Epigenetic regulation of oligodendrocyte regeneration in subcortical ischemic vascular dementia

项目总结/文摘

PROJECT SUMMARY/ABSTRACT Epigenetic regulation is an important biological process that regulates gene expression. Past studies have demonstrated that epigenetic regulation (e.g. histone modification and DNA methylation) is closely related to cell differentiation in most organs, including neurogenesis in the brain. In addition, dysregulation of epigenetic regulation is related to some chronic neurodegenerative diseases, such as Alzheimer’s disease. However, little is known how the epigenetic system contributes to the pathology of cerebrovascular diseases, including vascular cognitive impairment and dementia (VCID). Subcortical ischemic vascular dementia (SIVD) is the most common subtype of VCID syndrome that occurs with aging. SIVD is clinically defined as cognitive decline with evidence of subcortical brain infarction. Patients with SIVD suffer from white matter degeneration, many of whom exhibit prolonged cerebral hypoperfusion. Although the number of patients with SIVD is predicted to increase with the aging population, to date there is no established treatment for this pathological condition. Since white matter dysfunction is a major feature of this disease, it is important to elucidate the cellular and molecular mechanisms of white matter damage and recovery after cerebral hypoperfusion. Because oligodendrocytes do not proliferate, oligodendrocyte precursor cells (OPCs) play an indispensable role in regulating oligodendrocyte numbers. Regulatory mechanisms regarding OPC proliferation and differentiation have been extensively examined, and histone modification is confirmed to contribute to the generation of oligodendrocytes from OPCs. However, little is known whether and how DNA methylation by DNA methyltransferase enzymes (DNMTs) is involved in oligodendrocyte generation, especially under the conditions of white matter diseases. This is the major gap in knowledge that we seek to fill. This exploratory study aims to reveal the roles of DNMTs in oligodendrogenesis (oligodendrocyte regeneration) in cerebral white matter, by testing three hypotheses: (i) DNMTs regulate OPC proliferation and differentiation, (ii) expression level of DNMTs would change after cerebral hypoperfusion as a compensatory response, and (iii) downregulating DNMTs would decrease oligodendrogenesis after cerebral hypoperfusion in mice. For this purpose, we propose two integrated aims as below. In Aim 1, we will examine the roles of DNMTs in OPC proliferation and differentiation using in vitro cell culture system. In Aim 2, we aim to show that OPC proliferation and differentiation after cerebral hypoperfusion is dampened in OPC-DNMT1 or OPC-DNMT3a deficient mice. This exploratory study will provide novel insights into the mechanisms by which the epigenetic regulator DNMTs contribute to compensatory oligodendrogenesis during cerebral hypoperfusion.