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ChIP-seq analysis
Published in Altuna Akalin, Computational Genomics with R, 2020
In order to calculate the percentage of CTCF peaks which contain a known CTCF motif. We need to find the CTCF motif and have the computational tools to search for that motif. The DNA binding motifs can be extracted from the MotifDB Bioconductor database. The MotifDB is an agglomeration of multiple motif databases.
Radiobiology and Hadron Therapy
Published in Manjit Dosanjh, Jacques Bernier, Advances in Particle Therapy, 2018
Eleanor A. Blakely, Manjit Dosanjh
The key structural factor CTCF (CCCTC-binding factor) was found to be flanking the phospho-H2AX nanodomains that arrange into higher-order clustered structures of discontinuously phosphorylated chromatin. CTCF knockdown impaired the spreading of the phosphorylation throughout the 3D-looped nanodomains. Co-staining of phospho-H2AX with phosphor-Ku70 and TUNEL (Terminal deoxynucleotidyl transferase dUTP Nick End Labeling) revealed that clusters rather than nanofoci represent single DSBs. This work provided evidence that each chromatin loop is a nanofocus whose clusters corresponded to previously known phospho-H2AX foci. The subfoci structure of the local chromatin at the DSB sites likely denote elementary DNA repair units along the carbon-ion trajectories where there are multiple DSBs in proximity and bear a striking similarity to the disordered 5–24 nanometre diameter chromatin structure reported by Ou et al. (2017). This work also challenges the belief that each γ-H2AX focus represents one DSB since isolated subfoci were found outside of the ion track that may represent delta ray-induced damage from individual particle tracks. The authors point out that counting the number of γ-H2AX foci from densely ionising radiations using conventional microscopy may underestimate the actual number of DSBs in the DNA due to the number of large clustered DSB-damaged foci.
Genetics of Wilms tumor
Published in J. K. Cowell, Molecular Genetics of Cancer, 2003
Mathias A.E. Frevel, Bryan R.G. Williams
The IGF2 gene is one of a number of imprinted genes within a large chromosomal region of 11p15.5 that is hence referred to as an imprinted domain (Reid et al., 1997). The regulation of the monoallelic expression of imprinted genes within this domain involves long ranging chromatin effects and DNA methylation, processes that we know today are interrelated. The investigation of loss of IGF2 imprinting in Wilms tumor and in BWS has greatly contributed to the understanding of imprinting at the 11p15 locus. In the case of Wilms tumor biallelic expression of IGF2 was shown to correlate with silencing and abnormally high DNA methylation of the H19 gene (Moulton et al., 1994; Steenman et al., 1994; Taniguchi et al., 1995). The H19 gene, normally expressed from the maternal allele only, codes for an untranslated RNA of unknown function, and may itself be a growth suppressing gene (Hao et al., 1993). The abnormal methylation of the maternal H19 alleles was shown to effect an upstream region of the gene that is critical for maintaining IGF2 and H19 imprinting (Frevel et al., 1999; Thorvaldsen et al., 1998). This region contains several methylation sensitive binding sites for CTCF (CCCTC-binding factor), an eleven-zinc finger DNA-binding protein that has been shown to bind specific sites between enhancer elements and promotors to prevent gene activation (Bell et al., 1999). On the maternal allele, binding of CTCF to its unmethylated sites blocks the action of downstream enhancers on IGF2 but allows the same enhancers to promote H19 transcription. On the paternal allele, CTCF can not bind to the methylated binding sites, leaving the downstream enhancers free to promote IGF2 transcription (Bell and Felsenfeld, 2000; Hark et al., 2000; Kanduri et al., 2000; Szabo et al., 2000). Aberrant methylation of H19 was also detected in normal kidney tissue from Wilms tumor patients which implies that the epigenetic change occurred very early in kidney development (Okamoto et al., 1997). Taken together, these findings suggest that hypermethylation of HI9, either as a direct cause or in company with other undetected chromatin changes, is responsible for H19 silencing and LOI of IGF2 in Wilms tumors. However, other studies have found that the disruption of the monoallelic expression of H19 and IGF2 in Wilms tumors can also be independent events (Cui et al., 1997; Ohlsson et al., 1999). Finally, it is important to note that only approximately one third of Wilms tumors present maternal 11p15 LOH and another third LOI of IGF2, whereas one third of Wilms tumors exhibit normal monoallelic IGF2 expression. In this latter group other genetic changes may substitute for the consequences of aberrant IGF2 imprinting.
