Biochimica et Biophysica Acta-Gene Regulatory Mechanisms最新文献

Differential expression of genes involved in certain processes is a collaborative outcome of crosstalk between signalling molecules and epigenetic modifiers. In response to environmental stimulus, interplay between transcription factors and epigenetic modifiers together dictates the regulation of genes. MLLs and KDM5A are functionally antagonistic proteins, as one acts as a writer and the other erases the active chromatin mark, i.e., H3K4me3. KDM5A influences the process of EMT by binding to both epithelial and mesenchymal gene promoters. Through this work, we show that when bound to E-cadherin promoter, KDM5A acts as a classical repressor by demethylating H3K4me3, but on mesenchymal markers, it acts as a transcriptional activator by inhibiting the activity of HDACs and increasing H3K18ac. Further, through our chromatin immunoprecipitation experiments, we observed a co-occupancy of KDM5A with MLLs, we tested whether KDM5A might physically interact with MLLs and WDR5, and here we provide experimental evidence that KDM5A indeed interacts with MLLs and WDR5.

The transcription factor E2F1 participates in cell cycle control through transcriptional activation of genes that promote S-phase entry. E2F1 is also linked to the expression of proapoptotic genes, and the loss of E2F1 activity facilitates tumor progression by reducing cellular apoptosis. Phosphorylation controlled by protein kinases and phosphatases is the major posttranslational modification and regulates the cellular levels and transactivator function of E2F1. Here, we characterize the regulatory roles of serine-375 (S375), one of the major phosphorylation sites of E2F1. Cyclin-dependent kinases such as CDK8 phosphorylate at S375 of E2F1, which is dephosphorylated by protein phosphatase 2A (PP2A) containing the B55 regulatory subunit. The PP2A adapter protein IER5 binds to both PP2A/B55 and E2F1 and assists dephosphorylation at S375 by PP2A. S375-dephosphorylated E2F1 exhibits higher DNA-binding affinity than the phosphorylated form. Although the promoter regions of proapoptotic genes are less occupied by E2F1 in cells, an increase in S375-dephosphorylated E2F1 induces preferential binding of E2F1 to the proapoptotic gene promoters and their expression. Our data identify PP2A/B55-IER5 as a critical regulator of E2F1 and suggest that the phosphorylation state of E2F1 is an important determinant for the expression of proapoptotic genes.

Neuroblastoma is one of the most severe malignant tumors and accounts for substantial cancer-related mortality in children. Ras-GTPase-activating protein SH3 domain-binding protein 1 (G3BP1) is highly expressed in various cancers and acts as an important biomarker of poor prognosis. The ablation of G3BP1 inhibited the proliferation and migration of human SHSY5Y cells. Because of its important role in neuroblastoma, the regulation of G3BP1 protein homeostasis was probed. TRIM25, which belongs to the tripartite motif (TRIM) family of proteins, was identified as an interacting partner for G3BP1 using the yeast two-hybrid (Y2H) method. TRIM25 mediates the ubiquitination of G3BP1 at multiple sites and stabilizes its protein level. Then, our study found that TRIM25 knockdown also inhibited the proliferation and migration of neuroblastoma cells. The TRIM25 and G3BP1 double knockdown SHSY5Y cell line was generated, and double knockdown cells exhibited lower proliferation and migration ability than cells with only TRIM25 or G3BP1 knockdown. Further study demonstrated that TRIM25 promotes the proliferation and migration of neuroblastoma cells in a G3BP1-dependent manner. Tumor xenograft assays indicated that the ablation of TRIM25 and G3BP1 synergistically suppressed the tumorigenicity of neuroblastoma cells in nude mice, and TRIM25 promoted the tumorigenicity of G3BP1 intact SHSY5Y cells but not G3BP1 knockout cells. Thus, TRIM25 and G3BP1, two oncogenic genes, are suggested as potential therapeutic targets for neuroblastoma.

Sterol synthesis is an iron-dependent metabolic pathway in eukaryotes. Consequently, fungal ergosterol biosynthesis (ERG) is down-regulated in response to iron deficiency. In this report, we show that, upon iron limitation or overexpression of the iron-regulated mRNA-binding protein Cth2, the yeast Saccharomyces cerevisiae down-regulates the three initial enzymatic steps of ergosterol synthesis (ERG1, ERG7 and ERG11). Mechanistically, we show that Cth2 protein limits the translation and promotes the decrease in the mRNA levels of these specific ERG genes, which contain consensus Cth2-binding sites defined as AU-rich elements (AREs). Thus, expression of CTH2 leads to the accumulation of initial sterol intermediates, such as squalene, and to the drop of ergosterol levels. Changes in CTH2 expression levels disturb the response of yeast cells to stresses related to membrane integrity such as high ethanol and sorbitol concentrations. Therefore, CTH2 should be considered as a critical regulatory factor of ergosterol biosynthesis during iron deficiency.

