德国慕尼黑大学Magdalena Götz和Boyan Bonev课题组的研究显示小鼠星形胶质细胞的直接神经元重编程与多尺度表观基因组重塑有关并且需要Yy1。这一研究成果于2024年7月2日发表在国际学术期刊《自然-神经科学》上。

研究人员将单细胞多组学与由神经原蛋白2（Ngn2）介导的三维核结构全基因组测序，和小鼠星形胶质细胞到神经元重编程过程中由其磷酸化抗性形式（PmutNgn2）介导的DNA甲基化结合起来。研究发现，Ngn2在动态增强子-基因相互作用位点上诱导多层染色质重塑。PmutNgn2诱导更高的重编程效率，并增强与神经元成熟相关的表观遗传重塑。

然而，结合位点或下游基因激活的差异并不能完全解释这种效应。相反，研究人员发现了一种转录辅助因子Yy1，它通过与Ngn2的直接相互作用被招募到其靶基因。敲除Yy1后，神经元增强子、基因激活以及最终的重编程都会受到影响，但不影响Ngn2的结合。总的来说，该工作凸显了神经前体因子相互作用在神经元直接重编程中的关键作用。

据介绍，对神经元进行直接重编程是一种从局部胶质细胞再生神经元的可行方法。然而，表观基因组重塑的机制和促进这一过程的辅助因子尚不清楚。

附：英文原文

Title: Direct neuronal reprogramming of mouse astrocytes is associated with multiscale epigenome remodeling and requires Yy1

Author: Pereira, Allwyn, Diwakar, Jeisimhan, Masserdotti, Giacomo, Bekarde, Sude, Simon, Tatiana, So, Younju, Martn-Loarte, Luca, Bergemann, Franziska, Vasan, Lakshmy, Schauer, Tamas, Danese, Anna, Bocchi, Riccardo, Colom-Tatch, Maria, Schuurmans, Carol, Philpott, Anna, Straub, Tobias, Bonev, Boyan, Gtz, Magdalena

Issue&Volume: 2024-07-02

Abstract: Direct neuronal reprogramming is a promising approach to regenerate neurons from local glial cells. However, mechanisms of epigenome remodeling and co-factors facilitating this process are unclear. In this study, we combined single-cell multiomics with genome-wide profiling of three-dimensional nuclear architecture and DNA methylation in mouse astrocyte-to-neuron reprogramming mediated by Neurogenin2 (Ngn2) and its phosphorylation-resistant form (PmutNgn2), respectively. We show that Ngn2 drives multilayered chromatin remodeling at dynamic enhancer–gene interaction sites. PmutNgn2 leads to higher reprogramming efficiency and enhances epigenetic remodeling associated with neuronal maturation. However, the differences in binding sites or downstream gene activation cannot fully explain this effect. Instead, we identified Yy1, a transcriptional co-factor recruited by direct interaction with Ngn2 to its target sites. Upon deletion of Yy1, activation of neuronal enhancers, genes and ultimately reprogramming are impaired without affecting Ngn2 binding. Thus, our work highlights the key role of interactors of proneural factors in direct neuronal reprogramming.

DOI: 10.1038/s41593-024-01677-5

Source: https://www.nature.com/articles/s41593-024-01677-5