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The proper modulation of chromatin structure is dependent on the activities of chromatin-remodeling factors and their interplays. Here, we show that the Arabidopsis chromatin-remodeler AtINO80 interacts with the actin-related protein AtARP5 and can form a larger protein complex.Genetic analysis demonstrated that AtARP5 acts in concert with AtINO80 during plant cellular proliferation and replication stress response. At the same time, AtARP5 is not required for AtINO80-mediated control of flowering time and related transcriptional regulation, and their chromatin distribution patterns on regions of flowering-repressor genes FLC/MAF4/MAF5 are also different.An in vitro DNase I digestion assay revealed that the AtINO80N-terminus can weakly bind DNA, an interaction that is significantly inhibited by H2A.Z/H2B addition. AtARP6, a specific subunit of SWR1-C that mediates the H2A.Z exchange, was found to have a previously unexpected inhibitory role in the local chromatin enrichment of AtINO80. Further genetic analyses revealed the functional interplay between AtINO80 and AtARP6 and their critical roles in embryogenesis and post-embryonic organ development, as well as the synergy of AtARP5 and AtARP6 in maintaining genomic stability.Our findings provide insights into the common and distinct roles of AtINO80 and AtARP5 in diverse aspects of plant development.

Background Neuroblastoma (NB) is the most common solid tumor in children, characterized by high recurrence rates, drug resistance, and significant mortality. Methods In this study, we analyzed the proteomic profiles of NB tissue samples alongside other pathological categories, including ganglioneuroma (GN) and ganglioneuroblastoma (GNB). Using weighted gene co-expression network analysis (WGCNA), the core prognostic gene models associated with histopathology of NB were identified. Furthermore, by mapping our core prognostic gene models onto drug-perturbed transcriptome profiles from the L1000FWD and CMap databases, repurposing drug candidates were screened and validated for NB. Results Our proteomic analysis reveals that pathways associated with the cell cycle and DNA replication are significantly upregulated in NB, while oxidative phosphorylation, pyruvate metabolism, and the TCA cycle are notably downregulated compared to GNB and GN. By applying WGCNA, we identified a core prognostic gene model strongly associated with the unfavorable subtype and high MKI of NB and primarily related to chromatin binding and mRNA metabolic process. Protein–protein interaction network analysis identified 15 hub genes in this core prognostic module: SMARCA4, SMARCA5, SMARCC2, SMARCC1, PBRM1, BRD3, ARID1A, BRD2, ARID1B, KDM1A, TP53BP1, ALYREF, CBX1, SF3B1, and ADNP, which mainly related to chromatin remodeling. Notably, SMARCA4 and ALYREF are also high-risk genes of mortality and validated as potential prognostic biomarkers for NB. Through repurposing drugs screening, mocetinostat and clofarabine were validated as effective treatments in two NB cell lines. Conclusion Mocetinostat and clofarabine offer valuable insights for the development of novel targeted therapies in neuroblastoma.

Autism spectrum disorders (ASD) is a heterogeneous group of neurodevelopmental disorders characterized by synaptic dysfunction and defects in dendritic spine morphology. In the past decade, an extensive list of genes associated with ASD has been identified by genome-wide sequencing initiatives. Several of these genes functionally converge in the regulation of the Wnt/β-catenin signaling pathway, a conserved cascade essential for stem cell pluripotency and cell fate decisions during development. Here, we review current information regarding the transcriptional program of Wnt/β-catenin signaling in ASD. First, we discuss that Wnt/β-catenin gain and loss of function studies recapitulate brain developmental abnormalities associated with ASD. Second, transcriptomic approaches using patient-derived induced pluripotent stem cells (iPSC) cells, featuring mutations in high confidence ASD genes, reveal a significant dysregulation in the expression of Wnt signaling components. Finally, we focus on the activity of chromatin-remodeling proteins and transcription factors considered high confidence ASD genes, including CHD8, ARID1B, ADNP, and TBR1, that regulate Wnt/β-catenin-dependent transcriptional activity in multiple cell types, including pyramidal neurons, interneurons and oligodendrocytes, cells which are becoming increasingly relevant in the study of ASD. We conclude that the level of Wnt/β-catenin signaling activation could explain the high phenotypical heterogeneity of ASD and be instrumental in the development of new diagnostics tools and therapies.

