Histone modification landscape and the key significance of H3K27me3 in myocardial ischaemia/reperfusion injury

Histone modifications play crucial roles in the pathogenesis of myocardial ischaemia/reperfusion(I/R)injury.However,a genome-wide map of histone modifications and the underlying epigenetic signatures in myocardial I/R injury have not been established.Here,we integrated transcriptome and epigenome of histone modifications to characterize epigenetic signatures after I/R injury.Disease-specific histone mark alterations were mainly found in H3K27me3-,H3K27ac-,and H3K4me1-marked regions 24 and 48 h after I/R.Genes differentially modified by H3K27ac,H3K4me1 and H3K27me3 were involved in immune response,heart conduction or contraction,cytoskeleton,and angiogenesis.H3K27me3 and its methyltransferase polycomb repressor complex 2(PRC2)were upregulated in myocardial tissues after I/R.Upon selective inhibition of EZH2(the catalytic core of PRC2),the mice manifest improved cardiac function,enhanced angiogenesis,and reduced fibrosis.Further investigations confirmed that EZH2 inhibition regulated H3K27me3 modification of multiple pro-angiogenic genes and ultimately enhanced angiogenic properties in vivo and in vitro.This study delineates a landscape of histone modifications in myocardial I/R injury,and identifies H3K27me3 as a key epigenetic modifier in I/R process.The inhibition of H3K27me3 and its methyltransferase might be a potential strategy for myocardial I/R injury intervention.

Extracellular vesicles,from the pathogenesis to the therapy of neurodegenerative diseases

Extracellular vesicles(EVs)are small bilipid layer-enclosed vesicles that can be secreted by all tested types of brain cells.Being a key intercellular communicator,EVs have emerged as a key contributor to the pathogenesis of various neurodegenerative diseases(NDs)including Alzheimer’s disease,Parkinson’s disease,amyotrophic lateral sclerosis,and Huntington’s disease through delivery of bioactive cargos within the central nervous system(CNS).Importantly,CNS cell-derived EVs can be purified via immunoprecipitation,and EV cargos with altered levels have been identified as potential biomarkers for the diagnosis and prognosis of NDs.Given the essential impact of EVs on the pathogenesis of NDs,pathological EVs have been considered as therapeutic targets and EVs with therapeutic effects have been utilized as potential therapeutic agents or drug delivery platforms for the treatment of NDs.In this review,we focus on recent research progress on the pathological roles of EVs released from CNS cells in the pathogenesis of NDs,summarize findings that identify CNS-derived EV cargos as potential biomarkers to diagnose NDs,and comprehensively discuss promising potential of EVs as therapeutic targets,agents,and drug delivery systems in treating NDs,together with current concerns and challenges for basic research and clinical applications of EVs regarding NDs.

Neural stem cell-derived extracellular vesicles mitigate Alzheimer’s disease-like phenotypes in a preclinical mouse model

Dear Editor,Alzheimer’s disease(AD)is the most common neurodegenerative disorder and the No.1 cause of dementia in elderly with no effective treatments.1 The application of stem cell-derived extracellular vesicles(EVs)has emerged as a promising therapeutic strategy for AD.2 EVs are small bilipid layer-enclosed vesicles that display blood-brain barrier(BBB)penetrating ability and similar potency to their parental cells.