PTBP1 and PTBP2 Repress Nonconserved Cryptic Exons

Jonathan P Ling; Resham Chhabra; Jonathan D Merran; Paul M Schaughency; Sarah J Wheelan; Jeffry L Corden; Philip C Wong

doi:10.1016/j.celrep.2016.08.071

PTBP1 and PTBP2 Repress Nonconserved Cryptic Exons

Cell Rep. 2016 Sep 27;17(1):104-113. doi: 10.1016/j.celrep.2016.08.071.

Authors

Jonathan P Ling¹, Resham Chhabra¹, Jonathan D Merran², Paul M Schaughency³, Sarah J Wheelan⁴, Jeffry L Corden², Philip C Wong⁵

Affiliations

¹ Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205-2196, USA.
² Department of Molecular Biology and Genetics, The Johns Hopkins University School of Medicine, Baltimore, MD 21205-2196, USA.
³ Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205-2196, USA.
⁴ Department of Molecular Biology and Genetics, The Johns Hopkins University School of Medicine, Baltimore, MD 21205-2196, USA; Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205-2196, USA; Department of Biostatistics, The Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21205-2196, USA.
⁵ Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205-2196, USA; Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205-2196, USA. Electronic address: [email protected].

Abstract

The fidelity of RNA splicing is maintained by a network of factors, but the molecular mechanisms that govern this process have yet to be fully elucidated. We previously found that TDP-43, an RNA-binding protein implicated in neurodegenerative disease, utilizes UG microsatellites to repress nonconserved cryptic exons and prevent their incorporation into mRNA. Here, we report that two well-characterized splicing factors, polypyrimidine tract-binding protein 1 (PTBP1) and polypyrimidine tract-binding protein 2 (PTBP2), are also nonconserved cryptic exon repressors. In contrast to TDP-43, PTBP1 and PTBP2 utilize CU microsatellites to repress both conserved tissue-specific exons and nonconserved cryptic exons. Analysis of these conserved splicing events suggests that PTBP1 and PTBP2 repression is titrated to generate the transcriptome diversity required for neuronal differentiation. We establish that PTBP1 and PTBP2 are members of a family of cryptic exon repressors.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Base Sequence
Brain / cytology
Brain / metabolism
Cell Differentiation
Exons
HeLa Cells
Heterogeneous-Nuclear Ribonucleoproteins / antagonists & inhibitors
Heterogeneous-Nuclear Ribonucleoproteins / genetics*
Heterogeneous-Nuclear Ribonucleoproteins / metabolism
Humans
Mice
Microsatellite Repeats
Nerve Tissue Proteins / antagonists & inhibitors
Nerve Tissue Proteins / genetics*
Nerve Tissue Proteins / metabolism
Neurons / cytology
Neurons / metabolism*
Polypyrimidine Tract-Binding Protein / antagonists & inhibitors
Polypyrimidine Tract-Binding Protein / genetics*
Polypyrimidine Tract-Binding Protein / metabolism
RNA Splicing*
RNA, Messenger / genetics*
RNA, Messenger / metabolism
RNA, Small Interfering / genetics
RNA, Small Interfering / metabolism
Transcriptome*

Substances

Heterogeneous-Nuclear Ribonucleoproteins
Nerve Tissue Proteins
PTBP1 protein, human
PTBP2 protein, human
RNA, Messenger
RNA, Small Interfering
Polypyrimidine Tract-Binding Protein

Abstract

Publication types

MeSH terms

Substances

Grants and funding