Distinctive SWI/SNF-like ATP-dependent chromatin remodeling esBAF complexes are indispensable for the maintenance and pluripotency of mouse embryonic stem (ES) cells [Ho L, et al. (2009) Proc Natl Acad Sci USA 10.1073/pnas.0812889106]. To understand the mechanism underlying the roles of these complexes in ES cells, we performed high-resolution genome-wide mapping of the core ATPase subunit, Brg, using ChIP-Seq technology. We find that esBAF, as represented by Brg, binds to genes encoding components of the core ES transcriptional circuitry, including Polycomb group proteins. esBAF colocalizes extensively with transcription factors Oct4, Sox2 and Nanog genome-wide, and shows distinct functional interactions with Oct4 and Sox2 at its target genes. Surprisingly, no significant colocalization of esBAF with PRC2 complexes, represented by Suz12, is observed. Lastly, esBAF colocalizes with Stat3 and Smad1 genome-wide, consistent with a direct and critical role in LIF and BMP signaling for maintaining self-renewal. Taken together, our studies indicate that esBAF is an essential component of the core pluripotency transcriptional network, and might also be a critical component of the LIF and BMP signaling pathways essential for maintenance of self-renewal and pluripotency.

ISWI family chromatin remodeling motors use sophisticated autoinhibition mechanisms to control nucleosome sliding. Yet how the different autoinhibitory domains are regulated is not well understood. Here we show that an acidic patch formed by histones H2A and H2B of the nucleosome relieves the autoinhibition imposed by the AutoN and the NegC regions of the human ISWI remodeler SNF2h. Further, by single molecule FRET we show that the acidic patch helps control the distance travelled per translocation event. We propose a model in which the acidic patch activates SNF2h by providing a landing pad for the NegC and AutoN auto-inhibitory domains. Interestingly, the INO80 complex is also strongly dependent on the acidic patch for nucleosome sliding, indicating that this substrate feature can regulate remodeling enzymes with substantially different mechanisms. We therefore hypothesize that regulating access to the acidic patch of the nucleosome plays a key role in coordinating the activities of different remodelers in the cell. Every human cell contains nearly two meters of DNA, which is carefully packaged to form a dense structure known as chromatin. The building block of chromatin is the nucleosome, a unit composed of a short section of DNA tightly wound up around a spool-like core of proteins called histones. The tight structure of the nucleosome prevents the cell from accessing and ‘reading’ the genes in the packaged DNA, effectively switching off these genes. So the exact placement of nucleosomes helps manage which genes are turned on. Changing the position of the nucleosomes can ‘free’ the DNA and make genes available to the cell. Enzymes called chromatin remodelers move nucleosomes around – for example, they can make the histone core slide on the DNA strand. However, it is still unclear how these enzymes recognize nucleosomes. Previous research indicates that many proteins bind to nucleosomes by using a surface on the histone proteins called the acidic patch. Could chromatin remodelers also work by interacting with this acidic patch? To address this further, Gamarra et al. investigate how a chromatin remodeler enzyme known as SNF2h interacts with a nucleosome. By default, SNF2h is inactive because two of its regions called AutoN and NegC act as brakes. The experiments show that the acidic patch helps to bypass this inactivation and switches on SNF2h. Gamarra et al. propose that, when SNF2h docks on to the nucleosome, the patch provides a landing pad for the AutoN and NegC modules; this interaction activates the enzyme, which can then start remodeling the nucleosome. However, another type of chromatin remodeler also uses the patch to interact with nucleosomes but it does not have the AutoN and NegC regions. This suggests that chromatin remodelers work with the acidic patch in different ways. Overall, the findings deepen our understanding of how DNA is packaged in cells, and how this process may go wrong and cause disease.

Sucrose nonfermenting 2 (Snf2) family proteins, as the catalytic core of ATP-dependent chromatin remodeling complexes, play important roles in nuclear processes as diverse as DNA replication, transcriptional regulation, and DNA repair and recombination. The Snf2 gene family has been characterized in several plant species; some of its members regulate flower development in Arabidopsis. However, little is known about the members of the family in barley (Hordeum vulgare). Here, 38 Snf2 genes unevenly distributed among seven chromosomes were identified from the barley (cv. Morex) genome. Phylogenetic analysis categorized them into 18 subfamilies. They contained combinations of 21 domains and consisted of 3 to 34 exons. Evolution analysis revealed that segmental duplication contributed predominantly to the expansion of the family in barley, and the duplicated gene pairs have undergone purifying selection. About eight hundred Snf2 family genes were identified from 20 barley accessions, ranging from 38 to 41 genes in each. Most of these genes were subjected to purification selection during barley domestication. Most were expressed abundantly during spike development. This study provides a comprehensive characterization of barley Snf2 family members, which should help to improve our understanding of their potential regulatory roles in barley spike development.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with core symptoms that include poor social communication, restricted interests, and repetitive behaviors. Several ASD mouse models exhibit impaired social interaction, anxiety-like behavior, and elevated perseveration. Large-scale whole exome sequencing studies identified many genes putatively associated with ASD. Like chromodomain helicase DNA binding protein 8 (CHD8), the most frequently mutated gene in individuals with ASD, the candidate gene AT-rich interaction domain 1B (ARID1B) encodes a chromatin remodeling factor. Arid1b heterozygous knockout (hKO) mice exhibited ASD-like traits related to social behavior, anxiety, and perseveration, in addition to associated features reported in some cases of ASD, such as reduced weight, impaired motor coordination, and hydrocephalus. Hydrocephalus was present in 5 of 91 hKO mice, while it was not observed in wild-type littermates (0 of 188). Genome-wide gene expression patterns in Arid1b hKO mice were similar to those in ASD patients and Chd8-haploinsufficient mice, an ASD model, and to developmental changes in gene expression in fast-spiking cells in the mouse brain. Our results suggest that Arid1b haploinsufficiency causes ASD-like phenotypes in mice.

