SWI/SNF complex in disorder

Heterozygous germline mutations in components of switch/sucrose nonfermenting (SWI/SNF) chromatin remodeling complexes were recently identified in patients with non-syndromic intellectual disability, Coffin-Siris syndrome and Nicolaides-Baraitser syndrome. The common denominator of the phenotype of these patients is severe intellectual disability and speech delay. Somatic and germline mutations in SWI/SNF components were previously implicated in tumor development. This raises the question whether patients with intellectual disability caused by SWI/SNF mutations in the germline are exposed to an increased risk of developing cancer. Here we compare the mutational spectrum of SWI/SNF components in intellectual disability syndromes and cancer, and discuss the implications of the results of this comparison for the patients.     

Biochemical characterisation of the SWI/SNF family member HLTF

HLTF is highly similar in domain organisation to yeast Rad5. We identify PTIP and RPA70, both involved in DNA replication and DNA repair, as HLTF-interacting proteins although cells depleted of HLTF did not show defects in cellular responses to DNA damage. In vitro, HLTF has ATPase activity and E3 ubiquitin ligase activity with a range of E2 ubiquitin conjugating enzymes. HLTF expression is severely reduced in a range of cancer cells, and we suggest that the HLTF antibodies generated in this study could be used for cancer diagnostic purposes.     

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．     

Regulation of growth and cell fate during tissue regeneration by the two SWI/SNF chromatin-remodeling complexes of Drosophila

To regenerate, damaged tissue must heal the wound, regrow to the proper size, replace the correct cell types, and return to the normal gene-expression program. However, the mechanisms that temporally and spatially control the activation or repression of important genes during regeneration are not fully understood. To determine the role that chromatin modifiers play in regulating gene expression after tissue damage, we induced ablation in Drosophila melanogaster imaginal wing discs, and screened for chromatin regulators that are required for epithelial tissue regeneration. Here, we show that many of these genes are indeed important for promoting or constraining regeneration. Specifically, the two SWI/SNF chromatin-remodeling complexes play distinct roles in regulating different aspects of regeneration. The PBAP complex regulates regenerative growth and developmental timing, and is required for the expression of JNK signaling targets and the growth promoter Myc. By contrast, the BAP complex ensures correct patterning and cell fate by stabilizing the expression of the posterior gene engrailed. Thus, both SWI/SNF complexes are essential for proper gene expression during tissue regeneration, but they play distinct roles in regulating growth and cell fate.     

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...     

SWI/SNF complex in disorder: SWItching from malignancies to intellectual disability

Heterozygous germline mutations in components of switch/sucrose nonfermenting (SWI/SNF) chromatin remodeling complexes were recently identified in patients with non-syndromic intellectual disability, Coffin-Siris syndrome and Nicolaides-Baraitser syndrome. The common denominator of the phenotype of these patients is severe intellectual disability and speech delay. Somatic and germline mutations in SWI/SNF components were previously implicated in tumor development. This raises the question whether patients with intellectual disability caused by SWI/SNF mutations in the germline are exposed to an increased risk of developing cancer. Here we compare the mutational spectrum of SWI/SNF components in intellectual disability syndromes and cancer, and discuss the implications of the results of this comparison for the patients.     

The SWI/SNF complex acts to constrain distribution of the centromeric histone variant Cse4

In order to gain insight into the function of the Saccharomyces cerevisiae SWI/SNF complex, we have identified DNA sequences to which it is bound genomewide. One surprising observation is that the complex is enriched at the centromeres of each chromosome. Deletion of the gene encoding the Snf2 subunit of the complex was found to cause partial redistribution of the centromeric histone variant Cse4 to sites on chromosome arms. Cultures of snf2Δ yeast were found to progress through mitosis slowly. This was dependent on the mitotic checkpoint protein Mad2. In the absence of Mad2, defects in chromosome segregation were observed. In the absence of Snf2, chromatin organisation at centromeres is less distinct. In particular, hypersensitive sites flanking the Cse4 containing nucleosomes are less pronounced. Furthermore, SWI/SNF complex was found to be especially effective in the dissociation of Cse4 containing chromatin in vitro. This suggests a role for Snf2 in the maintenance of point centromeres involving the removal of Cse4 from ectopic sites.     

Essential role of ARID2 protein-containing SWI/SNF complex in tissue-specific gene expression

Unfolding of the gene expression program that converts precursor cells to their terminally differentiated counterparts is critically dependent on the nucleosome-remodeling activity of the mammalian SWI/SNF complex. The complex can be powered by either of two alternative ATPases, BRM or BRG1. BRG1 is critical for development and the activation of tissue specific genes and is found in two major stable configurations. The complex of BRG1-associated factors termed BAF is the originally characterized form of mammalian SWI/SNF. A more recently recognized configuration shares many of the same subunits but is termed PBAF in recognition of a unique subunit, the polybromo protein (PBRM1). Two other unique subunits, BRD7 and ARID2, are also diagnostic of PBAF. PBAF plays an essential role in development, apparent from the embryonic lethality of Pbmr1-null mice, but very little is known about the role of PBAF, or its signature subunits, in tissue-specific gene expression in individual differentiation programs. Osteoblast differentiation is an attractive model for tissue-specific gene expression because the process is highly regulated and remains tightly synchronized over a period of several weeks. This model was used here, with a stable shRNA-mediated depletion approach, to examine the role of the signature PBAF subunit, ARID2, during differentiation. This analysis identifies a critical role for ARID2-containing complexes in promoting osteoblast differentiation and supports a view that the PBAF subset of SWI/SNF contributes importantly to maintaining cellular identity and activating tissue-specific gene expression.     

The SWI/SNF chromatin-remodeling gene AtCHR12 mediates temporary growth arrest in Arabidopsis thaliana upon perceiving environmental stress

One of the earliest responses of plants to environmental stress is establishing a temporary growth arrest that allows adaptation to adverse conditions. The response to abiotic stress requires the modulation of gene expression, which may be mediated by the alteration of chromatin structures. This alteration can be accomplished with the help of chromatin-remodeling enzymes, such as the various SWI/SNF classes of ATPases. Here, we investigate the role of the Arabidopsis SNF2/Brahma-type AtCHR12 chromatin-remodeling gene in plant growth and development in reaction to adverse environmental conditions. We show that the AtCHR12 chromatin-remodeling gene plays a vital role in mediating the temporary growth arrest of Arabidopsis that is induced upon perception of stress. Exposing an AtCHR12 overexpressing mutant to stress conditions leads to growth arrest of normally active primary buds, as well as to reduced growth of the primary stem. In contrast, the AtCHR12 knockout mutant shows less growth arrest than the wild-type when exposed to moderate stress. Without stress, mutant plants are indistinguishable from the wild-type, and the growth arrest response seems to depend on the severity of the stress applied. Modulation of AtCHR12 expression correlates with changes in expression of dormancy-associated genes. This is in agreement with the concept of AtCHR12 participation in priming the plants for the growth arrest response. Our data indicate that AtCHR12-associated growth arrest differs from DELLA-mediated growth restraint. This establishes AtCHR12 as a novel gene involved in the response repertoire of plants that permits flexible modulation of growth in adverse and/or otherwise limiting environments.