RESUMO
This work is dedicated to the exploration of the role of epigenetic (epiG) factors in major psychosis. One of the key functions of epigenetic modification of the genome of eukaryotic cells is to suppress transcriptional activity of the retroelements. Examples of retroelements are endogenous retroviral sequences (ERVs), Alu's, and LINEs, among others, which as a rule are hypermethylated. There is evidence from schizophrenia (SCH) and other human complex diseases that some of the genomic retroelements become transcribed in the affected tissues. Our goal was to screen DNA samples from post-mortem brain tissues of individuals who were affected with major psychiatric illness for retroelements that were located in the hypomethylated fraction of the genomic DNA. Over 100 Alu sequences were cloned, sequenced, and mapped to the human genome. A substantial portion of the cloned Alu's are located close to or within the genes that may be interesting targets for further genetic, transcription, and epigenetic studies.
Assuntos
Epigênese Genética/genética , Genômica/métodos , Transtornos Psicóticos/genética , Retroelementos/genética , Adulto , Idoso , Elementos Alu/genética , Transtorno Bipolar/genética , Células Clonais , Feminino , Ligação Genética/genética , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Transtornos do Humor/genética , Esquizofrenia/genéticaRESUMO
The goal of this pilot study was to explore the putative molecular mechanisms underlying the phenotypic discordance of monozygotic (MZ) twins. Thus, patterns of epigenetic DNA modification were investigated in the 5'-regulatory region of the dopamine D2 receptor gene (DRD2) in two pairs of monozygotic twins, one concordant and one discordant for schizophrenia. The bisulfite DNA modification-based approach was used to fine-map methylated cytosines in DRD2 in genomic DNA extracted from lymphocytes. Numerous DNA methylation differences were identified in the analyzed region both within and between the pairs of MZ twins. "Epigenetic distances" between MZ twins were calculated and used for the comparison of twin DRD2 methylation profiles. It was detected that the affected twin from the pair discordant for schizophrenia was epigenetically "closer" to the affected concordant twins than to his unaffected MZ co-twin. Although the epigenetic analysis was conducted for only several hundred base pairs of DRD2, the fact that numerous studies identified nonuniform methylation patterns across the clones of bisulfite-modified DNA from the same individual, as well as nonuniform patterns across different individuals, argues for the universality of intra- and interindividual epigenetic variation. Epigenetic studies should provide insight into the molecular causes of differential susceptibility to a disease in genetically identical organisms that may generalize to singletons.
Assuntos
Epigênese Genética/genética , Gêmeos Monozigóticos/genética , Gêmeos Monozigóticos/psicologia , Gêmeos/genética , Gêmeos/psicologia , Adolescente , Adulto , Metilação de DNA , Humanos , Masculino , Regiões Promotoras Genéticas , Receptores de Dopamina D2/genéticaRESUMO
Elucidation of genetic factors in schizophrenia and bipolar disorder remains a challenging task to psychiatric researchers. As a rule, data from genetic linkage and association studies are quite controversial. In this article, we further explore the possibility that in addition to DNA sequences variation, a putative epigenetic dysregulation of brain genes plays an important role in the etiopathogenesis of major psychosis. We provide an epigenetic interpretation of unclear genetic findings specifically pertaining to chromosome 22 in schizophrenia and bipolar disorder. It is suggested that epigenetic strategies, when applied in conjunction with traditional genetic ones, may significantly expedite the uncovering of the molecular causes of major psychosis.