Purpose Determination of genotypic/phenotypic features of GATAD2B -associated neurodevelopmental disorder (GAND). Methods Fifty GAND subjects were evaluated to determine consistent genotypic/phenotypic features. Immunoprecipitation assays utilizing in vitro transcription–translation products were used to evaluate GATAD2B missense variants’ ability to interact with binding partners within the nucleosome remodeling and deacetylase (NuRD) complex. Results Subjects had clinical findings that included macrocephaly, hypotonia, intellectual disability, neonatal feeding issues, polyhydramnios, apraxia of speech, epilepsy, and bicuspid aortic valves. Forty-one novel GATAD2B variants were identified with multiple variant types (nonsense, truncating frameshift, splice-site variants, deletions, and missense). Seven subjects were identified with missense variants that localized within two conserved region domains (CR1 or CR2) of the GATAD2B protein. Immunoprecipitation assays revealed several of these missense variants disrupted GATAD2B interactions with its NuRD complex binding partners. Conclusions A consistent GAND phenotype was caused by a range of genetic variants in GATAD2B that include loss-of-function and missense subtypes. Missense variants were present in conserved region domains that disrupted assembly of NuRD complex proteins. GAND’s clinical phenotype had substantial clinical overlap with other disorders associated with the NuRD complex that involve CHD3 and CHD4, with clinical features of hypotonia, intellectual disability, cardiac defects, childhood apraxia of speech, and macrocephaly.

ATP‐dependent chromatin remodeling complexes are a group of epigenetic regulators that can alter the assembly of nucleosomes and regulate the accessibility of transcription factors to DNA in order to modulate gene expression. One of these complexes, the SWI/SNF chromatin remodeling complex is mutated in more than 20% of human cancers. We have investigated the roles of the SWI/SNF complex in pancreatic ductal adenocarcinoma (PDA), which is the most lethal type of cancer. Here, we reviewed the recent literature regarding the role of the SWI/SNF complex in pancreatic tumorigenesis and current knowledge about therapeutic strategies targeting the SWI/SNF complex in PDA. The subunits of the SWI/SNF complex are mutated in 14% of human PDA. Recent studies have shown that they have context‐dependent oncogenic or tumor‐suppressive roles in pancreatic carcinogenesis. To target its tumor‐suppressive properties, synthetic lethal strategies have recently been developed. In addition, their oncogenic properties could be novel therapeutic targets. The SWI/SNF subunits are potential therapeutic targets for PDA, and further understanding of the precise role of the SWI/SNF complex subunits in PDA is required for further development of novel strategies targeting SWI/SNF subunits against PDA. Here, we reviewed the recent literature regarding the role of the SWI/SNF complex in pancreatic tumorigenesis and current knowledge about therapeutic strategies targeting the SWI/SNF complex in pancreatic cancer. The SWI/SNF subunits are potential therapeutic targets for PDA, and further understanding of the precise role of the SWI/SNF complex subunits in PDA is required for further development of novel strategies targeting SWI/SNF subunits against PDA.

The epigenome controls all aspect of eukaryotic development as the packaging of DNA greatly affects gene expression. Epigenetic changes are reversible and do not affect the DNA sequence itself but rather control levels of gene expression. As a result, the science of epigenetics focuses on the physical configuration of chromatin in the proximity of gene promoters rather than on the mechanistic effects of gene sequences on transcription and translation. In the present review we discuss three prominent epigenetic modifications, DNA methylation, histone methylation/acetylation, and the effects of chromatin remodeling complexes. Specifically, we introduce changes to the methylated state of DNA through DNA methyltransferases and DNA demethylases, discuss the effects of histone tail modifications such as histone acetylation and methylation on gene expression and present the functions of major ATPase subunit containing chromatin remodeling complexes. We also introduce examples of how changes in these epigenetic factors affect early development in humans and mice. In summary, this review provides an overview over the most important epigenetic mechanisms and provides examples of the dramatic effects of epigenetic changes in early mammalian development.