Taf14 is a subunit of multiple fundamental complexes implicated in transcriptional regulation and DNA damage repair in yeast cells. Here, we investigate the association of Taf14 with the consensus sequence present in other subunits of these complexes and describe the mechanistic features that affect this association. We demonstrate that the precise molecular mechanisms and biological outcomes underlying the Taf14 interactions depend on the accessibility of binding interfaces, the ability to recognize other ligands, and a degree of sensitivity to temperature and chemical and osmotic stresses. Our findings aid in a better understanding of how the distribution of Taf14 among the complexes is mediated.

Plants control expression of their genes in a way that involves manipulating the chromatin structural dynamics in order to adapt to environmental changes and carry out developmental processes. Histone modifications like histone methylation are significant epigenetic marks which profoundly and globally modify chromatin, potentially affecting the expression of several genes. Methylation of histones is catalyzed by histone lysine methyltransferases (HKMTs), that features an evolutionary conserved domain known as SET [Su(var)3–9, E(Z), Trithorax]. This methylation is directed at particular lysine (K) residues on H3 or H4 histone. Plant SET domain group (SDG) proteins are categorized into different classes that have been conserved through evolution, and each class have specificity that influences how the chromatin structure operates. The domains discovered in plant SET domain proteins have typically been linked to protein-protein interactions, suggesting that majority of the SDGs function in complexes. Additionally, SDG-mediated histone mark deposition also affects alternative splicing events. In present review, we discussed the diversity of SDGs in plants including their structural properties. Additionally, we have provided comprehensive summary of the functions of the SDG-domain containing proteins in plant developmental processes and response to environmental stimuli have also been highlighted.

Through regulation of DNA packaging, histone proteins are fundamental to a wide array of biological processes. A variety of post-translational modifications (PTMs), including acetylation, constitute a proposed histone code that is interpreted by “reader” proteins to modulate chromatin structure. Canonical histones can be replaced with variant versions that add an additional layer of regulatory complexity. The protozoan parasite Toxoplasma gondii is unique among eukaryotes in possessing a novel variant of H2B designated H2B.Z. The combination of PTMs and the use of histone variants are important for gene regulation in T. gondii, offering new targets for drug development. In this work, T. gondii parasites were generated in which the 5 N-terminal acetylatable lysines in H2B.Z were mutated to either alanine (c-Myc-A) or arginine (c-Myc-R). The c-Myc-A mutant displayed no phenotype over than a mild defect in its ability to kill mice. The c-Myc-R mutant presented an impaired ability to grow and an increase in differentiation to latent bradyzoites. The c-Myc-R mutant was also more sensitive to DNA damage, displayed no virulence in mice, and provided protective immunity against future infection. While nucleosome composition was unaltered, key genes were abnormally expressed during in vitro bradyzoite differentiation. Our results show that regulation of the N-terminal positive charge patch of H2B.Z is important for these processes. We also show that acetylated N-terminal H2B.Z interacts with some unique proteins compared to its unacetylated counterpart; the acetylated peptide pulled down proteins associated with chromosome maintenance/segregation and cell cycle, suggesting a link between H2B.Z acetylation status and mitosis.

Inflammasomes are a central node of the innate immune defense system against the threat of homeostatic perturbance caused by pathogenic organisms or host-derived molecules. Inflammasomes are generally composed of multimeric protein complexes that assemble in the cytosol after sensing danger signals. Activated inflammasomes promote downstream proteolytic activation, which triggers the release of pro-inflammatory cytokines therefore inducing pyroptotic cell death. The inflammasome pathway is finely tuned by various mechanisms. Recent studies found that protein post-translational modifications such as ubiquitination also modulate inflammasome activation. Targeting the ubiquitination modification of the inflammasome pathway might be a promising strategy for related diseases. In this review, we extensively discuss the advances in inflammasome activation and pyroptosis modulated by ubiquitination which help in-depth understanding and controlling the inflammasome and pyroptosis in various diseases.

RNA polymerase II (RNAPII) encounters numerous impediments on its way to completing mRNA synthesis across a gene. Paused and arrested RNAPII are reactivated or rescued by elongation factors that travel with polymerase as it transcribes DNA. However, when RNAPII fails to resume transcription, such as when it encounters an unrepairable bulky DNA lesion, it is removed by the targeting of its largest subunit, Rpb1, for degradation by the ubiquitin-proteasome system (UPS). We are starting to understand this process better and how the UPS marks Rbp1 for degradation. This review will focus on the latest developments and describe new functions for elongation factors that were once thought to only promote elongation in unstressed conditions in the removal and degradation of RNAPII. I propose that in addition to changes in RNAPII structure, the composition and modification of elongation factors in the elongation complex determine whether to rescue or degrade RNAPII.

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  The number of cytosine-phosphate-guanine (CpG) sites differs due to sequence variation in the human apolipoprotein E (APOE) gene.

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  APOE DNA methylation is allele-dependently altered corresponding to the total number of CpG pairs in the brain of APOE targeted replacement mice (APOE εpsilon 4 > εpsilon 3 > εpsilon 2).

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  Binding of the methyl-CpG binding protein 2 to genomic APOE was in trend less pronounced in the brain of APOE4 mice.