The SWI/SNF Family of ATP-Dependent Chromatin Remodelers: Similar Mechanisms for Diverse Functions

While loss-of-function mutations in Cockayne syndrome group B protein (CSB) cause neurological diseases, this unique member of the SWI2/SNF2 family of chromatin remodelers has been broadly implicated in transcription elongation and transcription-coupled DNA damage repair, yet its mechanism remains largely elusive. Here, we use a reconstituted in vitro transcription system with purified polymerase II (Pol II) and Rad26, a yeast ortholog of CSB, to study the role of CSB in transcription elongation through nucleosome barriers. We show that CSB forms a stable complex with Pol II and acts as an ATP-dependent processivity factor that helps Pol II across a nucleosome barrier. This noncanonical mechanism is distinct from the canonical modes of chromatin remodelers that directly engage and remodel nucleosomes or transcription elongation factors that facilitate Pol II nucleosome bypass without hydrolyzing ATP. We propose a model where CSB facilitates gene expression by helping Pol II bypass chromatin obstacles while maintaining their structures.

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Ruler elements in chromatin remodelers set nucleosome array spacing and phasing

Nature Communications ◽

10.1038/s41467-021-23015-0 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Elisa Oberbeckmann ◽

Vanessa Niebauer ◽

Shinya Watanabe ◽

Lucas Farnung ◽

Manuela Moldt ◽

...

Keyword(s):

Phased Arrays ◽

Stable Steady State ◽

Reference Sites ◽

Chromatin Remodelers ◽

Sliding Direction ◽

Nucleosome Dynamics ◽

Genome Wide ◽

Sequence Elements ◽

Nucleosome Array ◽

Dna Ends

AbstractArrays of regularly spaced nucleosomes dominate chromatin and are often phased by alignment to reference sites like active promoters. How the distances between nucleosomes (spacing), and between phasing sites and nucleosomes are determined remains unclear, and specifically, how ATP-dependent chromatin remodelers impact these features. Here, we used genome-wide reconstitution to probe how Saccharomyces cerevisiae ATP-dependent remodelers generate phased arrays of regularly spaced nucleosomes. We find that remodelers bear a functional element named the ‘ruler’ that determines spacing and phasing in a remodeler-specific way. We use structure-based mutagenesis to identify and tune the ruler element residing in the Nhp10 and Arp8 modules of the INO80 remodeler complex. Generally, we propose that a remodeler ruler regulates nucleosome sliding direction bias in response to (epi)genetic information. This finally conceptualizes how remodeler-mediated nucleosome dynamics determine stable steady-state nucleosome positioning relative to other nucleosomes, DNA bound factors, DNA ends and DNA sequence elements.

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The Roles of Chromatin Accessibility in Regulating the Candida albicans White-Opaque Phenotypic Switch

Journal of Fungi ◽

10.3390/jof7010037 ◽

2021 ◽

Vol 7 (1) ◽

pp. 37

Author(s):

Mohammad N. Qasim ◽

Ashley Valle Arevalo ◽

Clarissa J. Nobile ◽

Aaron D. Hernday

Keyword(s):

Candida Albicans ◽

Cell Fate ◽

Cell Types ◽

Chromatin Accessibility ◽

Phenotypic Switching ◽

Phenotypic Switch ◽

Chromatin Remodelers ◽

Environmental Signals ◽

Cell Fate Decisions ◽

Simple Model System

Candida albicans, a diploid polymorphic fungus, has evolved a unique heritable epigenetic program that enables reversible phenotypic switching between two cell types, referred to as “white” and “opaque”. These cell types are established and maintained by distinct transcriptional programs that lead to differences in metabolic preferences, mating competencies, cellular morphologies, responses to environmental signals, interactions with the host innate immune system, and expression of approximately 20% of genes in the genome. Transcription factors (defined as sequence specific DNA-binding proteins) that regulate the establishment and heritable maintenance of the white and opaque cell types have been a primary focus of investigation in the field; however, other factors that impact chromatin accessibility, such as histone modifying enzymes, chromatin remodelers, and histone chaperone complexes, also modulate the dynamics of the white-opaque switch and have been much less studied to date. Overall, the white-opaque switch represents an attractive and relatively “simple” model system for understanding the logic and regulatory mechanisms by which heritable cell fate decisions are determined in higher eukaryotes. Here we review recent discoveries on the roles of chromatin accessibility in regulating the C. albicans white-opaque phenotypic switch.

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Functional antagonism of chromatin modulators regulates epithelial-mesenchymal transition

Science Advances ◽

10.1126/sciadv.abd7974 ◽

2021 ◽

Vol 7 (9) ◽

pp. eabd7974

Author(s):

Michela Serresi ◽

Sonia Kertalli ◽

Lifei Li ◽

Matthias Jürgen Schmitt ◽

Yuliia Dramaretska ◽

...

