The histone code hypothesis proposes that cell fate decisions are achieved through creation of stable epigenetic histone marks at gene loci. These marks can be localized to promoters and transcribed regions of genes or can extend many kilobases beyond these boundaries. Although it is well established that certain histone marks are associated with transcriptional activation and other histone marks are associated with transcriptional repression, the precise mechanisms by which histone marks activate or repress transcription is incompletely understood. Further, it is becoming increasingly apparent that both activating and repressive marks are formed at loci of developmentally regulated genes and it is thought that these dual marks ensure developmental plasticity. For example, the Ifng gene exhibits complex activating and repressive patterns of epigenetic modifications that cover a region spanning over 50 kb of upstream and downstream genomic DNA in cells that express or silence Ifng. Given the critical role epigenetic marks play in normal development, it is becoming increasingly apparent that epigenetic defects also contribute to disease processes, including autoimmunity. Our results also demonstrate that failure to properly establish this long-range histone code may contribute to the characteristic over-production of IFN-3 by proliferating T cells from mice that develop autoimmune diabetes. To investigate these questions, we plan a three-pronged approach. First, we will prepare and analyze functional properties of transgenic mice with a wild-type human bacterial artificial chromosome (BAC) containing the IFNG gene and approximately 100 kb of flanking upstream and downstream sequence and BAC transgenic mice with various large (20-40 kb) and small (1kb) deletions within the 200 kb BAC. Second, we will perform detailed structure-function and nuclear positioning analyses to identify genomic sequences critical for these essential processes. Third, we will use several approaches to manipulate the formation stable long-range epigenetic histone marks across the IFNG locus and evaluate alterations in transcription, chromosomal conformation and nuclear positioning of the IFNG locus. Together, these studies will provide direct links between the function of the genetic code and the epigenetic code. They will also identify defects in the epigenetic code that may contribute to autoimmune disease.

Public Health Relevance

The histone code hypothesis proposes that cell fate decisions are achieved through creation of stable epigenetic histone marks at gene loci. In this proposal, we plan to elucidate mechanisms underlying formation of long range histone marks across the Ifng locus in developing effector Th1 and Th2 cells and functional consequences created by these marks. Increasing evidence suggests that imbalance in the histone code may contribute to disease onset or pathogenesis, including autoimmune diseases, and it may be possible to affect the course of disease by altering the epigenetic code through increasing levels of activating histone acetylation marks or decreasing levels of inhibitory histone methylation marks, either generally or at specific genomic loci.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI044924-11
Application #
8197026
Study Section
Cellular and Molecular Immunology - A Study Section (CMIA)
Program Officer
Miller, Lara R
Project Start
2000-07-15
Project End
2014-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
11
Fiscal Year
2012
Total Cost
$386,100
Indirect Cost
$138,600
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Spurlock 3rd, Charles F; Crooke 3rd, Philip S; Aune, Thomas M (2016) Biogenesis and Transcriptional Regulation of Long Noncoding RNAs in the Human Immune System. J Immunol 197:4509-4517
Aune, Thomas M; Spurlock 3rd, Charles F (2016) Long non-coding RNAs in innate and adaptive immunity. Virus Res 212:146-60
Aune, Thomas M; Crooke 3rd, Phillip S; Spurlock 3rd, Charles F (2016) Long noncoding RNAs in T lymphocytes. J Leukoc Biol 99:31-44
Ohnuma, Kei; Hatano, Ryo; Aune, Thomas M et al. (2015) Regulation of pulmonary graft-versus-host disease by IL-26+CD26+CD4 T lymphocytes. J Immunol 194:3697-712
Spurlock 3rd, Charles F; Tossberg, John T; Guo, Yan et al. (2015) Expression and functions of long noncoding RNAs during human T helper cell differentiation. Nat Commun 6:6932
Spurlock 3rd, Charles F; Gass 4th, Henry M; Bryant, Carson J et al. (2015) Methotrexate-mediated inhibition of nuclear factor κB activation by distinct pathways in T cells and fibroblast-like synoviocytes. Rheumatology (Oxford) 54:178-87
Spurlock 3rd, Charles F; Tossberg, John T; Guo, Yan et al. (2015) Defective structural RNA processing in relapsing-remitting multiple sclerosis. Genome Biol 16:58
Spurlock 3rd, Charles F; Tossberg, John T; Olsen, Nancy J et al. (2015) Cutting Edge: Chronic NF-κB Activation in CD4+ T Cells in Rheumatoid Arthritis Is Genetically Determined by HLA Risk Alleles. J Immunol 195:791-5
Collier, Sarah P; Henderson, Melodie A; Tossberg, John T et al. (2014) Regulation of the Th1 genomic locus from Ifng through Tmevpg1 by T-bet. J Immunol 193:3959-65
Zhang, Fanglin; Tossberg, John T; Spurlock, Charles F et al. (2014) Expression of IL-33 and its epigenetic regulation in Multiple Sclerosis. Ann Clin Transl Neurol 1:307-318

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