RESUMO
Schizophrenia is a heterogeneous disease generally considered to result from a combination of heritable and environmental factors. Although its pathophysiology has not been fully determined, biological studies support the involvement of several possible components including altered DNA methylation, abnormal glutamatergic transmission, altered mitochondrial function, folate deficiency and high maternal homocysteine levels. Although these factors have been explored separately, they all involve one-carbon (C1) metabolism. Furthermore, C1 metabolism is well positioned to integrate gene-environment interactions by influencing epigenetic regulation. Here, we discuss the potential roles of C1 metabolism in the pathophysiology of schizophrenia. Understanding the contribution of these mechanisms could yield new therapeutic approaches aiming to counteract disease onset or progression.
Assuntos
Carbono/metabolismo , Esquizofrenia/metabolismo , Metilação de DNA , Meio Ambiente , Epigênese Genética , Deficiência de Ácido Fólico/complicações , Deficiência de Ácido Fólico/metabolismo , Deficiência de Ácido Fólico/fisiopatologia , Predisposição Genética para Doença , Homocisteína/metabolismo , Humanos , Redes e Vias Metabólicas , Metionina/metabolismo , Doenças Mitocondriais/complicações , Doenças Mitocondriais/metabolismo , Doenças Mitocondriais/fisiopatologia , Receptores de Glutamato/metabolismo , Esquizofrenia/etiologia , Esquizofrenia/fisiopatologia , Fatores de TempoRESUMO
The Hox clusters play a crucial role in body patterning during animal development. They encode both Hox transcription factor and micro-RNA genes that are activated in a precise temporal and spatial sequence that follows their chromosomal order. These remarkable collinear properties confer functional unit status for Hox clusters. We developed the TranscriptView platform to establish high resolution transcriptional profiling and report here that transcription in the Hox clusters is far more complex than previously described in both human and mouse. Unannotated transcripts can represent up to 60% of the total transcriptional output of a cluster. In particular, we identified 14 non-coding Transcriptional Units antisense to Hox genes, 10 of which (70%) have a detectable mouse homolog. Most of these Transcriptional Units in both human and mouse present conserved sizeable sequences (>40 bp) overlapping Hox transcripts, suggesting that these Hox antisense transcripts are functional. Hox clusters also display at least seven polycistronic clusters, i.e., different genes being co-transcribed on long isoforms (up to 30 kb). This work provides a reevaluated framework for understanding Hox gene function and dys-function. Such extensive transcriptions may provide a structural explanation for Hox clustering.
