Biology subjects

Stewart, S. A.

Publications and source records attributed to Stewart, S. A..

3 recordsLinked to original sources

bioRxiv2021

Gonadal sex patterns p21-induced cellular senescence in mouse and human glioblastoma

Males exhibit higher incidence and worse prognosis for the majority of cancers, including glioblastoma (GBM). Disparate survival may be related to sex-biased responses to treatment, including radiation. Using a mouse model of GBM, we show that female cells are more sensitive to radiation, and that senescence represents a major component of the radiation therapeutic response in both sexes. Correlation analyses revealed that the CDK inhibitor p21 and irradiation induced senescence were differentially regulated between male and female cells. Indeed, female cellular senescence was more sensitive to changes in p21 levels, a finding that was observed in both wildtype and transformed murine astrocytes and patient-derived GBM cell lines. Using a novel Four Core Genotypes model of GBM, we further show that sex differences in p21-induced senescence are patterned by gonadal sex. These data suggest that sex differences in p21 induced senescence contribute to the female survival advantage in GBM.

cancer biology↗

bioRxiv2020

Epigenetic aging of classical monocytes from healthy individuals

The impact of healthy aging on molecular programming of immune cells is poorly understood. Here, we report comprehensive characterization of healthy aging in human classical monocytes, with a focus on epigenomic, transcriptomic, and proteomic alterations, as well as the corresponding proteomic and metabolomic data for plasma, using healthy cohorts of 20 young and 20 older individuals (~27 and ~64 years old on average). For each individual, we performed eRRBS-based DNA methylation profiling, which allowed us to identify a set of age-associated differentially methylated regions (DMRs) - a novel, cell-type specific signature of aging in DNA methylome. Optimized ultra-low-input ChIP-seq (ULI-ChIP-seq) data acquisition and analysis pipelines applied to 5 chromatin marks for each individual revealed lack of large-scale age-associated changes in chromatin modifications and allowed us to link hypo- and hypermethylated DMRs to distinct chromatin modification patterns. Specifically, hypermethylation events were associated with H3K27me3 in the CpG islands near promoters of lowly-expressed genes, while hypomethylated DMRs were enriched in H3K4me1 marked regions and associated with normal pattern of expression. Furthermore, hypo- and hypermethylated DMRs followed distinct functional and genetic association patterns. Hypomethylation events were associated with age-related increase of expression of the corresponding genes, providing a link between DNA methylation and age-associated transcriptional changes in primary human cells. Furthermore, these locations were also enriched in genetic regions associated by GWAS with asthma, total blood protein, hemoglobin levels and MS. On the other side, acceleration of epigenetic age in HIV and asthma stems only from changes in hypermethylated DMRs but not from hypomethylated loci.

systems biology↗

bioRxiv2019

The p38MAPK-MK2-HSP27 Pathway Regulates the mRNA Stability of the Senescence-Associated Secretory Phenotype

Age is a significant risk factor for the development of cancer. Both age-dependent accumulation of cell autonomous mutations within preneoplastic cells and increases in senescent stromal cells within the tumor microenvironment are thought to collaborate to drive tumorigenesis. Senescent cells express pro-tumorigenic factors termed the senescence-associated secretory phenotype (SASP), subject to a variety of regulatory mechanisms that are not fully elucidated. Previous work demonstrated that p38 mitogen-activated protein kinase (p38MAPK)-dependent regulation of AUF1 occupancy on SASP factor mRNAs post-transcriptionally stabilizes many SASP mRNAs and contributes to their increased expression. Here, we address the mechanism by which p38MAPK regulates AUF1s occupancy and activity on SASP factor mRNAs. We found that the p38MAPK-MK2-HSP27 pathway regulates both mRNA stability and AUF1 occupancy in cells induced to senesce. Furthermore, the tumor-promoting abilities of senescent stromal cells were lost upon inhibition of MK2, suggesting that this pathway is a viable therapeutic target within the tumor microenvironment.

cancer biology↗