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Decline of FOXN1 gene expression in human thymus correlates with age: possible epigenetic regulation.

ABSTRACT: BACKGROUND:Thymic involution is thought to be an important factor of age related immunodeficiency. Understanding the molecular mechanisms of human thymic senescence may lead to the discovery of novel therapeutic approaches aimed at the reestablishment of central and peripheral T cell repertoire. RESULTS:As an initial approach, here we report that the decline of human thymic FOXN1 transcription correlates with age, while other genes, DLL1, DLL4 and WNT4, essential for thymopoiesis, are constitutively transcribed. Using a human thymic epithelial cell line (hTEC), we show that FOXN1 expression is refractory to signals that induce FOXN1 transcription in primary 3D culture conditions and by stimulation of the canonical WNT signaling pathway. Blockage of FOXN1 induceability in the hTEC line may be mediated by an epigenetic mechanism, the CpG methylation of the FOXN1 gene. CONCLUSION:We showed a suppression of FOXN1 transcription both in cultured human thymic epithelial cells and in the aging thymus. We hypothesize that the underlying mechanism may be associated with changes of the DNA methylation state of the FOXN1 gene.

SUBMITTER: Reis MD

PROVIDER: S-EPMC4625732 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Decline of FOXN1 gene expression in human thymus correlates with age: possible epigenetic regulation.

Reis Maria Danielma Dos Santos MD Csomos Krisztian K Dias Luciene Paschoal Braga LP Prodan Zsolt Z Szerafin Tamas T Savino Wilson W Takacs Laszlo L

Immunity & ageing : I & A 20151029

<h4>Background</h4>Thymic involution is thought to be an important factor of age related immunodeficiency. Understanding the molecular mechanisms of human thymic senescence may lead to the discovery of novel therapeutic approaches aimed at the reestablishment of central and peripheral T cell repertoire.<h4>Results</h4>As an initial approach, here we report that the decline of human thymic FOXN1 transcription correlates with age, while other genes, DLL1, DLL4 and WNT4, essential for thymopoiesis, ...[more]

PMID: 26516334

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Project description:Psychiatric stress has been associated with accelerated epigenetic aging (i.e., when estimates of cellular age based on DNA methylation exceed chronological age) in both blood and brain tissue. Little is known about the downstream biological effects of accelerated epigenetic age on gene expression. In this study we examined associations between DNA methylation-derived estimates of cellular age that range from decelerated to accelerated relative to chronological age ("DNAm age residuals") and transcriptome-wide gene expression. This was examined using tissue from three post-mortem cortical regions (ventromedial and dorsolateral prefrontal cortex and motor cortex, n = 97) from the VA National PTSD Brain Bank. In addition, we examined how posttraumatic stress disorder (PTSD) and alcohol-use disorders (AUD) moderated the association between DNAm age residuals and gene expression. Transcriptome-wide results across brain regions, psychiatric diagnoses, and cohorts (full sample and male and female subsets) revealed experiment-wide differential expression of 11 genes in association with PTSD or AUD in interaction with DNAm age residuals. This included the inflammation-related genes IL1B, RCOR2, and GCNT1. Candidate gene class analyses and gene network enrichment analyses further supported differential expression of inflammation/immune gene networks as well as glucocorticoid, circadian, and oxidative stress-related genes. Gene co-expression network modules suggested enrichment of myelination related processes and oligodendrocyte enrichment in association with DNAm age residuals in the presence of psychopathology. Collectively, results suggest that psychiatric stress accentuates the association between advanced epigenetic age and expression of inflammation genes in the brain. This highlights the role of inflammatory processes in the pathophysiology of accelerated cellular aging and suggests that inflammatory pathways may link accelerated cellular aging to premature disease onset and neurodegeneration, particularly in stressed populations. This suggests that anti-inflammatory interventions may be an important direction to pursue in evaluating ways to prevent or delay cellular aging and increase resilience to diseases of aging.

Dataset Information

Decline of FOXN1 gene expression in human thymus correlates with age: possible epigenetic regulation.

Publications

Decline of FOXN1 gene expression in human thymus correlates with age: possible epigenetic regulation.

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