Biochimica et Biophysica Acta-Gene Regulatory Mechanisms最新文献

The activation of peroxisome proliferator-activated receptor alpha (PPARα), a ligand-dependent transcription factor that regulates lipid oxidation-related genes, has been employed to treat hyperlipidemia. Emerging evidence indicates that Ppara gene expression decreases in adipose tissue under obese conditions; however, the underlying molecular mechanisms remain elusive. Here, we demonstrate that nitric oxide (NO) suppresses Ppara expression by regulating its promoter activity via suppression of specificity protein 1 (Sp1) transcriptional activity in adipocytes. NO derived from lipopolysaccharide (LPS) -activated macrophages or a NO donor (NOR5) treatment, suppressed Ppara mRNA expression in 10T1/2 adipocytes. In addition, Ppara transcript levels were reduced in the white adipose tissue (WAT) in both acute and chronic inflammation mouse models; however, such suppressive effects were attenuated via a nitric oxide synthase 2 (NOS2) inhibitor. Endoplasmic reticulum (ER) stress inhibitors attenuated the NO-induced repressive effects on Ppara gene expression in 10T1/2 adipocytes. Promoter mutagenesis and chromatin immunoprecipitation assays revealed that NO decreased the Sp1 occupancy in the proximal promoter regions of the Ppara gene, which might partially result from the reduced Sp1 expression levels by NO. This study delineated the molecular mechanism that modulates Ppara gene transcription upon NO stimulation in white adipocytes, suggesting a possible mechanism for the transcriptional downregulation of Ppara in WAT under obese conditions.

Plant-virus interaction is a complex phenomenon and involves the communication between plant and viral factors. Viruses have very limited coding ability yet, they are able to cause infection which results in huge agro-economic losses throughout the globe each year. Post-translational modifications (PTMs) are covalent modifications of proteins that have a drastic effect on their conformation, stability and function. Like the host proteins, geminiviral proteins are also subject to PTMs and these modifications greatly expand the diversity of their functions. Additionally, these viral proteins can also interact with the components of PTM pathways and modulate them. Several studies have highlighted the importance of PTMs such as phosphorylation, ubiquitination, SUMOylation, myristoylation, S-acylation, acetylation and methylation in plant-geminivirus interaction. PTMs also regulate epigenetic modifications during geminivirus infection which determines viral gene expression. In this review, we have summarized the role of PTMs in regulating geminiviral protein function, influence of PTMs on viral gene expression and how geminiviral proteins interact with the components of PTM pathways to modulate their function.

A global pandemic COVID-19 resulting from SARS-CoV-2 has affected a significant portion of the human population. Antiviral innate immunity is critical for controlling and eliminating the viral infection. Ubiquitination is extensively involved in antiviral signaling, and recent studies suggest that ubiquitin-like proteins (Ubls) modifications also participate in innate antiviral pathways such as RLR and cGAS-STING pathways. Notably, virus infection harnesses ubiquitination and Ubls modifications to facilitate viral replication and counteract innate antiviral immunity. These observations indicate that ubiquitination and Ubls modifications are critical checkpoints for the tug-of-war between virus and host. This review discusses the current progress regarding the modulation of the SARS-CoV-2 life cycle and antiviral innate immune pathways by ubiquitination and Ubls modifications. This paper emphasizes the arising concept that ubiquitination and Ubls modifications are powerful modulators of virus and host interaction and potential drug targets for treating the infection of SARS-CoV-2.

The human telomere contains multiple copies of the DNA sequence d(TTAGGG) which can fold into higher order intramolecular G-quadruplexes and regulate the maintenance of telomere length and chromosomal integrity. The nucleic acid binding protein heteronuclear ribonucleoprotein A1 (hnRNP A1) and its N-terminus proteolytic product UP1 have been shown to efficiently bind and unfold telomeric DNA G-quadruplex. However, the understanding of the molecular mechanism of the UP1 binding and unfolding telomeric G-quadruplexes is still limited. Here, we performed biochemical and biophysical characterizations of UP1 binding and unfolding of human telomeric DNA G-quadruplex d[AGGG(TTAGGG)₃], and in combination of systematic site-direct mutagenesis of two tandem RNA recognition motifs (RRMs) in UP1, revealed that RRM1 is responsible for initial binding and unfolding, whereas RRM2 assists RRM1 to complete the unfolding of G-quadruplex. Isothermal titration calorimetry (ITC) and circular dichroism (CD) studies of the interactions between UP1 and DNA G-quadruplex variants indicate that the “TAG” binding motif in Loop2 of telomeric G-quadruplex is critical for UP1 recognition and G-quadruplex unfolding initiation. Together we depict a model for molecular mechanism of hnRNP A1 (UP1) binding and unfolding of the human telomeric DNA G-quadruplex.

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.