doctoralThesis
Análise das alterações transcricionais sexo-específicas do transtorno depressivo maior
Fecha
2022-07-08Registro en:
SOUZA, Iara Dantas de. Análise das alterações transcricionais sexo-específicas do transtorno depressivo maior. 2022. 144f. Tese (Doutorado em Bioinformática) - Instituto Metrópole Digital, Universidade Federal do Rio Grande do Norte, Natal, 2022.
Autor
Souza, Iara Dantas de
Resumen
Major depressive disorder (MDD) is an important neuropsychiatric disorder with high
prevalence in Brazil, characterized by persistent depressed mood and/or loss of
pleasure for at least two weeks. MDD is a disabling condition that predisposes to other
complex pathologies, such as cardiovascular diseases, and may even result in suicide.
MDD is more prevalent in women than in men and there are anatomical,
immunological, neuronal and hormonal differences, which reflect different prognoses
and symptoms between the sexes. However, there is no consensus regarding the
MDD transcriptional alterations in men and women, as well as the functional
implications of these alterations in the cellular metabolism. Most MDD transcriptional
studies explain the disease’s pathophysiology by looking for changes in global gene
expression. However, gene expression changes can also occur at the transcript level,
as RNA splicing pathways may be altered. The present work seeks to investigate the
transcriptional alterations of MDD in women and men through differential gene
expression (DGE) analysis, differential transcript expression (DTE) analysis and
analysis of differential isoform use (DTU) in post-mortem samples of six brain regions.
The set of genes identified in at least one of the three approaches was called
transcriptionally altered genes (TAGs), which represent the comprehensive
transcriptional alteration profile of MDD. At total, 1075 TAGs were identified mainly in
the prefrontal cortex. Approximately half of the transcriptional changes occurred only
at the transcript level. We found a near absence of overlap between the altered genes
identified in men and the ones identified in women. This indicates that MDD
transcriptional alteration profile is sex-specific, considering both the gene- and the
transcript-level alterations. We verified alterations in the RNA processing and export
pathways in the orbitofrontal cortex of women. Additionally the DDX39B gene, an RNA
splicing machinery member, was altered in different brain regions of women and men,
respectively. Furthermore, we showed that the ATAT1 gene is altered in multiple brain
regions of women and the ABR gene is altered in multiple brain regions of men,
constituting potential sex-specific molecular biomarkers for MDD. Therefore, our work
shows that the MDD gene expression perturbation occurs through alteration at global
gene expression as well as alteration at isoform-level expression.