Cerebellar Granule Cells Develop Non-neuronal 3D Genome Architecture over the Lifespan.
Cerebellar Granule Cells Develop Non-neuronal 3D Genome Architecture over the Lifespan.
复制标题
小脑颗粒细胞在整个生命周期中形成非神经元 3D 基因组结构。
DOI：
10.1101/2023.02.25.530020
复制
发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Deisseroth,Karl
中科院分区：
文献类型：
--
作者：
Tan,Longzhi;Shi,Jenny;Moghadami,Siavash;Wright,CydneyP;Parasar,Bibudha;Seo,Yunji;Vallejo,Kristen;Cobos,Inma;Duncan,Laramie;Chen,Ritchie;Deisseroth,Karl
小脑包含了人类大脑中的大部分神经元，并表现出独特的发育、畸形和衰老模式。例如，颗粒细胞-最丰富的神经元类型-发育异常晚，并表现出独特的核形态。在这里，通过将我们的高分辨率单细胞3D基因组检测Dip-C开发成群体规模（Pop-C）和病毒富集（vDip-C）模式，我们能够解析单个小脑细胞的第一个3D基因组结构，为人类和小鼠创建跨越生命的3D基因组图谱，并在发育过程中联合测量转录组和染色质可及性。我们发现，虽然人类颗粒细胞的转录组和染色质可及性在出生后的第一年内表现出特征性的成熟模式，但3D基因组结构在整个生命过程中逐渐重塑为非神经元状态，具有超长范围的染色体内接触和特定的染色体间接触。这种3D基因组重塑在小鼠中是保守的，并且对染色质重塑疾病相关基因（Chd 8或Arid 1b）的杂合缺失具有鲁棒性。这些结果揭示了哺乳动物小脑独特的发育和衰老背后意想不到的和进化上保守的分子过程。
The cerebellum contains most of the neurons in the human brain, and exhibits unique modes of development, malformation, and aging. For example, granule cells—the most abundant neuron type—develop unusually late and exhibit unique nuclear morphology. Here, by developing our high-resolution single-cell 3D genome assay Dip-C into population-scale (Pop-C) and virus-enriched (vDip-C) modes, we were able to resolve the first 3D genome structures of single cerebellar cells, create life-spanning 3D genome atlases for both human and mouse, and jointly measure transcriptome and chromatin accessibility during development. We found that while the transcriptome and chromatin accessibility of human granule cells exhibit a characteristic maturation pattern within the first year of postnatal life, 3D genome architecture gradually remodels throughout life into a non-neuronal state with ultra-long-range intra-chromosomal contacts and specific inter-chromosomal contacts. This 3D genome remodeling is conserved in mice, and robust to heterozygous deletion of chromatin remodeling disease-associated genes (Chd8 or Arid1b). Together these results reveal unexpected and evolutionarily-conserved molecular processes underlying the unique development and aging of the mammalian cerebellum.