RESUMO
Psoriasis is a common inflammatory skin disease with complex etiology and chronic progression. To provide novel insights into the regulatory molecular mechanisms of the disease, we performed RNA sequencing analysis of 14 pairs of skin samples collected from patients with psoriasis. Subsequent pathway analysis and extraction of the transcriptional regulators governing psoriasis-associated pathways was executed using a combination of the MetaCore Interactome enrichment tool and the cisExpress algorithm, followed by comparison to a set of previously described psoriasis response elements. A comparative approach allowed us to identify 42 core transcriptional regulators of the disease associated with inflammation (NFκB, IRF9, JUN, FOS, SRF), the activity of T cells in psoriatic lesions (STAT6, FOXP3, NFATC2, GATA3, TCF7, RUNX1), the hyperproliferation and migration of keratinocytes (JUN, FOS, NFIB, TFAP2A, TFAP2C) and lipid metabolism (TFAP2, RARA, VDR). In addition to the core regulators, we identified 38 transcription factors previously not associated with the disease that can clarify the pathogenesis of psoriasis. To illustrate these findings, we analyzed the regulatory role of one of the identified transcription factors (TFs), FOXA1. Using ChIP-seq and RNA-seq data, we concluded that the atypical expression of the FOXA1 TF is an important player in the disease as it inhibits the maturation of naive T cells into the (CD4+FOXA1+CD47+CD69+PD-L1(hi)FOXP3-) regulatory T cell subpopulation, therefore contributing to the development of psoriatic skin lesions.
Assuntos
Psoríase/genética , Fatores de Transcrição/genética , Ativação Transcricional , Transcriptoma , Movimento Celular , Fator 3-alfa Nuclear de Hepatócito/genética , Fator 3-alfa Nuclear de Hepatócito/metabolismo , Humanos , Inflamação/genética , Inflamação/metabolismo , Queratinócitos/citologia , Queratinócitos/metabolismo , Metabolismo dos Lipídeos , Psoríase/metabolismo , Transdução de Sinais , Fatores de Transcrição/metabolismoRESUMO
Plant immunophilins are a broadly conserved family of proteins, which carry out a variety of cellular functions. In this study, we investigated three immunophilin genes involved in the Arabidopsis thaliana response to Pseudomonas syringae infection: a cytoplasmic localized AtCYP19, a cytoplasmic and nuclear localized AtCYP57, and one nucleus directed FKBP known as AtFKBP65. Arabidopsis knock-out mutations in these immunophilins result in an increased susceptibility to P. syringae, whereas overexpression of these genes alters the transcription profile of pathogen-related defense genes and led to enhanced resistance. Histochemical analysis revealed local gene expression of AtCYP19, AtCYP57, and AtFKBP65 in response to pathogen infection. AtCYP19 was shown to be involved in reactive oxygen species production, and both AtCYP57 and AtFKBP65 provided callose accumulation in plant cell wall. Identification of the involvement of these genes in biotic stress response brings a new set of data that will advance plant immune system research and can be widely used for further investigation in this area.
Assuntos
Proteínas de Arabidopsis/genética , Arabidopsis/genética , Aromatase/genética , Imunidade Vegetal/genética , Proteínas de Ligação a Tacrolimo/genética , Arabidopsis/metabolismo , Arabidopsis/microbiologia , Proteínas de Arabidopsis/metabolismo , Aromatase/metabolismo , Regulação da Expressão Gênica de Plantas , Glucanos/genética , Glucanos/metabolismo , Mutação , Pseudomonas syringae , Espécies Reativas de Oxigênio/metabolismo , Estresse Fisiológico , Proteínas de Ligação a Tacrolimo/metabolismoRESUMO
A new strategy for creating experimental models for functional genomics has been proposed. It is based on the expression in transgenic plants of genes from thermophilic bacteria encoding functional analogues of plant proteins with high specific activity and thermal stability. We have validated this strategy by comparing physiological, biochemical and molecular properties of control tobacco plants and transgenic plants expressing genes of beta-glucanases with different substrate specificity. We demonstrate that the expression of bacterial beta-1,3-1,4-glucanase gene exerts no significant influence on tobacco plant metabolism, while the expression of bacterial beta-1,3-glucanase affects plant metabolism only at early stages of growth and development. By contrast, the expression of bacterial beta-1,4-glucanase has a significant effect on transgenic tobacco plant metabolism, namely, it affects plant morphology, the thickness of the primary cell wall, phytohormonal status, and the relative sugar content. We propose a hypothesis of beta-glucanase action as an important factor of genetic regulation of metabolic processes in plants.
