialization, among others. These studies underscore the important roles for mSWI/SNF complexes in regulating timely and appropriate chromatin accessibility and gene expression during cell and tissue development. Our lab pursues biochemical, structural, and functional studies across a range of in vitro, cell-based, and organoid and murine model systems coupled with advanced bioinformatics approaches and systems biology to understand mechanisms governing mSWI/SNF complex function and to inform new therapeutic opportunities.

Ongoing studies in the laboratory aim to determine the mechanisms by which subunit perturbation and subsequent structural changes misdirect ATP-dependent chromatin remodeling complex targeting and activity genome-wide. In addition, we aim to define the constellation of chromatin landscape features that directly or indirectly impact mSWI/SNF complex function, associated kinetics and dynamics, and the mechanism of antagonism with repressive chromatin regulatory complexes such as polycomb repressor complexes, enabling a comprehensive understanding of chromatin topology and gene regulation driven by this family of ATP-dependent chromatin remodeling machines.



Last Update: 5/11/2021



Publications

For a complete listing of publications click here.

 


 

Valencia AM, Collings CK, Dao HT, St Pierre R, Cheng YC, Huang J, Sun ZY, Seo HS, Mashtalir N, Comstock DE, Bolonduro O, Vangos NE, Yeoh ZC, Dornon MK, Hermawan C, Barrett L, Dhe-Paganon S, Woolf CJ, Muir TW, Kadoch C. Recurrent SMARCB1 Mutations Reveal a Nucleosome Acidic Patch Interaction Site That Potentiates mSWI/SNF Complex Chromatin Remodeling. Cell. 2019 Nov 27;179(6): 1342-1356.

Mashtalir N, Suzuki H, Farrell DP, Sankar A, Luo J, Filipovski M, D’Avino AR, St. Pierre R, Valencia AM, Onikubo T, Roeder RG, Han Y, He Y, Ranish JA, DiMaio F, Walz T,
Kadoch C. A structural model of the endogenous human BAF complex informs disease mechanisms. Cell. 2020 Oct 9: 183(3): 802-817.

Michel BC*, D’Avino AR*, Cassel SH*, Mashtalir N, McKenzie ZM, McBride MJ, Valencia AM, Zhou Q, Bocker M, Soares LMM, Pan J, Remillard DI, Lareau CA, Zullow HJ, Fortoul N, Gray NS, Bradner JE, Chan H,
Kadoch C. A non-canonical SWI/SNF complex is a synthetic lethal target in cancers driven by BAF complex perturbation. Nat Cell Biol. 2018 Dec;20(12):1410-1420.

Sandoval GJ, Pulice, J, Schenone M, Takeda DY, Pop, M, McBride MJ, Boulay GS, Rivera MN, Hahn WC,
Kadoch C. Binding of TMPRSS2-ERG to mSWI/SNF (BAF) complexes mediates prostate oncogenesis. Molecular Cell. 2018 Aug 16; 71(4):554-566.

Mashtalir
N, D’Avino AR*, Michel BC*, Luo J, Pan J, Otto JE, Zullow HJ, McKenzie MZ, Kubiak RL, St. Pierre R, Valencia AM, Poynter SJ, Cassel SH, Ranish JA, Kadoch C. Modular organization and assembly of SWI/SNF family chromatin remodeling complexes. Cell. 2018 Nov 15;175(5):1272-1288.e20.

Kadoch C and Crabtree GR. Reversible disruption of mSWI/SNF (BAF) complexes by the SS18-SSX oncogenic fusion in synovial sarcoma. Cell 2013 Mar 28; 153(1): 71-85.

See also: Svejstrup JQ. Synovial sarcoma mechanisms: a series of unfortunate events.
Cell 2013 Mar 28; 153(1): 11-12.

Kadoch C, Hargreaves DC, Hodges C, Elias LA, Ho L, Ranish J, and Crabtree GR. Proteomic and bioinformatic analysis of mammalian SWI/SNF complexes identifies extensive roles in human malignancy. Nature Genetics 2013 Jun;45(6):592-601.



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