Differential 3' processing of specific transcripts expands regulatory and protein diversity across neuronal cell types

Abstract
Data availability
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Abstract

Alternative polyadenylation (APA) regulates mRNA translation, stability, and protein localization. However, it is unclear to what extent APA regulates these processes uniquely in specific cell types. Using a new technique, cTag-PAPERCLIP, we discovered significant differences in APA between the principal types of mouse cerebellar neurons, the Purkinje and granule cells, as well as between proliferating and differentiated granule cells. Transcripts that differed in APA in these comparisons were enriched in key neuronal functions and many differed in coding sequence in addition to 3'UTR length. We characterize Memo1, a transcript that shifted from expressing a short 3'UTR isoform to a longer one during granule cell differentiation. We show that Memo1 regulates granule cell precursor proliferation and that its long 3'TR isoform is targeted by miR-124, contributing to its downregulation during development. Our findings provide insight into roles for APA in specific cell types and establish a platform for further functional studies.

Data availability

The following data sets were generated

1. Saša Jereb
(2017) Differential 3' Processing of Specific Transcripts Expands Regulatory and Protein Diversity Across Neuronal Cell Types
Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE108480).

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE108480

The following previously published data sets were used

(2013) MeCP2 binds to 5hmC enriched within active genes and accessible chromatin in the nervous system
Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE42880).

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE42880
1. Hatten ME
(2015) Role of Tet1/3 Genes and Chromatin Remodeling Genes in Cerebellar Circuit Formation
Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE74402).

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE74402

Article and author information

Author details

Saša Jereb

Laboratory of Molecular Neuro-Oncology, The Rockefeller University, New York, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-6862-4475
Hun-Way Hwang

Laboratory of Molecular Neuro-Oncology, The Rockefeller University, New York, United States

Competing interests
The authors declare that no competing interests exist.
Eric Van Otterloo

Department of Craniofacial Biology, University of Colorado, Aurora, United States

Competing interests
The authors declare that no competing interests exist.
Eve-Ellen Govek

Laboratory of Developmental Neurobiology, The Rockefeller University, New York, United States

Competing interests
The authors declare that no competing interests exist.
John J Fak

Laboratory of Molecular Neuro-Oncology, The Rockefeller University, New York, United States

Competing interests
The authors declare that no competing interests exist.
Yuan Yuan

Laboratory of Molecular Neuro-Oncology, The Rockefeller University, New York, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-2718-8301
Mary E Hatten

Laboratory of Developmental Neurobiology, The Rockefeller University, New York, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-9059-660X
Robert B Darnell

Laboratory of Molecular Neuro-Oncology, The Rockefeller University, New York, United States

For correspondence
darnelr@rockefeller.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-5134-8088

Funding

National Institutes of Health (NS034389)

Robert B Darnell

Howard Hughes Medical Institute

Robert B Darnell

Simons Foundation (SFARI 240432)

Robert B Darnell

National Institute of Dental and Craniofacial Research (K99DE026823)

Eric Van Otterloo

National Institutes of Health (NS081706)

Robert B Darnell

National Institutes of Health (NS097404)

Robert B Darnell

National Institutes of Health (1UM1HG008901)

Robert B Darnell

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: Animals were maintained in an AAALAC-approved animal facility and all procedures were performed in accordance with IACUC guidelines (protocol number 17013).

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.