Advances in the role of SWI/SNF complexes in tumours

Cancer development is a complex process involving both genetic and epigenetic changes. The SWI/SNF (switch/sucrose non-fermentable) chromatin remodelling complex, one of the most studied ATP-dependent complexes, plays an important role in coordinating chromatin structural stability, gene expression and post-translational modifications. The SWI/SNF complex can be classified into BAF, PBAF and GBAF according to their constituent subunits. Cancer genome sequencing studies have shown a high incidence of mutations in genes encoding subunits of the SWI/SNF chromatin remodelling complex, with abnormalities in one or more of these genes present in nearly 25% of all cancers, which indicating that stabilizing normal expression of genes encoding subunits in the SWI/SNF complex may prevent tumorigenesis. In this paper, we will review the relationship between the SWI/SNF complex and some clinical tumours and its mechanism of action. The aim is to provide a theoretical basis to guide the diagnosis and treatment of tumours caused by mutations or inactivation of one or more genes encoding subunits of the SWI/SNF complex in the clinical setting.     

Remodelling chromatin to shape development of plants

Establishment and dynamic regulation of a higher order chromatin structure is an essential component of development. Chromatin remodelling complexes such as the SWI2/SNF2 family of ATP-dependent chromatin remodellers can alter chromatin architecture by changing nucleosome positioning or substituting histones with histone variants. These remodellers often act in concert with chromatin modifiers such as the polycomb group proteins which confer repressive states through modification of histone tails. These mechanisms are highly conserved across the eukaryotic kingdom although in plants, owing to the maintenance of dedifferentiated cell states that allow for post-embyronic changes in development, strict control of chromatin remodelling is even more paramount. Recent and ongoing studies in the model plant Arabidopsis thaliana have found that while the major families of the SWI2/SNF2 ATPase chromatin remodellers are represented, a number of redundancies and divergent functions have emerged that show a break from the roles of their metazoan counterparts. This review focusses on the SNF2 and CHD families of ATP-dependent remodellers and their roles in plant development.     

Chromatin remodeling in plants

In the past two years, a variety of forward genetic screens have revealed predicted plant chromatin remodeling components that are involved in either differential histone acetylation or ATP-dependent SWI2/SNF2-related complexes. Combined with the results of recent reverse genetic studies, these findings have begun to provide the groundwork for determining the function of chromatin-based control in plants.     

A SWI/SNF-like factor from chicken liver that disrupts nucleosomes and transfers histone octamers in cis and trans

ATP-dependent chromatin remodeling factors have been implicated in nuclear processes involving DNA. Here we report partial purification and characterization of an ATP-dependent chromatin remodeling activity from chicken liver. Nuclear extract from chicken liver was fractionated chromatographically to enrich proteins immunoreacting to antibodies against components of human SWI/SNF, namely BRG1, BAF170, BAF155, and BAF57. Immunoreactivity to these antibodies elutes with a mass of about 2MDa on Sepharose CL-6B gel filtration, suggesting that they constitute a SWI/SNF-like complex (SLC). The SLC displays three chromatin-remodeling activities, viz. nucleosome disruption, octamer transfer, and nucleosome sliding (octamer transfer in cis). We further show that components of SLC, as revealed by immunoreactivity to the above antibodies, display a dynamic nucleocytoplasmic distribution and colocalize with RNA polymerase II in the liver nuclei. This report contributes to the understanding of phylogenetic generality of chromatin remodeling factors in eukaryotes.     

高等植物中SWI/SNF染色质重塑研究的新进展

染色质重塑是真核生物表观遗传调控的重要方式．通过对染色质物理结构的调节,染色质重塑在高等动植物干细胞的自我更新及分化、器官和个体发育以及肿瘤发生等多种生物学过程中发挥重要作用．近年来,高等动植物染色质重塑方面的研究已经成为表观遗传学研究领域的热点．本综述总结近年来有关高等动植物染色质重塑的重要研究报道,介绍了染色质重塑的结构机制、分析比较了高等动植物染色质重塑复合体的组成及其生物学功能的多样性,并着重综述了高等植物SWI/SNF染色质重塑复合体各组分在调控植物发育与逆境生长等方面的功能,以期为今后植物中染色质重塑的研究提供启示．     

SWI/SNF protein component BAF250a regulates cardiac progenitor cell differentiation by modulating chromatin accessibility during second heart field development

ATP-dependent SWI/SNF chromatin remodeling complexes alter the structure of chromatin at specific loci and facilitate tissue-specific gene regulation during development. Several SWI/SNF subunits are required for cardiogenesis. However, the function and mechanisms of SWI/SNF in mediating cardiac progenitor cell (CPC) differentiation during cardiogenesis are not well understood. Our studies of the SWI/SNF chromatin remodeling complex identified that BAF250a, a regulatory subunit of the SWI/SNF, plays a key role in CPC differentiation. BAF250a ablation in mouse second heart field (SHF) led to trabeculation defects in the right ventricle, ventricular septal defect, persistent truncus arteriosus, reduced myocardial proliferation, and embryonic lethality around E13. Using an embryonic stem cell culture system that models the formation and differentiation of SHF CPCs in vivo, we have shown that BAF250a ablation in CPCs specifically inhibits cardiomyocyte formation. Moreover, BAF250a selectively regulates the expression of key cardiac factors Mef2c, Nkx2.5, and Bmp10 in SHF CPCs. Chromatin immunoprecipitation and DNase I digestion assays indicate that BAF250a regulates gene expression by binding selectively to its target gene promoters and recruiting Brg1, the catalytic subunit of SWI/SNF, to modulate chromatin accessibility. Our results thus identify BAF250a-mediated chromatin remodeling as an essential epigenetic mechanism mediating CPC differentiation.     

