Dysregulation of Distinct RNA Processing Steps in Myotonic Dystrophy

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Material Information

Title:
Dysregulation of Distinct RNA Processing Steps in Myotonic Dystrophy
Physical Description:
1 online resource (10 p.)
Language:
english
Creator:
Manchanda, Mini
Publisher:
University of Florida
Place of Publication:
Gainesville, Fla.
Publication Date:

Thesis/Dissertation Information

Degree:
Doctorate ( Ph.D.)
Degree Grantor:
University of Florida
Degree Disciplines:
Medical Sciences, Genetics (IDP)
Committee Chair:
SWANSON,MAURICE S
Committee Co-Chair:
BLOOM,DAVID C
Committee Members:
CONDIT,RICHARD C
RENNE,ROLF FRIEDRICH
FLANEGAN,JAMES B

Subjects

Subjects / Keywords:
mbnl -- polyadenylation -- rna -- splicing
Genetics (IDP) -- Dissertations, Academic -- UF
Genre:
Medical Sciences thesis, Ph.D.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract:
Many RNA-binding proteins (RBPs) regulate multiple steps in mRNA metabolism from transcription and maturation in the nucleus to localization, translation and decay in the cytoplasm. Tissue specific RNA binding proteins are key players that extensively regulate pre-mRNA processing, mRNA localization, translation and turnover to achieve the precise spatial and temporal expression of specific transcripts that is essential for maintaining cellular homeostasis. Often RBP family members regulate different aspects of mRNA metabolism, however the mechanism of coordinate regulation of specific steps by individual RBPs is unclear. Muscleblind-like proteins are alternative splicing factors expressed in a tissue and developmental stage specific manner and loss of their functions manifests into the multi-systemic disease, myotonic dystrophy (dystrophia myotonica, DM). In this study, we used advanced biochemical procedures and transcriptome wide high-throughput sequencing approaches to determine that, in addition to their roles in alternative RNA splicing, Mbnl proteins function as alternative polyadenylation factors through direct binding to cis-regulatory elements in the three prime untranslated regions (UTRs) of their RNA targets. Furthermore, we show that Mbnl1 and Mbn2 are functionally redundant irrespective of their spatial expression differences in vivo. These proteins bind to the similar (Y/R)GCY motifs in their mRNA targets and have similar binding distributions throughout the genome. Although alternative splicing (AS) of target mRNAs are maintained following the loss of single Mbnl paralogs, combined loss of Mbnl1 and Mbnl2 lead to widespread AS changes. These results suggest functional compensation among Mbnl paralogs. Moreover, integration of the splicing and polyadenylation data showed that the role of Mbnl proteins in alternative polyadenylation is largely independent of their splicing roles. While Mbnl proteins regulate AS and APA of distinct RNA targets, these binding targets are functionally linked and involved in common cellular pathways controlling cell proliferation and cytoskeletal organization in mouse embryonic fibroblast (MEFs). We conclude that the Mbnl proteins are multi-functional and coordinately regulate the co/post transcriptional processing of diverse, yet functionally linked RNAs. This study also provides experimental evidence that DM is an RNA processing, and not simply an AS, disorder. A systems biology approach is warranted to understand the multiple pathways that are impacted in DM, which should have a significant impact on the development of effective treatments for this hereditary disease.
General Note:
In the series University of Florida Digital Collections.
General Note:
Includes vita.
Bibliography:
Includes bibliographical references.
Source of Description:
Description based on online resource; title from PDF title page.
Source of Description:
This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Statement of Responsibility:
by Mini Manchanda.
Thesis:
Thesis (Ph.D.)--University of Florida, 2014.
Local:
Adviser: SWANSON,MAURICE S.
Local:
Co-adviser: BLOOM,DAVID C.
Electronic Access:
RESTRICTED TO UF STUDENTS, STAFF, FACULTY, AND ON-CAMPUS USE UNTIL 2015-05-31

Record Information

Source Institution:
UFRGP
Rights Management:
Applicable rights reserved.
Classification:
lcc - LD1780 2014
System ID:
UFE0046638:00001