RESUMEN
Epigenetics, meaning the variety of mechanisms underpinning gene regulation and chromatin states, plays a key role in normal development as well as in disease initiation and progression. Epigenetic mechanisms like alteration of DNA methylation, histone modifications, and non-coding RNAs, have been proposed as biomarkers for diagnosis, classification, or monitoring of responsiveness to treatment in many diseases. In prion diseases, the profound associations with human aging, the effects of cell type and differentiation on in vitro susceptibility, and recently identified human risk factors, all implicate causal epigenetic mechanisms. Here, we review the current state of the art of epigenetics in prion diseases and its interaction with genetic determinants. In particular, we will review recent advances made by several groups in the field profiling DNA methylation and microRNA expression in mammalian prion diseases and the potential for these discoveries to be exploited as biomarkers.
Asunto(s)
Epigénesis Genética , Enfermedades por Prión , Animales , Humanos , Metilación de ADN/genética , Biomarcadores , Enfermedades por Prión/genética , Expresión Génica , Mamíferos/genéticaRESUMEN
Sporadic Creutzfeldt-Jakob disease (sCJD) presents as a rapidly progressive dementia which is usually fatal within six months. No clinical blood tests are available for diagnosis or disease monitoring. Here, we profile blood microRNA (miRNA) expression in sCJD. Sequencing of 57 sCJD patients, and healthy controls reveals differential expression of hsa-let-7i-5p, hsa-miR-16-5p, hsa-miR-93-5p and hsa-miR-106b-3p. Downregulation of hsa-let-7i-5p, hsa-miR-16-5p and hsa-miR-93-5p replicates in an independent cohort using quantitative PCR, with concomitant upregulation of four mRNA targets. Absence of correlation in cross-sectional analysis with clinical phenotypes parallels the lack of association between rate of decline in miRNA expression, and rate of disease progression in a longitudinal cohort of samples from 21 patients. Finally, the miRNA signature shows a high level of accuracy in discriminating sCJD from Alzheimer's disease. These findings highlight molecular alterations in the periphery in sCJD which provide information about differential diagnosis and improve mechanistic understanding of human prion diseases.