An increase in ROS is required for repair of the neonatal cerebellum
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ABSTRACT:
PROVIDER: PRJNA1121249 | ENA |
REPOSITORIES: ENA
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Project description:The neonatal mouse cerebellum shows remarkable regenerative potential upon injury at birth. Nestin-expressing progenitors (NEPs) undergo adaptive reprogramming to replenish the lost granule cell progenitors. Here, we investigate how the injury microenvironment affects NEPs’ regenerative potential and adaptive reprogramming. Single cell transcriptomic and bulk chromatin accessibility analyses of the NEPs from control and injured neonatal cerebella show a temporary increase in mechanisms involved in the response to reactive oxygen species (ROS), a known damage-associated molecular pattern. Analysis of ROS levels also confirms a temporary increase in ROS levels upon injury at postanal day 1, 1-2 days after injury, overlapping with the induction in cell death in the cerebellum. Using a transgenic mouse model that overexpresses mitochondrial catalase (mCAT) and reduces ROS levels globally, we showed that the regenerative potential of NEPs decreases upon injury to the granule cell progenitors at birth and the repair is impaired. Finally, we demonstrated that microglia are involved in adaptive reprogramming by regulating NEP migration to the external granule layer, the site of injury. Collectively, our results highlight that the changes in the tissue microenvironment such as an increase in the ROS levels are required for the adaptative reprogramming of NEPs upon injury to the granule cell progenitors at birth, highlighting the instructive roles of microenvironmental signals during regeneration in the neonatal brain.
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Project description:Human tumors often contain slowly proliferating cancer cells that resist treatment but we do not know precisely how these cells arise. We show that rapidly proliferating cancer cells can divide asymmetrically to produce slowly proliferating “G0-like” progeny that are enriched following chemotherapy in breast cancer patients. Asymmetric cancer cell division results from asymmetric suppression of AKT/PKB kinase signaling in one daughter cell during telophase of mitosis. Moreover, inhibition of AKT signaling with small molecule drugs can induce asymmetric cancer cell division and the production of slow proliferators. Cancer cells therefore appear to continuously flux between symmetric and asymmetric division depending on the precise state of their AKT signaling network. This model may have significant implications for understanding how tumors grow, evade treatment, and recur. 3 replicates each of MCF7 Reactive Oxygen Species (ROS) high, HCT116 ROS high, MCF7 ROS low, and HCT116 ROS low.
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Project description:Faithful genome integrity maintenance plays an essential role in cell survival. Here, we identify the RNA demethylase ALKBH5 as a key regulator that protects cells from DNA damage and apoptosis during reactive oxygen species (ROS)-induced stress. We find that ROS significantly induces global mRNA N6-methyladenosine (m6A) levels by modulating ALKBH5 post-translational modifications (PTMs), leading to the rapid and efficient induction of thousands of genes involved in a variety of biological processes including DNA damage repair. Mechanistically, ROS promotes ALKBH5 SUMOylation through activating ERK/JNK signaling, leading to inhibition of ALKBH5 m6A demethylase activity by blocking substrate accessibility. Moreover, ERK/JNK/ALKBH5-PTMs/m6A axis is activated by ROS in hematopoietic stem/progenitor cells (HSPCs) in vivo in mice, suggesting a physiological role of this molecular pathway in the maintenance of genome stability in HSPCs. Together, our study uncovers a molecular mechanism involving ALKBH5 PTMs and increased mRNA m6A levels that protect genomic integrity of cells in response to ROS.
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Project description:Klebsiella quasipneumoniae strain:Neonatal | isolate:Neonatal Genome sequencing
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