Non-coding RNAs are ribonucleic acids that do not encode proteins. Some non-coding RNAs are well understood (introns, UTRs, rRNA, tRNA etc.), others are much more mysterious. Recent work implicated non-coding RNAs in regulation of genes important for development and response to environment. The long term goal of this proposal is to better understand how long non-coding RNAs control genome activity by affecting chromatin structure. We will study the molecular mechanisms of RNA-mediated control of chromatin structure using a plant model organism, Arabidopsis thaliana. Plants are especially well suited for studying this conserved process because like metazoans they have complex development. They also contain specialized RNA Polymerases producing long non-coding RNAs necessary for transcriptional gene silencing. These polymerases can be mutated without affecting viability of the organism. We will use the unique opportunity to specifically manipulate production of long non-coding RNAs by mutating the polymerases to study the mechanisms of long non-coding RNA-mediated changes in chromatin structure. We will determine how long non-coding RNA controls gene activity by active nucleosome positioning. We will test if long non-coding RNA is involved in delimiting heterochromatic domains. We will also establish how long non-coding RNA affects three-dimensional structure of chromatin. Non-coding RNAs are involved in genomic imprinting, X-chromosome inactivation, regulation of homeotic genes and several other essential developmental and physiological processes. Defects in their functions are implicated in human disease. Precise control of chromatin structure is also required for proper development and has been implicated in cancer and several congenital disorders. Explaining the conserved molecular mechanisms of non-coding RNA- mediated control of chromatin structure will contribute to better understanding of disorders involving aberrant non-coding transcription and chromatin. We hope that it will contribute to the development of future treatments.

Public Health Relevance

Non-coding RNA is an important factor regulating activity of genomes. The goal of this research is to understand how long non-coding RNA controls genome activity by affecting chromatin structure. It will facilitate understanding the etiology of medical conditios involving dysfunctional non-coding transcription and/or incorrect establishment of chromatin structures, which will help develop future treatments.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
1R01GM108722-01A1
Application #
8757272
Study Section
Molecular Genetics A Study Section (MGA)
Program Officer
Carter, Anthony D
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109