基因亚型
选择性拼接
生物
电池类型
外显子
细胞
RNA剪接
人脑
表型
基因
神经科学
细胞生物学
核糖核酸
遗传学
作者
Anoushka Joglekar,Wen Yang Hu,Bei Zhang,Oleksandr Narykov,Mark Diekhans,Jennifer Balacco,Lishomwa C. Ndhlovu,Teresa A. Milner,Olivier Fédrigo,Erich D. Jarvis,Gloria Sheynkman,Dmitry Korkin,M. Elizabeth Ross,Hagen U. Tilgner
标识
DOI:10.1101/2023.04.02.535281
摘要
Abstract RNA isoforms influence cell identity and function. Until recently, technological limitations prevented a genome-wide appraisal of isoform influence on cell identity in various parts of the brain. Using enhanced long-read single-cell isoform sequencing, we comprehensively analyze RNA isoforms in multiple mouse brain regions, cell subtypes, and developmental timepoints from postnatal day 14 (P14) to adult (P56). For 75% of genes, full-length isoform expression varies along one or more axes of phenotypic origin, underscoring the pervasiveness of isoform regulation across multiple scales. As expected, splicing varies strongly between cell types. However, certain gene classes including neurotransmitter release and reuptake as well as synapse turnover, harbor significant variability in the same cell type across anatomical regions, suggesting differences in network activity may influence cell-type identity. Glial brain-region specificity in isoform expression includes strong poly(A)-site regulation, whereas neurons have stronger TSS regulation. Furthermore, developmental patterns of cell-type specific splicing are especially pronounced in the murine adolescent transition from P21 to P28. The same cell type traced across development shows more isoform variability than across adult anatomical regions, indicating a coordinated modulation of functional programs dictating neural development. As most cell-type specific exons in P56 mouse hippocampus behave similarly in newly generated data from human hippocampi, these principles may be extrapolated to human brain. However, human brains have evolved additional cell-type specificity in splicing, suggesting gain-of-function isoforms. Taken together, we present a detailed single-cell atlas of full-length brain isoform regulation across development and anatomical regions, providing a previously unappreciated degree of isoform variability across multiple scales of the brain.
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