scholarly journals Diverse compositions and functions of chromatin remodeling machines in cancer

2019 ◽  
Vol 11 (501) ◽  
pp. eaay1018 ◽  
Author(s):  
Cigall Kadoch
Keyword(s):  
Chromatin Remodeling ◽  
Cancer Genetics ◽  
Human Cancer ◽  
Chromatin Remodeling Complexes

Human cancer genetics power biochemical and functional interrogation of chromatin remodeling complexes, informing therapeutic opportunities.

scholarly journals Structure and Function of ATP-Dependent Chromatin Remodeling Complexes in Human Cancer

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. SCI-48-SCI-48
Author(s):  
Cigall Kadoch
Keyword(s):  
Chromatin Remodeling ◽  
Developmental Disorders ◽  
Human Cancer ◽  
Malignant Rhabdoid Tumor ◽  
Advisory Committees ◽  
Sequencing Studies ◽  
Genes Encoding ◽  
Therapeutic Development ◽  
Chromatin Remodeling Complexes ◽  
And Function

Dr. Cigall Kadoch will discuss how recent exome-and genome-wide sequencing studies in human cancers have unmasked a striking frequency of mutations in the genes encoding subunits of the mammalian SWI/SNF (mSWI/SNF) family of ATP-dependent chromatin remodeling complexes. Her laboratory uses biochemistry, structural biology, systems biology, and genomics-based approaches to define the mechanisms of chromatin and gene regulation carried out by the mSWI/SNF family of chromatin regulators. Specifically, they have studied rare, genetically well-defined pediatric cancers including synovial sarcoma, Ewing sarcoma, malignant rhabdoid tumor and others, all of which involve mSWI/SNF complex perturbations as critical drivers of their oncogenic programs. These studies have informed the diverse mechanisms underlying mSWI/SNF complex targeting and function in a wide array of cancers (including hematologic cancers) and developmental disorders and have provided new foundations for therapeutic development. Disclosures Kadoch: Foghorn Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

scholarly journals The emerging role of ISWI chromatin remodeling complexes in cancer

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Yanan Li ◽  
Han Gong ◽  
Pan Wang ◽  
Yu Zhu ◽  
Hongling Peng ◽  
...  
Keyword(s):  
Tumor Progression ◽  
Chromatin Remodeling ◽  
Regulatory Networks ◽  
Drug Response ◽  
Human Cancer ◽  
Regulation Mechanism ◽  
Aberrant Expression ◽  
Chromatin Remodeling Complexes ◽  
And Function

AbstractDisordered chromatin remodeling regulation has emerged as an essential driving factor for cancers. Imitation switch (ISWI) family are evolutionarily conserved ATP-dependent chromatin remodeling complexes, which are essential for cellular survival and function through multiple genetic and epigenetic mechanisms. Omics sequencing and a growing number of basic and clinical studies found that ISWI family members displayed widespread gene expression and genetic status abnormalities in human cancer. Their aberrant expression is closely linked to patient outcome and drug response. Functional or componential alteration in ISWI-containing complexes is critical for tumor initiation and development. Furthermore, ISWI-non-coding RNA regulatory networks and some non-coding RNAs derived from exons of ISWI member genes play important roles in tumor progression. Therefore, unveiling the transcriptional regulation mechanism underlying ISWI family sparked a booming interest in finding ISWI-based therapies in cancer. This review aims at describing the current state-of-the-art in the role of ISWI subunits and complexes in tumorigenesis, tumor progression, immunity and drug response, and presenting deep insight into the physiological and pathological implications of the ISWI transcription machinery in cancers.

scholarly journals Mammalian SWI/SNF chromatin remodeling complexes and cancer: Mechanistic insights gained from human genomics

2015 ◽  
Vol 1 (5) ◽  
pp. e1500447 ◽  
Author(s):  
Cigall Kadoch ◽  
Gerald R. Crabtree
Keyword(s):  
Chromatin Remodeling ◽  
Human Cancer ◽  
Human Genomics ◽  
Chromatin Remodelers ◽  
Fundamental Process ◽  
Sequencing Studies ◽  
Genes Encoding ◽  
Chromatin Remodeling Complexes ◽  
Tumor Types ◽  
Oncogenic Function

Over the past 4 years, nearly 100 exome sequencing studies have revealed the high frequency of mutations in the genes encoding the subunits of ATP-dependent chromatin remodelers in human cancer. Most of these mutations are within the genes encoding subunits of the BAF (Brg/Brahma-associated factors) or mSWI/SNF complex, which is one of two dozen predicted ATP-dependent chromatin remodeling complexes in mammals. Considering BAF complexes as a single entity, the 15 subunits encoded by 29 genes are mutated in >20% of human cancer, across a broad range of tumor types. These observations demonstrate that there is little redundancy in the oncogenic function of BAF complexes with the other remodeling complexes, underscoring their unique roles. Several important conclusions emerge from these genomic data: specific subunits appear to be mutated in specific cancers, highlighting tissue-specific protective roles; mutations can function as tumor suppressors or oncogenes; mutations can be homozygous or, more commonly, heterozygous, implying their dosage-sensitive roles in an unknown yet fundamental process used to suppress the genesis of cancer. These new human genetic findings paired with biochemical studies are challenging old ideas on how chromatin remodeling complexes function, generating new hypotheses with respect to their normal and oncogenic mechanisms and highlighting potential avenues for therapeutic intervention in human cancer.

