Chen, A. S. | Search bioRxiv

bioRxiv2024

Early-life stress alters chromatin modifications in VTA to prime stress sensitivity

Early-life stress increases sensitivity to subsequent stress, which has been observed at behavioral, neural activity, and gene expression levels. However, the molecular mechanisms underlying such long-lasting sensitivity are poorly understood. We tested the hypothesis that persistent changes in transcription and transcriptional potential were maintained at the level of the epigenome, through changes in chromatin. We used a combination of bottom-up mass spectrometry, viral-mediated epigenome-editing, RNA-sequencing, patch clamp electrophysiology of dopamine neurons, and behavioral quantification in a mouse model of early-life stress, focusing on the ventral tegmental area (VTA), a dopaminergic brain region critically implicated in motivation, reward learning, stress response, and mood and drug disorders. We found that early-life stress alters histone dynamics in VTA, including enrichment of histone-3 lysine-4 monomethylation -- associated with open chromatin and primed or active enhancers -- and the H3K4 monomethylase Setd7. Mimicking early-life stress through postnatal overexpression of Setd7 and enrichment of H3K4me1 in VTA sensitizes transcriptional, physiological, and behavioral response to adult stress. These findings link early-life stress experience to long-term stress hypersensitivity within the brains dopaminergic circuitry, providing a mechanism by which early-life stress increases risk for mood and anxiety disorders later in life.

neuroscience↗

bioRxiv2020

RIOK2 drives glioblastoma cell growth and proliferation by modulating MYC through the RNA-binding protein IMP3

Glioblastoma (GBM) is the most common primary malignant brain tumor and is resistant to current therapies. Here, using a combination of proteomic and genetic approaches in both Drosophila and human GBM models, we identify novel signaling effectors that act downstream of EGFR and PI3K signaling pathways, which drive GBM. Our results indicate that RIOK2, an atypical serine/threonine kinase, forms a complex with the RNA-binding protein, IMP3 (Imp in Drosophila), and that the dRIOK2/RIOK-Imp/IMP3 pathway is necessary for tumorigenesis. Furthermore, our results indicate that RIOK2 catalytic activity is important for neoplasia and recruits TORC2 to phosphorylate IMP3. Finally, the dRIOK2-Imp pathway regulates protein levels of dMyc, a known Imp target mRNA, and these key findings were recapitulated in human GBM models. Collectively, our data indicates that RIOK2 catalytic activity promotes the activation of TORC2 and recruitment of IMP3, which in turn, modulates MYC mRNA and protein levels to promote tumorigenesis.

cancer biology↗