Changes in Gene Expression During Aging of Mammals
Alvaro Macieira-Coelho in Molecular Basis of Aging, 2017
Song et al.20 found that AR is expressed in the hepatocytes. The steady-state level of AR mRNA correlates with the three phases of hepatic androgen sensitivity, that is, insensitivity to androgen during prepuberty, responsiveness during adulthood, and gradual loss of responsiveness during aging. Both prepubertal and senescent rats are relatively insensitive to the induction of α2μ-globulin. The age-dependent decline in AR mRNA can be delayed by reducing caloric intake by 40%. Thus, it appears that changes in androgen sensitivity of the liver during aging is due to the age-dependent expression of AR-mRNA and the level of AR. The expression of the AR gene appears to be due to a cis-acting element present in its promoter.21 It has two contiguous sites, one of 19 bp that binds to a nuclear androgen-dependent factor (ADF), and another of 25 bp that binds to an associated factor (AF). ADF appears to be ubiquitous and is evolutionarily conserved, whereas AF is tissue specific. Thus the age-dependent androgen responsiveness of the gene appears to be modulated through this sequence.
The Role of Plasminogen Activator Inhibitor Type 1 (PAI-1) in the Clinical Setting, Including Deep Vein Thrombosis
Pia Glas-Greenwalt in Fibrinolysis in Disease Molecular and Hemovascular Aspects of Fibrinolysis, 2019
More recently a third polymorphism was found in the promoter region of the PAI-1 gene.48,50 The single base pair insertion/deletion polymorphism (GACACGTG4 or 5AGT) is located 675 base pairs upstream from the transcription initiation site of the PAI-1 gene. Individuals homozygous for the del allele (GGGG) exhibited higher plasma PAI-1 activity than those with at least one ins allele (5 Gs). In the patients, the difference was significant (4G/4G: 21.5 ng/ml versus at least one 5G: 16.1 mg/ml; p = 0.03). Gelshift assays, footprinting studies, and transfection experiments with the promoter region linked to a reporter gene suggested that the 5G polymorphic site functions as a part of a cis-acting element for the binding of a protein that acts as a transcription repressor: in particular, this element appears to be involved in the blunting of the cells’ response to the stimulating effect of interleukin-1 on PAI-1 expression.
Heme Oxygenase-1 in Kidney Health and Disease
Shamim I. Ahmad in Handbook of Mitochondrial Dysfunction, 2019
Both cytosolic and nuclear HO-1, whether enzymatic active or not, protected cells against hydrogen peroxide-mediated injury equally well, indicating a non-canonical HO-1 signaling pathway (78). This truncated and enzymatically inactive nuclear HO-1 (Figure 2C) was demonstrated to alter binding of transcription factors to alter gene expression. For examples, nuclear factor erythroid 2-related factor 2 (NF-E2-related factor 2, Nrf2), a master transcriptional factor of the cellular redox homeostasis, which binds to a cis-acting element called the antioxidant responsive element (ARE) and regulates numerous antioxidants and cytoprotective proteins, including HO-1 itself. Nrf2 is accumulated in nucleus during OS. Nuclear HO-1 interacts with Nrf2 and stabilizes it from ubiquitin-proteasomal degradation (79). Interestingly, Nrf2 also support mitochondria biogenesis and integrity (80) (Figure 3A). High level of nuclear HO-1 is linked to numerous tumor growth and drug resistance (81). The underlying mechanism has been attributed to its activation of a panel of transcription factors during oxidative stress such as activator protein-1, Nrf2 (70,78). The nuclear HO-1 also regulates its own expression in prostate cancer (82) and has been shown when undergoing acetylation by post-translational modification could promote tumor cells proliferation and invasion (77,83).