scholarly journals Human cancer genetics

2006 ◽  
Vol 7 (2) ◽  
pp. 164-164
Author(s):  
Marilyn Li ◽  
Donna Albertson
Keyword(s):  
Cancer Genetics ◽  
Human Cancer

Abstract 17084: Nuclear Smooth Muscle α-actin Participates in Chromatin Remodeling at Smooth Muscle Contractile Gene Promoters

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Callie Kwartler ◽  
Shuangtao Ma ◽  
Caroline Kernell ◽  
Xue-yan Duan ◽  
Charis Wang ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Cardiac Muscle ◽  
Chromatin Remodeling ◽  
Muscle Cells ◽  
Cytoskeletal Proteins ◽  
Nuclear Localization Sequence ◽  
Serum Starvation ◽  
Cell Fractionation ◽  
Gene Promoters ◽  
Chromatin Remodeling Complexes

Actin genes encode for cytoskeletal proteins that polymerize to function in cellular motility, adhesion, and contraction. In mammalian cells, ubiquitously expressed β-actin also moves into the nucleus and associates with chromatin remodeling complexes, however a nuclear function of muscle-specific α-actins has not been previously assessed. We hypothesized that smooth muscle α-actin (SMA) plays a role in chromatin remodeling during the differentiation of smooth muscle cells (SMCs) to enable cell fate specification of SMCs. In explanted SMCs from human and mouse ascending aortas, cell fractionation and 2D gel electrophoresis identify both SMA and β-actin in the nuclear lysates. Nuclear SMA but not β-actin accumulates with SMC differentiation driven by serum starvation and transforming growth factor-β1 treatment. SMA accumulates into the nucleus early in the differentiation of SMCs from neural crest progenitor cells, prior to cytosolic accumulation. Immunoprecipitation studies show that SMA binds specifically to the INO80 and the SWI/SNF chromatin remodeling complexes, and this binding increases with SMC differentiation. Chromatin immunoprecipitation reveals that SMA is bound to the promoters of SMC-specific genes, including Acta2 , Cnn1, and Myh11 and that SMA is enriched over β-actin at these promoters with SMC differentiation. Finally, overexpression of SMA tagged with a nuclear localization sequence (NLS) in multiple cell types increases expression of SMC markers, whereas NLS-tagged β-actin localizes to the nucleus to the same extent but does not increase SMC marker expression in any cell type. Finally, we assessed whether skeletal muscle α-actin (SKA) and cardiac muscle α-actin (CMA) may play a similar role in skeletal and cardiac muscle cells. Both SKA and CMA translocate into the nucleus. CMA accumulates into the nucleus early in the differentiation of cardiomyocytes from pluripotent stem cells. Immunoprecipitation reveals that SKA binds to the SWI/SNF complex in differentiated C2C12 myotube cell cultures. These data support that nuclear SMA enriches with and participates in SMC differentiation, and suggest a potential nuclear role for other muscle specific α-actins in developing muscle cells.

scholarly journals Combinatorial depletion analysis to assemble the network architecture of the SAGA and ADA chromatin remodeling complexes

2011 ◽  
Vol 7 (1) ◽  
pp. 503 ◽  
Author(s):  
Kenneth K Lee ◽  
Mihaela E Sardiu ◽  
Selene K Swanson ◽  
Joshua M Gilmore ◽  
Michael Torok ◽  
...  
Keyword(s):  
Chromatin Remodeling ◽  
Network Architecture ◽  
Chromatin Remodeling Complexes

scholarly journals Identification and Functional Characterization of Protest SWI/SNF and ISWI Complexes

2021 ◽  
Author(s):  
Alejandro Saettone Chipana
Keyword(s):  
Chromatin Remodeling ◽  
Tetrahymena Thermophila ◽  
Affinity Purification ◽  
Functional Characterization ◽  
Peptide Array ◽  
Interacting Proteins ◽  
Silent Chromatin ◽  
Lysine Residues ◽  
Chromatin Remodeling Complexes

The thesis aims to identify and initiate functional characterization of the SWI/SNF and ISWI complexes in Tetrahymena thermophila. Through affinity purification of the conserved subunit Snf5 followed by mass spectrometry (AP-MS), I identified the first SWI/SNF complex in protists. One of the subunits I found is a small bromodomain containing protein named Ibd1. Through AP-MS of Ibd1 I found Ibd1 is versatile and interacts with several additional chromatin remodeling complexes. Bromodomains are known to have affinity for acetylated lysine residues within proteins such as histones. A peptide array experiment suggests that Ibd1 also has affinity for acetylated chromatin. Indirect immunofluorescence (IF) of Ibd1 hints at a role in transcription. My analysis of Tetrahymena Iswi1 shows expression during meiosis, vegetative growth and starvation. IF data shows its localization is consistent with Iswi1 function in mitosis/meiosis or maintenance of silent chromatin. AP-MS of ISW1 discovered several interacting proteins of unknown function.

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