Single‐cell polyadenylation site mapping reveals 3′ isoform choice variability

Molecular Systems Biology

Lars Velten¹  Simon Anders¹  Aleksandra Pekowska¹  Aino I Järvelin¹  Wolfgang Huber¹  Vicent Pelechano¹ 

[1] European Molecular Biology Laboratory, Genome Biology Unit, Heidelberg, Germany

关键词: single‐cell transcriptomics;    alternative polyadenylation;    transcript isoform;    non‐genetic heterogeneity;    Bayesian inference;   

DOI  :  10.15252/msb.20156198

来源: Wiley

【 摘 要 】

Abstract

Cell-to-cell variability in gene expression is important for many processes in biology, including embryonic development and stem cell homeostasis. While heterogeneity of gene expression levels has been extensively studied, less attention has been paid to mRNA polyadenylation isoform choice. 3′ untranslated regions regulate mRNA fate, and their choice is tightly controlled during development, but how 3′ isoform usage varies within genetically and developmentally homogeneous cell populations has not been explored. Here, we perform genome-wide quantification of polyadenylation site usage in single mouse embryonic and neural stem cells using a novel single-cell transcriptomic method, BATSeq. By applying BATBayes, a statistical framework for analyzing single-cell isoform data, we find that while the developmental state of the cell globally determines isoform usage, single cells from the same state differ in the choice of isoforms. Notably this variation exceeds random selection with equal preference in all cells, a finding that was confirmed by RNA FISH data. Variability in 3′ isoform choice has potential implications on functional cell-to-cell heterogeneity as well as utility in resolving cell populations.

Synopsis

BATSeq, the first transcriptomic method to quantify polyadenylation site use in single cells, reveals that stem cells from homogeneous populations differ in their preference for 3′ mRNA isoforms.

• We introduce BATBayes, a Bayesian framework that accounts for technical and biological sources of noise to quantify underlying variability in isoform preference
• 3′ isoform usage is sufficient to distinguish between cells from different stem cell populations
• Within homogeneous cell populations, cells differ in their use of isoforms more than expected from random choice
• An intrinsic mechanism acting at the level of individual genes is likely to contribute to isoform choice variability

【 授权许可】

CC BY   
© 2015 The Authors. Published under the terms of the CC BY 4.0 license

Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.