RESUMO
AIRE expression in thymus is downregulated by estrogen after puberty, what probably renders women more susceptible to autoimmune disorders. Here we investigated the effects of minipuberty on male and female infant human thymic tissue in order to verify if this initial transient increase in sex hormones - along the first six months of life - could affect thymic transcriptional network regulation and AIRE expression. Gene co-expression network analysis for differentially expressed genes and miRNA-target analysis revealed sex differences in thymic tissue during minipuberty, but such differences were not detected in the thymic tissue of infants aged 7-18 months, i.e. the non-puberty group. AIRE expression was essentially the same in both sexes in minipuberty and in non-puberty groups, as assessed by genomic and immunohistochemical assays. However, AIRE-interactors networks showed several differences in all groups regarding gene-gene expression correlation. Therefore, minipuberty and genomic mechanisms interact in shaping thymic sexual dimorphism along the first six months of life.
Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Redes Reguladoras de Genes , MicroRNAs/genética , Caracteres Sexuais , Timo/metabolismo , Fatores de Transcrição/genética , Estrogênios/metabolismo , Feminino , Perfilação da Expressão Gênica , Ontologia Genética , Humanos , Lactente , Masculino , MicroRNAs/classificação , MicroRNAs/metabolismo , Anotação de Sequência Molecular , Fatores Sexuais , Timo/crescimento & desenvolvimento , Fatores de Transcrição/metabolismo , Proteína AIRERESUMO
AIRE expression in thymus is downregulated by estrogen after puberty, what probably renders women more susceptible to autoimmune disorders. Here we investigated the efects of minipuberty on male and female infant human thymic tissue in order to verify if this initial transient increase in sex hormones - along the frst six months of life - could afect thymic transcriptional network regulation and AIRE expression. Gene co-expression network analysis for diferentially expressed genes and miRNA-target analysis revealed sex diferences in thymic tissue during minipuberty, but such diferences were not detected in the thymic tissue of infants aged 718 months, i.e. the non-puberty group. AIRE expression was essentially the same in both sexes in minipuberty and in non-puberty groups, as assessed by genomic and immunohistochemical assays. However, AIRE-interactors networks showed several diferences in all groups regarding gene-gene expression correlation. Therefore, minipuberty and genomic mechanisms interact in shaping thymic sexual dimorphism along the frst six months of life.
Assuntos
Timo , Linfócitos T , Caracteres SexuaisRESUMO
During the early thymus colonization, Notch signaling activation on hematopoietic progenitor cells (HPCs) drives proliferation and T cell commitment. Although these processes are driven by transcription factors such as HOXB4 and GATA3, there is no evidence that Notch directly regulates their transcription. To evaluate the role of NOTCH and TNF signaling in this process, human CD34+ HPCs were cocultured with OP9-DL1 cells, in the presence or absence of TNF. The use of a Notch signaling inhibitor and a protein synthesis inhibitor allowed us to distinguish primary effects, mediated by direct signaling downstream Notch and TNF, from secondary effects, mediated by de novo synthesized proteins. A low and physiologically relevant concentration of TNF promoted T lymphopoiesis in OP9-DL1 cocultures. TNF positively modulated the expression of both transcripts in a Notch-dependent manner; however, GATA3 induction was mediated by a direct mechanism, while HOXB4 induction was indirect. Induction of both transcripts was repressed by a GSK3ß inhibitor, indicating that activation of canonical Wnt signaling inhibits rather than induces their expression. Our study provides novel evidences of the mechanisms integrating Notch and TNF-alpha signaling in the transcriptional induction of GATA3 and HOXB4. This mechanism has direct implications in the control of self-renewal, proliferation, commitment, and T cell differentiation.