Transcriptional regulation of CYP3A4 by nuclear receptors in human hepatocytes under hypoxia
Published in Drug Metabolism Reviews, 2020
Xuechun Yuan, Hui Lu, Anpeng Zhao, Yidan Ding, Qiong Min, Rong Wang
Moreover, another response element located on the upstream of CYP3A4 gene (from −11.4 to −10.5 kb relative to the transcription start site) has been identified as the constitutive liver enhancer module of CYP3A4 gene (CLEM4), which contains an array of cis-acting elements encompassing ∼900 bp, activated by the collaboration of several transcription factors including HNF-1, HNF-4, USF1 and AP-1. Among them, HNF-4 and its binding sites may be more crucial for the expression of hepatic CYP3A4 gene (Matsumura et al. 2004). Furthermore, a specific cis-acting element has been confirmed to exist in CYP3A4 gene enhancer, which allows the binding of HNF4α and thereby permits PXR- and CAR-mediated gene activation (Tirona et al. 2003). As a result, HNF-4 should not be overlooked in mediating the transcription of CYP3A4 gene. A brief overview of the 5′-flanking region of CYP3A4 gene regulation by these mentioned NRs in the liver is showed in Figure 1.
Integrated analysis of human transcriptome data for Rett syndrome finds a network of involved genes
Published in The World Journal of Biological Psychiatry, 2020
Friederike Ehrhart, Susan L. Coort, Lars Eijssen, Elisa Cirillo, Eric E. Smeets, Nasim Bahram Sangani, Chris T. Evelo, Leopold M.G. Curfs
Using network extension, we investigated whether there are known transcription factors that may explain the regulation of genes and processes back to their core gene MECP2. Several transcription factors, which were added by network extension, are already known to interact with MECP2: E2F1, MEF2C, REST, SIN3A, SMC3, SP1 and TAF1. E2F1 and TAF1 are promotor elements of MECP2 (Ehrhart et al. 2016). SP1 is known as a cis regulatory element and promotor element of MECP2. REST is a cis regulatory element of MECP2. SIN3A is an integral part of the MECP2-HDAC complex and SMC3 is one of the cofactors of this complex. MEF2C expression is inhibited by MECP2 together with HDAC complex. It interacts with EP300, several histone deacetylases and SP1. Mutations of MEF2C are known to cause mental retardation and psychomotor impairment (Le Meur et al. 2010). Furthermore, the network extension with known transcription factors revealed a possible connection between cytoskeleton organisation and MECP2 via MEF2C and CAPG. We hypothesise that MECP2 regulates CAPG expression via MEF2C (Figure 4).
Transcriptional control of the MUC16 promoter facilitates follicle-stimulating hormone peptide-conjugated shRNA nanoparticle-mediated inhibition of ovarian carcinoma in vivo
Published in Drug Delivery, 2018
Ming-Xing Zhang, Shan-Shan Hong, Qing-Qing Cai, Meng Zhang, Jun Chen, Xiao-Yan Zhang, Cong-Jian Xu
Here, we predicted the promoter sequences in the regions that were 4 kbp upstream of MUC16 and measured transcriptional activity in ovarian cancer cells with dual-luciferase reporter assay. As shown in our study, although the MUC16.1 and MUC16.2 promoter constructs resulted in higher luciferase gene expression in HEY cells, the nanoparticle complexes containing the MUC16.2 promoter-driven plasmid did not significantly reduce the gro-α levels. It seemed that the promoter sequence with TAAA repeats, the MUC16.1 promoter, showed high transcriptional activity, and this sequence might contain an atypical TATA box and be a transcriptional recognition site. The plasmid containing gro-α shRNA driven by this MUC16 promoter sequence decreased gro-α protein secretion in ovarian cancer cells. However, the MUC16.2 promoter sequence had no possible transcriptional recognition sites such as TATA box. The MUC16.3 promoter sequence with CT repeats that made up a potential cis-acting element did not exhibit transcriptional activity. However, the transcriptional activity of the MUC16 promoter that we screened was lower than that of the positive control, namely, the CMV promoter. Some DNA elements, including enhancers, might need to be integrated into vectors to increase transcriptional activity in future studies (Rama et al., 2015).
Related Knowledge Centers
- Anatomy
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- Transcription
- Gene
- Evolutionary Developmental Biology
- Transcription Factor