美国威尔康奈尔医学院Hagen U. Tilgner研究小组发现，基于单细胞长序列测序的图谱揭示发育中和成年小鼠及人类大脑中的特殊剪接模式。2024年4月9日，《自然—神经科学》杂志在线发表了这项成果。

研究人员分析了跨脑区、细胞亚型、发育时间点和物种的单细胞RNA亚型。72%的基因的全长亚型表达沿着一条或多条轴线变化。不同细胞类型的剪接、转录起始和多聚腺苷酸化位点差异很大，影响蛋白质结构，并与疾病相关。此外，神经递质转运和突触转换基因在不同解剖区域也存在细胞类型差异。细胞类型特异性剪接的调控在出生后第21天到出生后第28天的青春期过渡阶段非常明显。

对于同一细胞类型，发育亚型的调控强于区域调控。小鼠的细胞类型特异性亚型调控在人类海马中基本保持不变，因此可以推断人类大脑也存在这种调控。相反，人脑中存在额外的细胞类型特异性，表明存在功能增益亚型。总之，这种跨发育、解剖区域和物种的全长亚型调控的详细单细胞图谱揭示了跨多个轴的亚型变异性，而这种变异性的程度尚未被人们所认识。

研究人员表示，RNA亚型影响细胞的特性和功能。然而，目前还缺乏全面的大脑亚型图谱。

附：英文原文

Title: Single-cell long-read sequencing-based mapping reveals specialized splicing patterns in developing and adult mouse and human brain

Author: Joglekar, Anoushka, Hu, Wen, Zhang, Bei, Narykov, Oleksandr, Diekhans, Mark, Marrocco, Jordan, Balacco, Jennifer, Ndhlovu, Lishomwa C., Milner, Teresa A., Fedrigo, Olivier, Jarvis, Erich D., Sheynkman, Gloria, Korkin, Dmitry, Ross, M. Elizabeth, Tilgner, Hagen U.

Issue&Volume: 2024-04-09

Abstract: RNA isoforms influence cell identity and function. However, a comprehensive brain isoform map was lacking. We analyze single-cell RNA isoforms across brain regions, cell subtypes, developmental time points and species. For 72% of genes, full-length isoform expression varies along one or more axes. Splicing, transcription start and polyadenylation sites vary strongly between cell types, influence protein architecture and associate with disease-linked variation. Additionally, neurotransmitter transport and synapse turnover genes harbor cell-type variability across anatomical regions. Regulation of cell-type-specific splicing is pronounced in the postnatal day 21-to-postnatal day 28 adolescent transition. Developmental isoform regulation is stronger than regional regulation for the same cell type. Cell-type-specific isoform regulation in mice is mostly maintained in the human hippocampus, allowing extrapolation to the human brain. Conversely, the human brain harbors additional cell-type specificity, suggesting gain-of-function isoforms. Together, this detailed single-cell atlas of full-length isoform regulation across development, anatomical regions and species reveals an unappreciated degree of isoform variability across multiple axes.

DOI: 10.1038/s41593-024-01616-4

Source: https://www.nature.com/articles/s41593-024-01616-4