Project description:Establishing and maintaining phenotypic heterogeneity within cell and organismal populations is an evolutionarily conserved strategy that ensures survival of the population following stressful exposures. We previously identified a transient, reversible, drug-tolerant cancer cell subpopulation that survives otherwise lethal drug exposures. Here we show that these drug-tolerant persisters (DTPs) assume a highly heterochromatic state, which requires factors that modify or bind trimethylated H3 lysine 9 (H3K9me3). The increased H3K9me3 in DTPs is largely restricted to evolutionarily young Long Interspersed Repeat elements (LINEs). This transcriptionally repressive state, which decreases the expression of these retrotransposable elements, is critical for DTP survival, and disruption of this heterochromatic state results in re-expression of LINE elements and ablation of this subpopulation. Together, these findings establish a role for epigenetic silencing of transposable elements as a population survival strategy to maintain genomic integrity in subpopulations of cancer cells during lethal drug exposures.
Project description:Establishing and maintaining phenotypic heterogeneity within cell and organismal populations is an evolutionarily conserved strategy that ensures survival of the population following stressful exposures. We previously identified a transient, reversible, drug-tolerant cancer cell subpopulation that survives otherwise lethal drug exposures. Here we show that these drug-tolerant persisters (DTPs) assume a highly heterochromatic state, which requires factors that modify or bind trimethylated H3 lysine 9 (H3K9me3). The increased H3K9me3 in DTPs is largely restricted to evolutionarily young Long Interspersed Repeat elements (LINEs). This transcriptionally repressive state, which decreases the expression of these retrotransposable elements, is critical for DTP survival, and disruption of this heterochromatic state results in re-expression of LINE elements and ablation of this subpopulation. Together, these findings establish a role for epigenetic silencing of transposable elements as a population survival strategy to maintain genomic integrity in subpopulations of cancer cells during lethal drug exposures.
Project description:Cytokine release syndrome (CRS) is a major cause of death in lethal T cell activation and presents a significant barrier for CAR-T immunotherapy or allogenic hematopoietic cell transplantation. We reported here that adrenal stress response, defined by a 5-10-fold increase in induced glucocorticoid (iGC) production, is an essential host response against lethal T cell activation. We identified scavenger receptor BI (SR-BI), a HDL receptor, as a key regulator for iGC production. Using SR-BI null mice as an adrenal stress response deficiency model, we demonstrated that adrenal stress response protects anti-CD3 induced death through keeping CRS under control and relative adrenal insufficiency (RAI) – lacking adrenal stress response, is a risk factor.
Project description:Primary mouse embryonic fibroblasts (pass 3 to 4) were treated with tunicamycin (2 micrograms/ml) for specified times - genotypes were WILDTYPE and CHOP-/-. Each time point n=4. C/EBP homologous protein CHOP is activated by ER stress, and CHOP deletion protects against its lethal consequences.
Project description:Major depressive disorder (MDD) is a debilitating illness that affects millions of individuals worldwide. While chronic stress increases incidence levels of MDD, stress-mediated disruptions in brain function that precipitate the disorder remain elusive. Serotonin-associated antidepressants (ADs) remain the first line of therapy for many with MDD, yet low remission rates and delays between treatment and symptomatic alleviation have prompted skepticism regarding precise roles for serotonin in the precipitation of MDD. Our group recently demonstrated that serotonin epigenetically modifies histone proteins (H3K4me3Q5ser) to regulate transcriptional permissiveness in brain. However, this phenomenon has not yet been explored following stress and/or AD exposures. Here, we employed a combination of genome-wide (ChIP-seq, RNA-seq) and western blotting analyses in dorsal raphe nucleus (DRN) of male and female mice exposed to chronic social defeat stress to examine the impact of stress exposures on H3K4me3Q5ser dynamics in DRN, as well as associations between the mark and stress-induced gene expression. Stress-induced regulation of H3K4me3Q5ser levels were also assessed in the context of AD exposures, and viralmediated gene therapy was employed to manipulate H3K4me3Q5ser levels to examine the impact of reducing the mark in DRN on stress-associated gene expression and behavior. We found that H3K4me3Q5ser plays important roles in stress-mediated transcriptional plasticity in DRN. Mice exposed to chronic stress displayed dysregulated dynamics of These findings establish a neurotransmission-independent role for serotonin in stress-associated transcriptional and behavioral plasticity in DRN.
