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Introduction to Genomics
Published in Altuna Akalin, Computational Genomics with R, 2020
Proximal regulation is not the only or the most important mode of gene regulation. Most of the transcription factor binding sites in the human genome are found in intergenic regions or in introns. This indicates the widespread usage of distal regulatory elements in animal genomes. On a molecular function level, enhancers are similar to proximal promoters; they contain binding sites for the same transcriptional activators and they basically enhance the gene expression. However, they are often highly modular and several of them can affect the same promoter at the same time or in different time-points or tissues. In addition, their activity is independent of their orientation and their distance to the promoter they interact with. A number of studies showed that enhancers can act upon their target genes over several kilobases away. According to a popular model, enhancers achieve this by looping the DNA and coming into contact with their target genes.
Regulation of C-Reactive Protein, Haptoglobin, and Hemopexin Gene Expression
Published in Andrzej Mackiewicz, Irving Kushner, Heinz Baumann, Acute Phase Proteins, 2020
Dipak P. Ramji, Riccardo Cortese, Gennaro Ciliberto
The three members of class I AP genes analyzed by our laboratory all contain in their promoter region at least one IL-6 APRE which is able to interact with C/EBP-related transcription factors. All these factors are characterized by a leucine zipper/basic amino acid DNA binding domain through which they can form heterodimers in vivo and in vitro. Among these proteins, IL-6DBP emerges as a clear signal transducer of IL-6 response. However, we cannot exclude the possibility that modulation of heterodimeric interactions between the different members, with potentially distinct activation properties, could influence the regulation of AP gene transcription. Given the number of members belonging to the family, which is likely to expand in the future, it is vital to establish an in vitro transcription system that mimics aspects of the AP reaction. This would allow direct evaluation of the role of individual members in transcriptional activation. Alternatively, cell lines lacking the different members can be used to directly assess their role in vivo by transfection studies.
Animal Models of Down Syndrome and Other Genetic Diseases Associated with Mental Retardation
Published in Merlin G. Butler, F. John Meaney, Genetics of Developmental Disabilities, 2019
Angela J. Villar, Charles J. Epstein
Mutations in the X-linked FMR2 gene cause FRAXE, a nonspecific form of X-linked MR with an incidence of 1:50,000 (185). Methylation of an expanded CCG trinucleotide repeat located in exon 1 of the gene results in transcriptional silencing and lack of its product, the FMR2 protein. This protein has been hypothesized to be a transcriptional activator (186). Fmr2 knockout mice (187) display a delaydependent deficit in contextual fear conditioning, indicating dysfunction of the hippocampus and amygdala (188,189), a slight deficit in spatial learning in a Morris water maze task, and increased sensitivity to the heat source in the hot plate test. Surprisingly, LTP was found to be enhanced in hippocampal slices of Fmr2 knockouts as compared to control littermate. Although a number of studies have suggested that diminished LTP is associated with memory impairment (60,61), these data suggest that increased LTP also may be as detrimental to the cognitive processes as diminished LTP (187).
MicroRNA-217: a therapeutic and diagnostic tumor marker
Published in Expert Review of Molecular Diagnostics, 2022
Amir Abbas Hamidi, Malihe Zangoue, Daniel Kashani, Amir Sadra Zangouei, Hamid Reza Rahimi, Mohammad Reza Abbaszadegan, Meysam Moghbeli
Arsenic poisoning occurs during permanent exposure to arsenic-contaminated water or burning of coal with high levels of arsenic. Even a low arsenite dose, as a biologically-active compound containing arsenic, can transform human keratinocytes into malignant cells [90]. Enhancer of zeste homolog 2 (EZH2), as one of the subunits of the polycomb repressive complex, is capable of methylating histone H3 on lysine 27 (H3K27) in order to enhance transcriptional gene silencing. It can also act as a transcriptional activator [91,92]. This transcriptional activator is associated with initiation, progression, drug resistance, and metastasis of cancers [93]. It regulates prolongs cell survival, while inhibits E2F1-dependent apoptosis [94]. EMT is a critical process during tumor cell invasion and metastasis. EZH2 is involved in EMT induction via up regulation of Vimentin and down regulation of CDH1 in tumor cells [95]. It has been shown that circ100284 increased cell cycle progression in As-HaCaT cells. Arsenite also up regulated the circ100284 that sponged miR-217 to up regulate EZH2 and CCND1. Arsenic, as an environmental carcinogen, induces the expression of circ100284, affecting the migratory, invasive, and colony-forming abilities of T-HaCaT cells through regulating EZH2 by miR-217 [96].
The involvement of regulatory T cells in amyotrophic lateral sclerosis and their therapeutic potential
Published in Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 2020
I. Giovannelli, P. Heath, P. J. Shaw, J. Kirby
Clearly, FOXP3 has a crucial role for Tregs. It is a transcriptional regulator which is fundamental for their development and function. It can act both as a transcriptional activator or repressor because it interacts with several transcription factors and proteins involved in epigenetic regulation (13). In particular, it prevents the transcription of pro-inflammatory cytokines such as IL-2 and IFN-γ and it concomitantly activates immune suppressors including cytotoxic T lymphocyte antigen 4 (CTLA4) (13). Furthermore, other key markers for Tregs are glucocorticoid-induced tumor necrosis factor receptor (GITR) and inducible T cell co-stimulator (ICOS). GITR, also referred to as TNFRSF18, plays a role in Treg suppressive activities, in fact, antibodies against GITR can abrogate Treg immune modulatory functions, and it is also crucial for thymus Tregs differentiation process (14–16). ICOS is a costimulatory molecule which is known to exert various roles within the immune system, participating both to inflammatory and suppressive processes (17). However, ICOS appears to play a role in Treg functions. In fact, the blockage of ICOS interaction with its ligand (ICOSL) causes a decrease in the expression of CTLA4 and ICOS deficiency induces reduction in FOXP3 expression (18,19).
Association of functional MMP-2 gene variant with intracranial aneurysms: case-control genetic association study and meta-analysis
Published in British Journal of Neurosurgery, 2018
Varinder S. Alg, Xiayi Ke, Joan Grieve, Stephen Bonner, Daniel C. Walsh, Diederik Bulters, Neil Kitchen, Henry Houlden, David J. Werring
This genetic variant is functional, leading to altered MMP-2 gene promoter activity, through its effect on transcription factor Sp1 (Specificity protein) which is ubiquitously expressed regulating several genes in an inducible or constitutive manner by binding to GC/GT-rich elements. Sp1 is multi-functional and can bend DNA thereby inhibiting the action of other promoter sites within the MMP-2 gene or affecting tissue-specific expression. The MMP-2 polymorphism (C > T) can abolish Sp1 binding, affecting specificity and level of gene transcription. Sp1 can also act as a transcriptional activator by recruiting and combining with other transcription factors, but can also serve as a repressor, depending upon which promoter site it binds to.17 By affecting promoter activity in this way, deleterious effects on MMP-2 expression could lead to an imbalance of ECM regulatory elements, potentially leading to development or rupture of intracranial aneurysms. Interestingly, overexpression of Sp1 has been shown to induce apoptosis in tumour cells,22 which is also a key pre-terminal event in IA rupture.23