Deciphering impact of single nucleotide polymorphisms on cotranscriptional modification in CCM gene mRNAs

• Published in: American Journal of Physiology: Cell Physiology Vol. 323; no. 4; pp. C1274 - C1284
• Main Authors: Scimone, Concetta, Donato, Luigi, Alibrandi, Simona, Alafaci, Concetta, D’Ascola, Angela, Vinci, Sergio, D’Angelo, Rosalia, Sidoti, Antonina
• Format: Journal Article
• Language: English
• Published: United States 01.10.2022
• Subjects: Adenosine - genetics; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; Carrier Proteins - metabolism; Cytosine; Hemangioma, Cavernous, Central Nervous System - genetics; Hemangioma, Cavernous, Central Nervous System - metabolism; Humans; Membrane Proteins - metabolism; Polymorphism, Single Nucleotide - genetics; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; RNA, Messenger - genetics; cerebral cavernous malformation; nucleotide variants; single nucleotide polymorphism; epitranscriptomics; gene expression
• ISSN: 0363-6143; 1522-1563; 1522-1563
• DOI: 10.1152/ajpcell.00279.2022

Novel insights on regulation of gene expression mechanisms highlight the pivotal role of epitranscriptomic modifications on decision about transcript fate. These modifications include methylation of adenosine and cytosine in RNA molecules. Impairment of the normal epitranscriptome profile was observed in several pathological conditions, such as cancer and neurodegeneration. However, it is still unknown if alteration of this regulatory mechanism can be involved in cerebral cavernous malformation (CCM) development. CCM is a rare genetic condition affecting brain microvasculature, resulting from mutations in the three genes KRIT1, CCM2, and PDCD10. By data integration of association study, in silico prediction, and gene expression analysis, we evaluated role of single nucleotide polymorphisms (SNPs) highly recurrent in patients with CCM, on CCM gene expression regulation. Results showed that several of these SNPs lead to a drastic downexpression, in KRIT1 and CCM2 genes and this downregulation can be due to alteration of epitranscriptome profile, occurring these SNPs in gene regions that are subject to epitranscriptome modifications. These data suggest that this novel mechanism of gene expression regulation can be consider to further investigation on CCM pathogenesis.