For many genes, steady state mRNA levels provide an inaccurate reflection of the extent to which they are translated into proteins. The factors influencing the translation of individual mRNAs during cardiac hypertrophy are poorly understood. Our objective is to determine the function of the cytosolic polyA-binding protein C1 (PABPC1) as a novel regulator of cardiac hypertrophy. PABPC1 selectively binds to the 3'- poly(A) tail sequence of most eukaryotic mRNAs and is critical for their overall translation and turnover. We demonstrate that PABPC1 protein levels in mice and humans are post-transcriptionally suppressed during postnatal heart development. Importantly, PABPC1 protein levels increase during cardiac hypertrophy, and we show that PABPC1 depleted mouse cardiac myocytes are resistant to pathologic hypertrophy. To directly test the role of PABPC1 in cardiac hypertrophy, we have developed a tetracycline-inducible and cardiac-specific PABPC1 transgenic mouse model. Further, we demonstrate that the poly(A) tail length of Pabpc1 mRNAs decreases during heart development, which is consistent with its reduced association with polysomes and poor translation. More significantly, we have discovered other stable, distinct, populations of short poly(A) tail containing mRNAs in adult hearts of mice and humans.
The Specific Aims of this proposal are to: (1) Identify mechanism(s) that control cell-type specific expression of PABPC1; (2) Determine the requirement of PABPC1 in hypertrophic growth of cardiac cells; and (3) Determine the role of PABPC1 in modulating the poly(A) tail length and translation control of its target mRNAs in heart. We will use a combination of molecular, biochemical, transgenic and high-throughput sequencing approaches to address these important questions. PUBLIC HEALTH RELVANCE: This proposal will establish a new gene regulatory mechanism based on regulated changes in poly(A) tail length influencing the efficiency with which subset of cardiac mRNAs are translated. This project will also dissect the functional role of a poly(A) binding protein in stimulation of cardiac hypertrophy, a condition that is involved in number of heart diseases. Successful completion of the proposed research will produce detailed understanding of an unexplored mechanism of gene regulation and will open exciting new therapeutic opportunities to treat cardiac hypertrophy and its associated pathologies that affect millions of Americans.

Public Health Relevance

This proposal aims to delineate a new gene regulatory mechanism where regulated changes in poly (A) tail length affect translation of select cardiac transcripts. This project will also dissect the functional role of a poly (A) binding protein in stimulation of cardiac hypertrophy, a condition that often accompanies the response to myocardial infarction and heart failure. Successful completion of this research will produce detailed understanding of an unexplored mechanism of gene regulation and may offer novel therapeutic strategies for this serious, life-threatening condition affecting millions of Americans

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL126845-04
Application #
9431241
Study Section
Cardiovascular Differentiation and Development Study Section (CDD)
Program Officer
Schwartz, Lisa
Project Start
2015-04-01
Project End
2020-02-29
Budget Start
2018-03-01
Budget End
2019-02-28
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Illinois Urbana-Champaign
Department
Engineering (All Types)
Type
Biomed Engr/Col Engr/Engr Sta
DUNS #
041544081
City
Champaign
State
IL
Country
United States
Zip Code
61820
Bangru, Sushant; Arif, Waqar; Seimetz, Joseph et al. (2018) Alternative splicing rewires Hippo signaling pathway in hepatocytes to promote liver regeneration. Nat Struct Mol Biol 25:928-939
Misra, Chaitali; Lin, Feikai; Kalsotra, Auinash (2018) Deregulation of RNA Metabolism in Microsatellite Expansion Diseases. Adv Neurobiol 20:213-238
Seimetz, Joseph; Arif, Waqar; Bangru, Sushant et al. (2018) Cell-type specific polysome profiling from mammalian tissues. Methods :
Liu, Dai-Chi; Seimetz, Joseph; Lee, Kwan Young et al. (2017) Mdm2 mediates FMRP- and Gp1 mGluR-dependent protein translation and neural network activity. Hum Mol Genet 26:3895-3908
Yum, Kevin; Wang, Eric T; Kalsotra, Auinash (2017) Myotonic dystrophy: disease repeat range, penetrance, age of onset, and relationship between repeat size and phenotypes. Curr Opin Genet Dev 44:30-37
Chorghade, Sandip; Seimetz, Joseph; Emmons, Russell et al. (2017) Poly(A) tail length regulates PABPC1 expression to tune translation in the heart. Elife 6:
Arif, Waqar; Datar, Gandhar; Kalsotra, Auinash (2017) Intersections of post-transcriptional gene regulatory mechanisms with intermediary metabolism. Biochim Biophys Acta Gene Regul Mech 1860:349-362
Skariah, Geena; Seimetz, Joseph; Norsworthy, Miles et al. (2017) Mov10 suppresses retroelements and regulates neuronal development and function in the developing brain. BMC Biol 15:54
Aguero, Tristan; Jin, Zhigang; Chorghade, Sandip et al. (2017) Maternal Dead-end 1 promotes translation of nanos1 by binding the eIF3 complex. Development 144:3755-3765
Lewis, Cole J T; Pan, Tao; Kalsotra, Auinash (2017) RNA modifications and structures cooperate to guide RNA-protein interactions. Nat Rev Mol Cell Biol 18:202-210

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