Association and epistatic analysis of white matter related genes across the continuum schizophrenia and autism spectrum disorders: The joint effect of NRG1-ErbB genes
Published in The World Journal of Biological Psychiatry, 2022
C. Prats, M. Fatjó-Vilas, M. J. Penzol, O. Kebir, L. Pina-Camacho, D. Demontis, B. Crespo-Facorro, V. Peralta, A. González-Pinto, E. Pomarol-Clotet, S. Papiol, M. Parellada, M. O. Krebs, L. Fañanás
Even though the two SNPs detected in the second-order interaction are intronic, it is of note that the vast majority of the genome has gene regulatory properties (Bernstein et al. 2012), in which intronic and intergenic variants are involved. The impact of the non-coding variants captured by this interaction NRG1 × ERBB4 (rs6989777 × rs707284) can be evaluated using HaploReg (Ward and Kellis 2012). This is a tool that uses LD information from the 1000 Genomes Project to provide data on the predicted chromatin state of the queried SNPs, their sequence conservation mammals, and their effect on regulatory motifs. In this case, both SNPs are associated with putative changes in regulatory motifs (multi-tissue eQTL data). For example, NRG1-rs6989777 (also associated with SSD risk in our single-gene approach) is in an intronic region, and it is predicted to alter several motifs that overlap the recognition sequences of transcription factors, such as AP-1, CTCF, and Maf. In this sense, AP-1 and CTCF have been proposed as key players in maintaining a chromatin conformation of gene regulatory elements (Park et al. 2012). Interestingly, there is also evidence that this SNP is included in one of the top identified genes through polygenic scoring and pathway analyses in SZ (Ayalew et al. 2012). Besides the putative regulatory properties of the identified SNPs, it has also to be considered that the detected effects could reflect the involvement of other SNPs in linkage disequilibrium.
Relevance of sperm imprinted gene methylation on assisted reproductive technique outcomes and pregnancy loss: a systematic review
Published in Systems Biology in Reproductive Medicine, 2021
Rossella Cannarella, Andrea Crafa, Rosita A. Condorelli, Laura M. Mongioì, Sandro La Vignera, Aldo E. Calogero
The altered methylation of imprinted genes has been correlated with the risk of abortion. Akolkar and colleagues showed hypomethylation of CpG at the H19 imprinting control region (ICR) in 26 normozoospermic men whose wives had a history positive for recurrent pregnancy loss compared to 26 fertile controls. In particular, they reported a lower percentage of methylated CpGs in the clones analyzed, a lower percentage of complete H19 ICR methylation, and a lower percentage of methylation in the CTCF6-binding region (Ankolkar et al. 2012). CTCF is a vertebrate enhancer blocking protein. Hypomethylation of its binding site facilitates its adhesion to DNA with consequent silencing of the expression of the IGF2 gene. This, in turn, would lead to embryo loss. Global hypomethylation seems to be associated with increased fertilization by ‘epigenetically abnormal’ spermatozoa with a consequent increased risk of abortion (Ankolkar et al. 2012). The same authors, in another study involving 23 patient partners of women with a history of recurrent pregnancy loss (RPL) and 23 fertile controls, showed how the altered methylation of imprinted control regions (ICRs) of other paternally-expressed imprinted genes, such as DLK1-GTL2, MEST, PLAGL1, and global methylation of LINE1 elements, unlike to H19 ICR (Ankolkar et al. 2013), was not associated with idiopathic RPL (Ankolkar et al. 2013).
Further understanding of glioma mechanisms of pathogenesis: implications for therapeutic development
Published in Expert Review of Anticancer Therapy, 2020
Michael Ruff, Sani Kizilbash, Jan Buckner
In cells harboring IDH mutation there are blanket genome-wide effects, the best described and most relevant of which is an inhibitory effect on multiple enzymes within the cell including the Ten-eleven translocation (TET) class of DNA demethylases [32]. Simplistically, global inhibition of DNA demethylases results in a net increase in DNA methylation including methylation of CpG islands. The methylation of CpG islands (referred to as the G-CIMP phenotype) interferes with the tertiary structure of DNA by interrupting the binding site for CTCF. CTCF is an insulator protein and transcription factor that binds to thousands of sites across the genome, where it interacts with transcription factors involved in the maintenance of chromatin loops. The insulator function of CTCF holds the DNA in a specific spatial orientation, forming chromatin loops, and spatially separating genes and transcriptional regulatory elements. Interference with CTCF binding disrupts the formation of chromatin loops and therefore disrupts the physical segregation of DNA, bringing together disparate genetic elements in close physical proximity to influence one another. This is a newly discovered mechanism of oncogenesis, elucidated in glioma and, presumably identical in other IDH mutation-associated malignancies (chondrosarcoma, cholangiocarcinoma, Acute Myeloid Leukemia, and Ollier disease/Maffucci syndrome). In cases other than glioma, it is associated with a worse prognosis [32].