STUDY OF EPIGENETIC REGULATORS AND SIGNATURES OF AGING

Ph.DDOCTOR OF PHILOSOPHY (FOS

NELF-A controls Drosophila healthspan by regulating heat-shock protein-mediated cellular protection and heterochromatin maintenance

10.1111/acel.13348Aging Cell205e1334

ApoE maintains neuronal integrity via microRNA and H3K27me3-mediated repression

Summary: ApoE regulates neurogenesis, although how it influences genetic programs remains elusive. Cortical neurons induced from isogenic control and ApoE−/− human neural stem cells (NSCs) recapitulated key transcriptomic signatures of in vivo counterparts identified from single-cell human midbrain. Surprisingly, ApoE expression in NSC and neural progenitor cells (NPCs) is not required for differentiation. Instead, ApoE prevents the over-proliferation of non-neuronal cells during extended neuronal culture when it is not expressed. Elevated miR-199a-5p level in ApoE−/− cells lowers the EZH1 protein and the repressive H3K27me3 mark, a phenotype rescued by miR-199a-5p steric inhibitor. Reduced H3K27me3 at genes linked to extracellular matrix organization and angiogenesis in ApoE−/− NPC correlates with their aberrant expression and phenotypes in neurons. Interestingly, the ApoE coding sequence, which contains many predicted miR-199a-5p binding sites, can repress miR-199a-5p without translating into protein. This suggests that ApoE maintains neurons integrity through the target-directed miRNA degradation of miR-199a-5p, imparting the H3K27me3-mediated repression of non-neuronal genes during differentiation

E2F and STAT3 provide transcriptional synergy for histone variant H2AZ activation to sustain glioblastoma chromatin accessibility and tumorigenicity

10.1038/s41418-021-00926-5CELL DEATH AND DIFFERENTIATION2971379-139

A neurodegeneration checkpoint mediated by REST protects against the onset of Alzheimer’s disease

Abstract Many aging individuals accumulate the pathology of Alzheimer’s disease (AD) without evidence of cognitive decline. Here we describe an integrated neurodegeneration checkpoint response to early pathological changes that restricts further disease progression and preserves cognitive function. Checkpoint activation is mediated by the REST transcriptional repressor, which is induced in cognitively-intact aging humans and AD mouse models at the onset of amyloid β-protein (Aβ) deposition and tau accumulation. REST induction is mediated by the unfolded protein response together with β-catenin signaling. A consequence of this response is the targeting of REST to genes involved in key pathogenic pathways, resulting in downregulation of gamma secretase, tau kinases, and pro-apoptotic proteins. Deletion of REST in the 3xTg and J20 AD mouse models accelerates Aβ deposition and the accumulation of misfolded and phosphorylated tau, leading to neurodegeneration and cognitive decline. Conversely, viral-mediated overexpression of REST in the hippocampus suppresses Aβ and tau pathology. Thus, REST mediates a neurodegeneration checkpoint response with multiple molecular targets that may protect against the onset of AD