The Drosophila Brahma (SWI/SNF) chromatin remodeling complex exhibits cell-type specific activation and repression functions

The Brahma (Brm) complex of Drosophila melanogaster is a SWI/SNF-related chromatin remodeling complex required to correctly maintain proper states of gene expression through ATP-dependent effects on chromatin structure. The SWI/SNF complexes are comprised of 8-11 stable components, even though the SWI2/SNF2 (BRM, BRG1, hBRM) ATPase subunit alone is partially sufficient to carry out chromatin remodeling in vitro. The remaining subunits are required for stable complex assembly and/or proper promoter targeting in vivo. Our data reveals that SNR1 (SNF5-Related-1), a highly conserved subunit of the Brm complex, is required to restrict complex activity during the development of wing vein and intervein cells, illustrating a functional requirement for SNR1 in modifying whole complex activation functions. Specifically, we found that snr1 and brm exhibited opposite mutant phenotypes in the wing and differential misregulation of genes required for vein and intervein cell development, including rhomboid, decapentaplegic, thick veins, and blistered, suggesting possible regulatory targets for the Brm complex in vivo. Our genetic results suggest a novel mechanism for SWI/SNF-mediated gene repression that relies on the function of a 'core' subunit to block or shield BRM (SWI2/SNF2) activity in specific cells. The SNR1-mediated repression is dependent on cooperation with histone deacetylases (HDAC) and physical associations with NET, a localized vein repressor.     

BRCA1 interacts with dominant negative SWI/SNF enzymes without affecting homologous recombination or radiation-induced gene activation of p21 or Mdm2

BRCA1 is a tumor suppressor gene linked to familial breast and ovarian cancer. The BRCA1 protein has been implicated in a diverse set of cellular functions, including activation of gene expression by the p53 tumor suppressor and control of homologous recombination (HR) during DNA repair. Prior reports have demonstrated that BRCA1 can exist in cells in a complex with the BRG1-based SWI/SNF ATP-dependent chromatin remodeling enzymes and that SWI/SNF components contribute to p53-mediated gene activation. To investigate the link between SWI/SNF function and BRCA1 mediated effects on p53-mediated gene activation and on mechanisms of homologous recombination, we have utilized mammalian cells that inducibly express an ATPase-deficient, dominant negative SWI/SNF enzymes. Mutant SWI/SNF ATPases retain the ability to interact with BRCA1 in cells. We report that expression of dominant negative SWI/SNF enzymes does not affect p53-mediated induction of the p21 cyclin dependent kinase inhibitor or the Mdm2 E3 ubiquitin ligase that regulates p53 in cells exposed to UV or gamma irradiation. Similarly, integration of a reporter that monitors homologous recombination by gene conversion into these cells demonstrated no change in the recombination rate in the absence of functional SWI/SNF enzyme. We conclude that the SWI/SNF chromatin remodeling enzymes may contribute to but are not required for these processes.     

CHB2, a member of the SWI3 gene family,is a global regulator in Arabidopsis

The SWI/SNF complex is an ATP-dependent chromatin remodeling complex that plays an important role in the regulation of eukaryotic gene expression. Very little is known about the function of SWI/SNF complex in plants compared with animals and yeast. SWI3 is one of the core components of the SWI/SNF chromatin remodeling complexes in yeast. We have identified a putative SWI3-like cDNA clone, CHB2 (AtSWI3B), from Arabidopsis thaliana by screening the expressed sequence tag database. CHB2 encodes a putative protein of 469 amino acids and shares 23% amino acid sequence identity and 64% similarity with the yeast SWI3. The Arabidopsis genome contains four SWI3-like genes, namely CHB1 (AtSWI3A), CHB2 (AtSWI3B), CHB3 (AtSWI3C) and CHB4 (AtSWI3D). The expression of CHB2, CHB3 and CHB4 mRNA was detected in all tissues analyzed by RT-PCR. The expression of CHB1 mRNA, however, could not be detected in the siliques, suggesting that there is differential expression among CHB genes in different Arabidopsis tissues. To investigate the role of CHB2 in plants, Arabidopsis plants were transformed with a gene construct comprising a CHB2 cDNA in the antisense orientation driven by the CaMV 35S promoter. Repression of CHB2 expression resulted in pleiotropic developmental abnormalities including abnormal seedling and leaf phenotypes, dwarfism, delayed flowering and no apical dominance, suggesting a global role for CHB2 in the regulation of gene expression. Our results indicate that CHB2 plays an essential role in plant growth and development.     

ATP-dependent chromatin remodeling complex SWI/SNF in cardiogenesis and cardiac progenitor cell development

The recent identification of cardiac progenitor cells (CPCs) provides a new paradigm for studying and treating heart disease.To realize the full potential of CPCs for therapeutic purposes,it is essenti...