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Glucocorticoid Signaling in the Heart
Published in Shyam S. Bansal, Immune Cells, Inflammation, and Cardiovascular Diseases, 2022
Under unstimulated conditions, GR is located in the cytosolic fraction of the cellular compartment bound to a large, multiprotein chaperone complex, which includes heat-shock protein (HSP) 90, HSP70, and HSP40 and several other co-chaperones (16) (17). Binding of glucocorticoid to GR results in conformational change, exposing the nuclear localization signal and resulting in its nuclear translocation (18). Genomic and non-genomic effects of GR have been identified and implicated in downstream signaling and change in cardiac phenotype (19). Several underlying mechanisms have been identified, through which activated GR can impart anti-inflammatory effects (20). Direct targets of GR include the induction of anti-inflammatory genes like mitogen-activated protein kinase phosphatase-1 (MKP-1) (21) or the inhibition of inflammatory genes like nuclear factor-kB (NF-kb) and activated protein-1 (AP-1) (22). Activated GR can recruit histone deacetylases (HDACs) at inflammatory genes, thus resulting in gene repression (23). Further, by regulating the expression of genes involved in mRNA destabilization, glucocorticoids have also been shown to promote the rapid degradation of pro-inflammatory transcripts, like TNF-α, thus regulating the protein levels of these genes (24) (25). Because glucocorticoid signaling is mediated predominantly by GR activation, it presents as the best target to study the downstream cellular effects of glucocorticoids.
Role of Histone Methyltransferase in Breast Cancer
Published in Meenu Gupta, Rachna Jain, Arun Solanki, Fadi Al-Turjman, Cancer Prediction for Industrial IoT 4.0: A Machine Learning Perspective, 2021
Surekha Manhas, Zaved Ahmed Khan
Moreover, the role of G9a in gene repression studies has been studied predominantly by its histone methyltransferase activity; it is more clearly illustrated that G9a might play a role in active gene activation on certain specific conditions [100–102], that is markedly methyltransferase independent. In addition, this function mentioned above was clearly mapped in the N-protein terminal as 280 amino acids that present first in the protein chain as highly sufficient to promote the expression of the gene through acting as a scaffold to promote transcriptional co-activator recruitment including CARM1 and p300 [101,103]. At last, G9a is a protein with complexity that is highly involved in activating and repressing genes through specific but distinct mechanisms.
The Precision Medicine Approach in Oncology
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Another mechanism involves a physical change in the location of nucleosomes. These noncovalent mechanisms play a significant role in chromatin structure and gene regulation. Nucleosomes not only help to pack the DNA within the nucleus of cells but also enable transcription factors to access the regulatory regions of DNA sequences to facilitate gene expression. At the 5’- and 3’-ends of genes there are nucleosome-free-regions (NFRs) (Figure 11.16) which are thought to be responsible for transcription factor assembly and disassembly. Having an NFR region at gene-promoter sites allows for rapid gene activation when stimulated. Conversely, if an NFR within a transcription start site is occluded, then this can lead to gene repression.
Epigenetic regulation of T cell development
Published in International Reviews of Immunology, 2023
Avik Dutta, Harini Venkataganesh, Paul E. Love
DNA methylation and demethylation have been shown to be key epigenetic events for proper thymocyte development [48–50]. One group showed that in the case of human αβ − T cell development, about 85% of DNA demethylation events that occur typically are associated with increased gene expression, reflecting how methylation of the promoter region of genes correlates with gene repression [50, 51]. They further showed a positive correlation of demethylation and increased expression of genes important for T cell development including RAG1, RAG2, CD8A, CD1A, PTCRA, OSBPL5, ZP1, CBFA2T3, AXIN2, ARPP21, BCL11B, RORC, RUNX3, CCR7, IKZF1 (IKAROS), and TCF7 [51]. Mbd2 (methyl-CpG-binding domain protein 2) is known as a “reader” of DNA methylation. Deletion of Mbd2 (germline deletion) resulted in a developmental block at the DN3 stage (Figure 2B) [52]. β-selection was severely affected with increased apoptosis and decreased proliferation of DN3 thymocytes [52]. It was also reported that WNT signaling was downregulated along with decreased expression of Tcf7 and c-Myc upon deletion of Mbd2 (Figure 2B) [52]. Further study is needed to decode how the change in methylation pattern due to loss of Mbd2 regulates expression of key genes.
Atypical teratoid rhabdoid tumor (ATRT): disease mechanisms and potential drug targets
Published in Expert Opinion on Therapeutic Targets, 2022
Julian S. Rechberger, Cody L. Nesvick, David J. Daniels
Polycomb inhibition using the clinically available EZH2 inhibitor tazemetostat is one approach that has gained traction in the pediatric oncology community. EZH2 inhibition is attractive not only due to its targetability but its biological relevance: in developmental systems, BAF has been shown to antagonize polycomb-mediated gene repression [57], and EZH2 inhibition using RNA interference or pharmacologic inhibition has been shown to variably inhibit ATRT cell growth in vitro and in vivo [28,58]. In a phase I clinical trial or relapsed or refractory SMARCB1-deficient tumors, tazemetostat treatment resulted in a clinically measurable response in 19% of patients with ATRT [59]. Final results of clinical trials of tazemetostat in ATRT and other tumors (NCT02601937, NCT03213665) are necessary in determining the long-term efficacy of this treatment.
Role of oxidative stress in pathophysiology of rheumatoid arthritis: insights into NRF2-KEAP1 signalling
Published in Autoimmunity, 2021
Gurjasmine Kaur, Aman Sharma, Archana Bhatnagar
An article entitled “Nrf2, a guardian of health-span and gatekeeper of species longevity” highlighted the immense role of Nrf2 in cellular function and stated that “There is mounting evidence across evolutionarily distant species that Nrf2-ARE dependent components are associated with both longevity and extension of health-span” [46]. Overall Nrf2, via transcription regulation of roughly 500 genes, directly or indirectly, monitors antioxidant responses, mitochondrial biogenesis, energy metabolism, detoxification of carbon-containing xenobiotics and toxic metals, autophagy and greatly lowers many inflammatory responses via downstream signalling cascade including HIF-1, NF-κB, AP-1, JAK-STAT [47] (Figure 2). Also, Nrf2 mediates gene repression either via activation of downstream transcription factors or via AREs repressive effects. Coordinated control of multiple genes expressing proteins that are functionally linked in order to bring out an important biological response has been found repeatedly in Nrf2-mediated gene regulation. Dysfunctional Nrf2-ARE signalling may aggravate oxidative damage and inflammatory injury in diseases, including cancer, neurodegenerative, inflammatory, and autoimmune disorders i.e. chronic obstructive pulmonary disease, asthma, atherosclerosis, diabetes, multiple sclerosis, OA, and RA [43].