Genetic variations in G-quadruplex forming sequences affect the transcription of human disease-related genes

Author:

Lorenzatti Agustín1,Piga Ernesto J1,Gismondi Mauro2,Binolfi Andrés13,Margarit Ezequiel2ORCID,Calcaterra Nora B1,Armas Pablo1ORCID

Affiliation:

1. Instituto de Biología Molecular y Celular de Rosario (IBR), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) - Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario (UNR) , Ocampo y Esmeralda, Rosario S2000EZP, Santa Fe, Argentina

2. Centro de Estudios Fotosintéticos y Bioquímicos (CEFOBI), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) - Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario (UNR) , Suipacha 531, Rosario, Santa Fe, Argentina

3. Plataforma Argentina de Biología Estructural y Metabolómica (PLABEM), Ocampo y Esmeralda , Rosario S200EZP, Santa Fe, Argentina

Abstract

Abstract Guanine-rich DNA strands can fold into non-canonical four-stranded secondary structures named G-quadruplexes (G4s). G4s folded in proximal promoter regions (PPR) are associated either with positive or negative transcriptional regulation. Given that single nucleotide variants (SNVs) affecting G4 folding (G4-Vars) may alter gene transcription, and that SNVs are associated with the human diseases’ onset, we undertook a novel comprehensive study of the G4-Vars genome-wide (G4-variome) to find disease-associated G4-Vars located into PPRs. We developed a bioinformatics strategy to find disease-related SNVs located into PPRs simultaneously overlapping with putative G4-forming sequences (PQSs). We studied five G4-Vars disturbing in vitro the folding and stability of the G4s located into PPRs, which had been formerly associated with sporadic Alzheimer's disease (GRIN2B), a severe familiar coagulopathy (F7), atopic dermatitis (CSF2), myocardial infarction (SIRT1) and deafness (LHFPL5). Results obtained in cultured cells for these five G4-Vars suggest that the changes in the G4s affect the transcription, potentially contributing to the development of the mentioned diseases. Collectively, data reinforce the general idea that G4-Vars may impact on the different susceptibilities to human genetic diseases’ onset, and could be novel targets for diagnosis and drug design in precision medicine.

Funder

Agencia Nacional de Promoción Científica y Tecnológica

Consejo Nacional de Investigaciones Científicas y Técnicas

Universidad Nacional de Rosario

Publisher

Oxford University Press (OUP)

Subject

Genetics

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