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Cellular and Immunobiology
Published in Karl H. Pang, Nadir I. Osman, James W.F. Catto, Christopher R. Chapple, Basic Urological Sciences, 2021
Masood Moghul, Sarah McClelland, Prabhakar Rajan
Epigenetic processes can be inherited by cells after mitotic division. Processes include:Cytosine methylation.Post-translational modification of histone proteins and remodelling of chromatin.Transcription factors binding to specific DNA sequences to promote/inhibit gene expression.MicroRNA binds to specific mRNA sequence, inhibiting gene expression.
Nucleic Acids as Therapeutic Targets and Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Transcription factors are proteins that control the DNA transcriptional process by selectively binding to a target sequence in the promoter region of the relevant gene to stimulate or inhibit transcription. They work by modifying the activity of RNA Polymerase II (Pol II) to ensure that transcription occurs (or not) at the appropriate time and place in the genome. Cancer therapies based on inhibiting the transcription of oncogenes such as C-Myc, HIF-1, NFκB, and STAT-3 have been envisaged. A number of small molecules inhibitors have been reported such as alvocidib, echinomycin, PBD molecules (e.g., TSG-1301), and the hairpin polyamides that can bind to duplex DNA in a sequence-selective manner and inhibit transcription. Some of these molecules are described in Section 5.7.1.1.1, although none have reached the approval stage.
Genetics and genomics of exposure to high altitude
Published in Andrew M. Luks, Philip N. Ainslie, Justin S. Lawley, Robert C. Roach, Tatum S. Simonson, Ward, Milledge and West's High Altitude Medicine and Physiology, 2021
Andrew M. Luks, Philip N. Ainslie, Justin S. Lawley, Robert C. Roach, Tatum S. Simonson
HIFs are transcription factors that respond to changes in available oxygen in the cellular environment. A transcription factor is a protein that binds to a specific DNA sequence and regulates the transcription of genetic information from DNA to messenger RNA (mRNA). Increasing the rate of gene transcription is referred to as upregulation, while decreasing the rate of gene transcription is called downregulation. There are additional proteins such as coactivators that also play a role in transcription of DNA but typically do not contain DNA-binding domains.
TYK2 as a novel therapeutic target in psoriasis
Published in Expert Review of Clinical Pharmacology, 2023
Sarah Elyoussfi, Shraddha S Rane, Steve Eyre, Richard B Warren
Experimental techniques include investigation of how transcription factors and other proteins interact with DNA (ChIP), chromatin structure and interactions (3C), and gene expression (eQTL and reporter gene assays) in the relevant cell types. Methods such as Clustered Regularly Interspaced Short Palindromic Repeats and CRISPR-associated protein 9 (CRISPR/Cas9) genome-editing systems can evaluate the effect of altering individual SNP alleles on gene expression [39]. By using relevant cell types, such as T-cells or keratinocytes, the effect of regulatory genome regions on subsequent gene expression can be examined using reporter gene assays. CRISPR interference systems can be used to downregulate or upregulate transcription of these regulatory regions. Informative functional readouts are then used to help us understand the function of disease-associated variants and the biological pathways on which they act [40].
Down-regulation of KLF9 ameliorates LPS-caused acute lung injury and inflammation in mice via reducing GSDMD expression
Published in Autoimmunity, 2022
Renliang Qu, Jingjing Liu, Lili Feng, Lianbing Li, Junwei Liu, Fengnan Sun, Lin Sun
Transcription factor is a type of nucleus protein, which can regulate the target genes through binding to DNA. They are recognised as the hub of various signalling pathways and play great therapeutic capabilities in multiple inflammatory diseases [42,43]. KLF9 has been reported as transcription factor of several genes. For example, KLF9 transcriptionally modulates 6-phosphofructo-2-kinase/fructose-2, 6-biphosphatase 3 (PFKFB3), and participates in the metastasis of cutaneous squamous cell carcinoma [43]. KLF9 has also been proven to transcriptionally inhibit matrix metalloproteinase 28 (MMP28) expression in gastric cancer [44]. To explain the underlying mechanism of KLF9 in ALI, we accessed to JASPAR database and predicted the binding between KLF9 and the GSDMD promoter. GSDMD is a member of gasdermins, consisting of two conserved domains [45]. It can be cleaved N-terminal and C-terminal domains and extensively explored in pyroptosis [46]. Kovacs et al. have verified that cleaved N-terminal of GSDMD can form the memberane pores via cooperating with cell plasma membrane. This membrane pore could further contribute to the release of inflammatory cytokines [21]. Our results manifested that KLF9 knockdown induced a decreased expression of GSDMD in both in-vivo and in-vitro models. As expected, the levels of inflammatory factors were all reduced.
The state of the art of fetal hemoglobin-inducing agents
Published in Expert Opinion on Drug Discovery, 2022
Aline Renata Pavan, Juliana Romano Lopes, Jean Leandro Dos Santos
The HbF gene regulation is also performed by transcription factors, which acts on the beta-locus. The transcription factors that regulate γ-globin expression were investigated as potential targets for inducing HbF synthesis. Among them, TR2/TR4, BCL11A, KLF1, NRF2, GATA1, FOG1, c-Myb, SOX6, and FOXO3 were found to influence γ-globin gene regulation. The modulation of transcription factors is complex and has some challenges due to its low druggability. In some transcription factors, the catalytic domains commonly found in enzymes are missing. For most of them, the absence of ligands is a common feature, making it challenging to design suitable drugs. Moreover, since most null mice lacking some of these transcription factors die during the perinatal period due to the participation of these proteins in vital processes, their viability as potential drug targets must be addressed and pharmacological interventions on these targets require a special caution. Table 2 summarizes examples of small molecules acting on the modulation of transcription factors.