RESUMEN
ATRX-DAXX-H3.3 chromatin remodeler complex is a well known epigenetic factor responsible for the heterochromatin maintenance and control. ATRX is an important nucleosome controller, especially in tandem repeat regions, and DAXX is a multi-function protein with particular role in histone H3.3 deposition due to its chaperone characteristic. Abnormalities in this complex have been associated with telomere dysfunction and consequently with activation of alternative lengthening of telomeres mechanism, genomic instability, and tumor progression in different types of cancer. However, the characterization of this complex is still incomplete in meningioma. We analyzed ATRX, DAXX and H3.3 expressions and the telomere length in a cohort of meningioma of different malignant grades. We observed ATRX upregulation at gene and protein levels in grade II/III meningiomas. A low variability of telomere length was observed in meningiomas across different ages and malignant grades, in contrast to the shortening of telomere length with aging in normal controls.
Asunto(s)
Proteínas Co-Represoras/metabolismo , Histonas/metabolismo , Neoplasias Meníngeas/metabolismo , Meningioma/metabolismo , Chaperonas Moleculares/metabolismo , Telómero/metabolismo , Proteína Nuclear Ligada al Cromosoma X/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Proteínas Co-Represoras/genética , Femenino , Histonas/genética , Humanos , Masculino , Neoplasias Meníngeas/genética , Neoplasias Meníngeas/patología , Meningioma/genética , Meningioma/patología , Persona de Mediana Edad , Chaperonas Moleculares/genética , Telómero/genética , Proteína Nuclear Ligada al Cromosoma X/genéticaRESUMEN
Glioblastoma (GBM) is the most aggressive brain primary malignancy. Toll-like receptor 4 (TLR4) has a dual role in cell fate, promoting cell survival or death depending on the context. Here, we analyzed TLR4 expression in different grades of astrocytoma, and observed increased expression in tumors, mainly in GBM, compared to non-neoplastic brain tissue. TLR4 role was investigated in U87MG, a GBM mesenchymal subtype cell line, upon LPS stimulation. p65 nuclear translocation was observed in late phase, suggesting TLR4-non-canonical pathway activation. In fact, components of ripoptosome and inflammasome cascades were upregulated and they were significantly correlated in GBMs of the TCGA-RNASeq dataset. Moreover, an increased apoptotic rate was observed when the GBM-derived U87MG cells were co-treated with LPS and Temozolomide (TMZ) in comparison to TMZ alone. Increased TLR4 immunostaining was detected in nuclei of U87MG cells 12 h after LPS treatment, concomitant to activation of DNA repair genes. Time-dependent increased RAD51, FEN1 and UNG expression levels were confirmed after LPS stimulation, which may contribute to tumor cell fitness. Moreover, the combined treatment with the RAD51 inhibitor, Amuvatinib in combination with, TMZ after LPS stimulation reduced tumor cell viability more than with each treatment alone. In conclusion, our results suggest that stimulation of TLR4 combined with pharmacological inhibition of the DNA repair pathway may be an alternative treatment for GBM patients.
Asunto(s)
Neoplasias Encefálicas/metabolismo , Núcleo Celular/metabolismo , Reparación del ADN , ADN de Neoplasias/metabolismo , Glioblastoma/metabolismo , Proteínas de Neoplasias/metabolismo , Transducción de Señal , Receptor Toll-Like 4/metabolismo , Factor de Transcripción ReIA/metabolismo , Transporte Activo de Núcleo Celular , Neoplasias Encefálicas/genética , Línea Celular Tumoral , Núcleo Celular/genética , ADN de Neoplasias/genética , Femenino , Glioblastoma/genética , Humanos , Masculino , Proteínas de Neoplasias/genética , Receptor Toll-Like 4/genética , Factor de Transcripción ReIA/genéticaRESUMEN
The chromatin-remodeling complex ATRX/DAXX is one of the major epigenetic factors that controls heterochromatin maintenance due to its role in histone deposition. ATRX is involved in nucleosome configuration and maintenance of higher order chromatin structure, and DAXX is a specific histone chaperone for H3.3 deposition. Dysfunctions in this complex have been associated with telomere shortening, which influences cell senescence. However, data about this complex in brain tissue related to aging are still scarce. Therefore, in the present study, we analyzed ATRX and DAXX expressions in autopsied human brain specimens and the telomere length. A significant decrease in gene and protein expressions was observed in the brain tissues from the elderly compared with those from the young, which were related to short telomeres. These findings may motivate further functional analysis to confirm the ATRX-DAXX complex involvement in telomere maintenance and brain aging.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Envejecimiento/genética , Encéfalo/metabolismo , Proteínas Nucleares/genética , Proteína Nuclear Ligada al Cromosoma X/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Encéfalo/crecimiento & desarrollo , Proteínas Co-Represoras , Humanos , Persona de Mediana Edad , Chaperonas Moleculares , Proteínas Nucleares/metabolismo , Homeostasis del Telómero , Proteína Nuclear Ligada al Cromosoma X/metabolismoRESUMEN
Microglia are essential for CNS homeostasis and innate neuroimmune function, and play important roles in neurodegeneration and brain aging. Here we present gene expression profiles of purified microglia isolated at autopsy from the parietal cortex of 39 human subjects with intact cognition. Overall, genes expressed by human microglia were similar to those in mouse, including established microglial genes CX3CR1, P2RY12 and ITGAM (CD11B). However, a number of immune genes, not identified as part of the mouse microglial signature, were abundantly expressed in human microglia, including TLR, Fcγ and SIGLEC receptors, as well as TAL1 and IFI16, regulators of proliferation and cell cycle. Age-associated changes in human microglia were enriched for genes involved in cell adhesion, axonal guidance, cell surface receptor expression and actin (dis)assembly. Limited overlap was observed in microglial genes regulated during aging between mice and humans, indicating that human and mouse microglia age differently.