Previous studies have characterized chromatin conformation and DNA methylation dynamics in early postnatal and adult brain tissues. To gain single-cell resolution, Heffel et al. used single-nucleus methyl-3C sequencing to profile chromatin conformation and DNA methylation during human prenatal development of the prefrontal cortex and hippocampus and compared these with postnatal and adult tissues. Cell-type classification based on DNA methylation and chromatin conformation was largely concordant, except for a neural progenitor radial glia population that was better defined by chromatin conformation. The cross-modality comparison focused on the radial-glia-to-astrocyte differentiation trajectory, and by extending the pseudotime analysis to other cell types the authors identified a temporal separation of DNA methylation and chromatin interaction dynamics with cell-type-specific patterns. Single-cell imaging-based approaches showed that neurons are enriched in short-range chromatin interactions, whereas glial cells and non-brain tissues are enriched in long-range chromatin interactions. Finally, a greater enrichment of heritability signals for neuropsychiatric disorders was found in loop-connected differentially methylated regions (DMRs) versus all DMRs, and a peak of heritability enrichment was observed during the third trimester and infancy. It will be exciting to profile chromatin conformation and DNA methylation in single cells in other organs during development or disease.

Original reference: Nature https://doi.org/10.1038/s41586-024-08030-7 (2024)

以前的研究已经表征了出生后早期和成人脑组织中的染色质构象和 DNA 甲基化动力学。为了获得单细胞分辨率，Heffel 等人使用单核甲基-3C 测序来分析人类前额叶皮层和海马体产前发育过程中的染色质构象和 DNA 甲基化，并将其与出生后和成人组织进行比较。基于 DNA 甲基化和染色质构象的细胞类型分类在很大程度上是一致的，除了神经祖细胞放射状神经胶质细胞群由染色质构象更好地定义。跨模式比较侧重于桡神经胶质细胞到星形胶质细胞的分化轨迹，通过将伪时间分析扩展到其他细胞类型，作者确定了 DNA 甲基化和染色质相互作用动力学与细胞类型特异性模式的时间分离。基于单细胞成像的方法表明，神经元在短程染色质相互作用中富集，而神经胶质细胞和非脑组织在长程染色质相互作用中富集。最后，与所有 DMR 相比，在环连接的差异甲基化区域 （DMR） 中发现神经精神疾病的遗传性信号更加富集，并且在妊娠晚期和婴儿期观察到遗传力富集的峰值。在发育或疾病过程中分析其他器官中单个细胞的染色质构象和 DNA 甲基化将是令人兴奋的。

原文参考：Nature https://doi.org/10.1038/s41586-024-08030-7 （2024）