Brg1对少突胶质细胞髓鞘形成及损伤修复的表观遗传调控机制

Demyelinating diseases in the central nervous system (CNS) such as periventricular leukomalacia, leukodystrophy in the developmental stage and multiple sclerosis have been proposed to result from the combined effects of damage to oligodendrocytes and failure of remyelination, leading to the progressive loss of CNS myelin. A common feature of demyelinated lesions is the differentiation block of oligodendrocyte precursor cells (OPC) at a pre-myelinating stage. However,the mechanistic basis for inhibition of myelin repair is not fully understood. Brg1,the central catalytic ATPase of the SWI/SNF chromatin-remodeling complex, uses the energy derived from ATP-hydrolysis to disrupt the chromatin architecture of target promoters.It is a critical modulator of gene transcriptional regulation in cellular processes. Previous study have found that, Brg1 plays an important role in the development of central nerves system and neuron growth. So far, there is no study explored the function of the chromatin-remodeling molecule Brg1 in oligodendrocyte myelination and remyelination..The proposed study will 1)define the in vivo function of Brg1 in oligodendrocyte differentiation and myelinogenesis in a cell type-specific manner; 2)explore the effect of Brg1 in cuprizone induced de/remyeliantion mice model; 3)employ genome-wide strategies to identify and characterize Brg1 downstream targets that control oligodendrocyte differentiation. In the fullness of time, the present study could be of practical value to offer new strategies to target chromatin-remodeling molecule Brg1 downstream genes for treating patients with demyelination diseases such as periventricular leukomalacia, leukodystrophy and multiple sclerosis.

发育期常见的脑白质营养不良、脑室周围白质软化以及多发性硬化症均为CNS脱髓鞘疾病。它的发病是由于少突胶质细胞(OL)受损后，少突胶质前体细胞(OPC)无法正常分化成熟，最终导致髓鞘的损伤与修复障碍。对OL髓鞘形成及损伤修复过程调控的分子机制还不十分清楚。研究发现，Brg1作为SWI/SNF染色质重塑复合物的中心组成单位，通过改变染色质的结构参与了对基因的基础转录调控，并在CNS早期发育和神经元生成过程中发挥了重要作用。然而Brg1在OL髓鞘形成及损伤修复过程中的作用尚未见报道。.本研究将采用在OL中条件性敲除Brg1和铜腙诱导的脱髓鞘小鼠模型来探讨Brg1在OL髓鞘形成及髓鞘损伤修复中的作用。同时将采用ChIP-seq和基因微阵列技术在全基因组范围内准确锁定Brg1的下游靶基因，分析小鼠基因表达谱的变化，阐明Brg1在OL分化成熟中的分子机制，为脱髓鞘疾病的药物及靶向治疗提供可靠的依据。

发育期常见的脑白质营养不良、脑室周围白质软化以及多发性硬化症均为CNS脱髓鞘疾病。它的发病是由于少突胶质细胞(OL)受损后，少突胶质前体细胞(OPC)无法正常分化成熟，最终导致髓鞘的损伤与修复障碍。对OL髓鞘形成及损伤修复过程调控的分子机制还不十分清楚。研究发现，Brg1作为SWI/SNF染色质重塑复合物的中心组成单位，通过改变染色质的结构参与了对基因的基础转录调控，并在CNS早期发育和神经元生成过程中发挥了重要作用。本研究采用在OL中条件性敲除Brg1和铜腙诱导的脱髓鞘小鼠模型来探讨Brg1在OL髓鞘形成及髓鞘损伤修复中的作用。同时采用ChIP-seq和基因微阵列技术在全基因组范围内准确锁定Brg1的下游靶基因，分析小鼠基因表达谱的变化。我们发现，Brg1为少突胶质细胞分化成熟的关键因子，且Brg1主要结合与髓鞘形成、少突胶质细胞分化相关基因，如Cnp, Mbp, Klf9和Sirt2等基因调控着少突胶质细胞的早期分化。