Keyword(s):

Cancer Cells ◽

Transcriptional Control ◽

Molecular Mechanisms ◽

Developmental Process ◽

Epithelial Mesenchymal Transition ◽

Chromatin Remodelers ◽

Mesenchymal Transition ◽

Signature Genes ◽

Chromatin Regulators ◽

The Impact

Epithelial-mesenchymal transition (EMT) is a developmental process hijacked by cancer cells to modulate proliferation, migration, and stress response. Whereas kinase signaling is believed to be an EMT driver, the molecular mechanisms underlying epithelial-mesenchymal interconversion are incompletely understood. Here, we show that the impact of chromatin regulators on EMT interconversion is broader than that of kinases. By combining pharmacological modulation of EMT, synthetic genetic tracing, and CRISPR interference screens, we uncovered a minority of kinases and several chromatin remodelers, writers, and readers governing homeostatic EMT in lung cancer cells. Loss of ARID1A, DOT1L, BRD2, and ZMYND8 had nondeterministic and sometimes opposite consequences on epithelial-mesenchymal interconversion. Together with RNAPII and AP-1, these antagonistic gatekeepers control chromatin of active enhancers, including pan-cancer-EMT signature genes enabling supraclassification of anatomically diverse tumors. Thus, our data uncover general principles underlying transcriptional control of cancer cell plasticity and offer a platform to systematically explore chromatin regulators in tumor-state–specific therapy.

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ARID2 Chromatin Remodeler in Hepatocellular Carcinoma

Cells ◽

10.3390/cells9102152 ◽

2020 ◽

Vol 9 (10) ◽

pp. 2152

Author(s):

Robin Loesch ◽

Linda Chenane ◽

Sabine Colnot

Keyword(s):

Gene Expression ◽

Hepatocellular Carcinoma ◽

Associated Factors ◽

Regulation Of Gene Expression ◽

Specific Gene ◽

Chromatin Remodeler ◽

Chromatin Remodelers ◽

Genes Encoding ◽

Gene Alterations

Chromatin remodelers are found highly mutated in cancer including hepatocellular carcinoma. These mutations frequently occur in ARID (AT-rich Interactive Domain) genes, encoding subunits of the ATP-dependent SWI/SNF remodelers. The increasingly prevalent complexity that surrounds the functions and specificities of the highly modular BAF (BG1/BRM-associated factors) and PBAF (polybromo-associated BAF) complexes, including ARID1A/B or ARID2, is baffling. The involvement of the SWI/SNF complexes in diverse tissues and processes, and especially in the regulation of gene expression, multiplies the specific outcomes of specific gene alterations. A better understanding of the molecular consequences of specific mutations impairing chromatin remodelers is needed. In this review, we summarize what we know about the tumor-modulating properties of ARID2 in hepatocellular carcinoma.

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Quantifying transient binding of ISWI chromatin remodelers in living cells by pixel-wise photobleaching profile evolution analysis

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1209579109 ◽

2012 ◽

Vol 109 (47) ◽

pp. E3221-E3230 ◽

Cited By ~ 9

Author(s):

F. Erdel ◽

K. Rippe

Keyword(s):

Living Cells ◽

Chromatin Remodelers ◽

Evolution Analysis

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The Landscape of Signaling Pathways and Proteasome Inhibitors Combinations in Multiple Myeloma

Cancers ◽

10.3390/cancers13061235 ◽

2021 ◽

Vol 13 (6) ◽

pp. 1235

Author(s):

Tina Paradzik ◽

Cecilia Bandini ◽

Elisabetta Mereu ◽

Maria Labrador ◽

Elisa Taiana ◽

...

Keyword(s):

Multiple Myeloma ◽

Signaling Pathways ◽

Plasma Cells ◽

Proteasome Inhibitors ◽

Treatment Resistance ◽

Positive Outcome ◽

Chromatin Remodelers ◽

Histone Modifiers ◽

Substantial Progress ◽

Immune Dysfunctions

Multiple myeloma is a malignancy of terminally differentiated plasma cells, characterized by an extreme genetic heterogeneity that poses great challenges for its successful treatment. Due to antibody overproduction, MM cells depend on the precise regulation of the protein degradation systems. Despite the success of PIs in MM treatment, resistance and adverse toxic effects such as peripheral neuropathy and cardiotoxicity could arise. To this end, the use of rational combinatorial treatments might allow lowering the dose of inhibitors and therefore, minimize their side-effects. Even though the suppression of different cellular pathways in combination with proteasome inhibitors have shown remarkable anti-myeloma activities in preclinical models, many of these promising combinations often failed in clinical trials. Substantial progress has been made by the simultaneous targeting of proteasome and different aspects of MM-associated immune dysfunctions. Moreover, targeting deranged metabolic hubs could represent a new avenue to identify effective therapeutic combinations with PIs. Finally, epigenetic drugs targeting either DNA methylation, histone modifiers/readers, or chromatin remodelers are showing pleiotropic anti-myeloma effects alone and in combination with PIs. We envisage that the positive outcome of patients will probably depend on the availability of more effective drug combinations and treatment of early MM stages. Therefore, the identification of sensitive targets and aberrant signaling pathways is instrumental for the development of new personalized therapies for MM patients.

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