Epigenetic heterogeneity shapes the transcriptional landscape of regional microglia

Alexander Ve Margetts, Samara Jo Vilca, Florence Bourgain-Guglielmetti, Luis Miguel Tuesta
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Abstract

Microglia, the innate immune cells in the central nervous system, exhibit distinct transcriptional profiles across brain regions that are important for facilitating their specialized function. There has been recent interest in identifying the epigenetic modifications associated with these distinct transcriptional profiles, as these may improve our understanding of the underlying mechanisms governing the functional specialization of microglia. One obstacle to achieving this goal is the large number of microglia required to obtain a genome-wide profile for a single histone modification. Given the cellular and regional heterogeneity of the brain, this would require pooling many samples which would impede biological applications that are limited by numbers of available animals. To overcome this obstacle, we have adapted a method of chromatin profiling known as Cleavage Under Targets and Tagmentation (CUT&Tag-Direct) to profile histone modifications associated with regional differences in gene expression throughout the brain reward system. Consistent with previous studies, we find that transcriptional profiles of microglia vary by brain region. However, here we report that these regional differences also exhibit transcriptional network signatures specific to each region. Additionally, we find that these region-dependent network signatures are associated with differential deposition of H3K27ac and H3K7me3, and while the H3K27me3 landscape is remarkably stable across brain regions, the H3K27ac landscape is most consistent with the anatomical location of microglia which explain their distinct transcriptional profiles. Altogether, these findings underscore the established role of H3K27me3 in cell fate determination and support the active role of H3K27ac in the dynamic regulation of microglial gene expression. In this study, we report a molecular and computational framework that can be applied to improve our understanding of the role of epigenetic regulation in microglia in both health and disease, using as few as 2,500 cells per histone mark.
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表观遗传异质性塑造了区域小胶质细胞的转录景观
小胶质细胞是中枢神经系统中的先天性免疫细胞,在不同脑区表现出不同的转录特征,这对促进其专门化功能非常重要。最近,人们对鉴定与这些不同转录特征相关的表观遗传修饰产生了兴趣,因为这些修饰可能会增进我们对支配小胶质细胞功能特化的潜在机制的了解。实现这一目标的一个障碍是,获得单个组蛋白修饰的全基因组图谱需要大量小胶质细胞。鉴于大脑的细胞和区域异质性,这将需要汇集许多样本,这将阻碍受可用动物数量限制的生物学应用。为了克服这一障碍,我们采用了一种名为 "目标下裂解和标记(CUT&Tag-Direct)"的染色质剖析方法,来剖析与整个大脑奖赏系统中基因表达的区域差异相关的组蛋白修饰。与之前的研究一致,我们发现小胶质细胞的转录特征因大脑区域而异。然而,在这里我们报告说,这些区域差异也表现出了每个区域特有的转录网络特征。此外,我们还发现这些依赖于区域的网络特征与 H3K27ac 和 H3K7me3 的不同沉积有关,虽然 H3K27me3 的分布在不同脑区非常稳定,但 H3K27ac 的分布与小胶质细胞的解剖位置最为一致,这就解释了它们不同的转录特征。总之,这些发现强调了 H3K27me3 在细胞命运决定中的既定作用,并支持 H3K27ac 在小胶质细胞基因表达的动态调控中的积极作用。在这项研究中,我们报告了一个分子和计算框架,该框架可用于提高我们对小胶质细胞在健康和疾病中的表观遗传调控作用的理解,每个组蛋白标记只需使用 2500 个细胞。
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