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Epigenetics in Sperm, Epigenetic Diagnostics, and Transgenerational Inheritance
Published in Carlos Simón, Carmen Rubio, Handbook of Genetic Diagnostic Technologies in Reproductive Medicine, 2022
Jennifer L. M. Thorson, Millissia Ben Maamar, Michael K. Skinner
Chemical modifications of RNAs can have dynamic regulatory roles similar to the epigenetic modifications of DNA and histone proteins (41) (Figure 7.1). The most prevalent known mammalian RNA modification is N6-methyladenosine (m6A), a reversible methylation of the messenger RNA (mRNA) (42). The methylation of RNA alters the structure of the RNA to change function and protein or DNA association. Methylation of numerous RNA species results in a diversity of functions on RNA including biophysical, biochemical, and metabolic stabilization of RNA and further crucial functional processes (43).
Translation
Published in Paul Pumpens, Single-Stranded RNA Phages, 2020
Finally, Hobson and Uhlenbeck (2006) performed alanine scanning of the MS2 coat and revealed protein-phosphate contacts involved in thermodynamic hot spots. Since the co-crystal structure of the MS2 coat dimer with the RNA operator found eight amino acid side chains contacting seven of the RNA phosphates, these eight amino acids and five nearby control positions were individually changed to an alanine residue, and the binding affinities of the mutant proteins to the RNA were determined. In general, the data agreed well with the crystal structure and previous RNA modification data. Interestingly, the amino acid residues that were energetically most important for complex formation clustered in the middle of the RNA binding interface, forming thermodynamic hot spots, and were surrounded by energetically less relevant amino acids. In order to evaluate whether or not a given alanine mutation caused a global change in the RNA-protein interface, the affinities of the mutant proteins to RNAs containing one of 14 backbone modifications spanning the entire interface were determined. In three of the six protein mutations tested, the thermodynamic coupling between the site of the mutation and the RNA groups that could be even more than 16 Å away was detected.
Hemoglobinopathies
Published in Victor A. Bernstam, Pocket Guide to GENE LEVEL DIAGNOSTICS in Clinical Practice, 2019
Variations in the clinical phenotype of β-thalassemia have been traced to mutations in the regulatory sequences outside the b-globin gene, which control the transcriptional efficiency of the b-globin genemutations affecting RNA processing: RNA modification at the cap (7-methylguanosine) siteRNA cleavagepolyadenylationsplicingmutations affecting translation of the mRNA into globin
High tRNA Transferase NSUN2 Gene Expression is Associated with Poor Prognosis in Head and Neck Squamous Carcinoma
Published in Cancer Investigation, 2018
Lingeng Lu, Gongjian Zhu, Hongmei Zeng, Qian Xu, Klaus Holzmann
The dynamics of RNA methylation is controlled by RNA modification-associated enzymes through methylation and demethylation. NOP2/Sun domain family, member 2 protein (NSUN2), which is encoded by NSUN2 gene at chromosome 10, is one such RNA modification protein for m5C methylation in tRNAs (11), thereby preventing endonucleolytic cleavage of tRNA by angiogenin, and controlling the efficacy of protein translation (12–16). The reduction of protein synthesis is observed in NSUN2-deficient cells, which show the dysregulation of cell cycle, abnormal cell differentiation and proliferation (3,13–16). Hussain et al. demonstrated the lack of spermatids and sperm formation in NSUN2-knockout testes (17). Inhibition of NSUN2 expression suppresses the migration of neural cells toward the chemoattractant growth factor (18). Xing et al. (19) showed that the stimulation of cell growth by NSUN2 was mediated by CDK1 mRNA methylation and consequently the high levels of CDK1 translation. It has been reported that NSUN2 is overexpressed in breast cancer tissues, and high NSUN2 expression promotes invasion and metastasis (20). Recently, the NSUN2/IGF-II signature increased the mortality risk when both molecules were at the high levels in ovarian cancer (21).
RNA A-to-I editing, environmental exposure, and human diseases
Published in Critical Reviews in Toxicology, 2021
RNA editing is a unique type of RNA modification and occurs in the specific nucleic acids of RNAs after transcription. There are two common forms of RNA editing in mammals including Adenosine to Inosine (A-to-I) and Cytidine to Uridine (C-to-U) conversion. RNA editing was initially discovered in the embryos of African clawed frog, Xenopus laevis, more than 30 years ago (Bass BL and Weintraub 1987; Rebagliati and Melton 1987). The first finding in human tissues was reported in 1987, regarding C-to-U conversion in the human mRNA of apolipoprotein-B48 gene in the intestine which was suggested as a tissue-specific modification of a single mRNA nucleotide (Powell et al. 1987). After these preliminary findings, RNA editing has been documented over three decades, leaving some aspects unexplored. Today, like several RNA modifications, such as m6A, RNA editing is associated with various diseases with limited findings. Furthermore, a few studies indicated that environmental stress could affect the RNA edition (Dorn et al. 2019). Together, we review a general overview of RNA editing- environmental exposures associations and RNA editing-diseases associations (cancer). This work presents initial evidence and raises awareness, thereby providing a comprehensive approach to understand the association between RNA A-to-I editing and environmental exposures and between RNA A-to-I editing and diseases, mainly cancer. By using the publicly available data, it also aims to present the association between environmental exposures and expression RNA A-to-I editing genes, and to provide the association between RNA A-to-I editing genes and cancer.
M6A Regulatory Genes Play an Important Role in the Prognosis, Progression and Immune Microenvironment of Pancreatic Adenocarcinoma
Published in Cancer Investigation, 2021
Fangshi Xu, Zhengliang Zhang, Miao Yuan, Yidi Zhao, Yang Zhou, Honghong Pei, Ling Bai
Pancreatic adenocarcinoma (PAAD) is an extremely challenging disease, since only 15- 20% of PAAD patients are suitable for surgery (5). Even some classic MTT drugs, such as Erlotinib and Everolimus, normally cannot prolong the median OS time of treated PAAD patients longer than 10 months (37). Recently, an increasing number of reports have been indicating that epigenetic alterations can largely impact cancer progression (38). Among that, M6A RNA methylation has been demonstrated as the most common type of RNA modification (39). Nevertheless, the role of m6A regulatory genes in PAAD has not been fully elucidated. Therefore, we explored the function of m6A regulatory genes in malignant progression, prognosis and immune microenvironment of PAAD in present study.