RESUMEN
Major depressive disorder (MDD) is associated with a significantly elevated risk of developing serious medical illnesses such as cardiovascular disease, immune impairments, infection, dementia and premature death. Previous work has demonstrated immune dysregulation in subjects with MDD. Using genome-wide transcriptional profiling and promoter-based bioinformatic strategies, we assessed leukocyte transcription factor (TF) activity in leukocytes from 20 unmedicated MDD subjects versus 20 age-, sex- and ethnicity-matched healthy controls, before initiation of antidepressant therapy, and in 17 of the MDD subjects after 8 weeks of sertraline treatment. In leukocytes from unmedicated MDD subjects, bioinformatic analysis of transcription control pathway activity indicated an increased transcriptional activity of cAMP response element-binding/activating TF (CREB/ATF) and increased activity of TFs associated with cellular responses to oxidative stress (nuclear factor erythroid-derived 2-like 2, NFE2l2 or NRF2). Eight weeks of antidepressant therapy was associated with significant reductions in Hamilton Depression Rating Scale scores and reduced activity of NRF2, but not in CREB/ATF activity. Several other transcriptional regulation pathways, including the glucocorticoid receptor (GR), nuclear factor kappa-B cells (NF-κB), early growth response proteins 1-4 (EGR1-4) and interferon-responsive TFs, showed either no significant differences as a function of disease or treatment, or activities that were opposite to those previously hypothesized to be involved in the etiology of MDD or effective treatment. Our results suggest that CREB/ATF and NRF2 signaling may contribute to MDD by activating immune cell transcriptome dynamics that ultimately influence central nervous system (CNS) motivational and affective processes via circulating mediators.
Asunto(s)
Trastorno Depresivo Mayor/genética , Leucocitos/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Adulto , Antidepresivos/uso terapéutico , Trastorno Depresivo Mayor/tratamiento farmacológico , Proteína 1 de la Respuesta de Crecimiento Precoz/genética , Proteína 2 de la Respuesta de Crecimiento Precoz/genética , Proteína 3 de la Respuesta de Crecimiento Precoz/genética , Factores de Transcripción de la Respuesta de Crecimiento Precoz/genética , Femenino , Perfilación de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Factor 2 Relacionado con NF-E2/genética , FN-kappa B/genética , Receptores de Glucocorticoides/genéticaRESUMEN
We present the first comprehensive transcriptome-to-genome mapping for human cartilage. First, we determined that the cartilage transcriptome represents between 13,200 and 15,800 unique genes. Next, a subset of approximately 10,000 of the best characterized cartilage-expressed transcripts (CETs) was selected and mapped to the human genome. The distribution of CETs across the genome was found to be significantly different compared to the expected distribution. Furthermore, clusters of adjacent coordinately transcribed genes, as well as numerous "hot spots" and "cold spots" for transcription in cartilage, were identified. We propose that transcriptional control in cartilage can be exerted over genomic domains containing as few as four neighboring genes. Our findings, which are consistent with recent "chromatin domain" models of transcription, are further supported by our identification of CETs that putatively encode components of the HDAC- and Swi/SNF-mediated chromatin remodeling pathways. Our study illustrates the value of comprehensive high-resolution scans to detect transcription patterns within the human genome.
Asunto(s)
Cartílago/metabolismo , Mapeo Cromosómico , Genoma Humano , ARN Mensajero/genética , Transcripción Genética/genética , Cromatina/genética , Análisis Citogenético , Etiquetas de Secuencia Expresada , Biblioteca de Genes , Humanos , Modelos Genéticos , ARN Mensajero/metabolismo , Análisis de Secuencia de ADNRESUMEN
Identifying key genes that regulate the complex diseases of the cardiovascular system can be greatly facilitated with the use of microarrays. In an effort to obtain a global portrait of gene expression in the failing heart, we have constructed in-house a glass microscope slide cDNA microarray (termed "CardioChip") containing 10,368 redundant and randomly-selected sequenced expressed sequence tags (representing known genes, other matched ESTs, and novel, unmatched ESTs) derived from several human heart and artery cDNA libraries. From our preliminary data with Cy3- and Cy5-labeled probes, we have identified 38 transcripts showing a minimum twofold differential expression, among which are several novel or previously-uncharacterized genes. This array-representing what we believe to be the largest cardiovascular-based cDNA array to date-establishes a practical and invaluable platform for obtaining a global genetic portrait of complex cardiovascular diseases, particularly in the failing heart.
