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cAMP responsive element modulator (CREM) α mediates chromatin remodeling of CD8 during the generation of CD3+ CD4- CD8- T cells.

TitlecAMP responsive element modulator (CREM) α mediates chromatin remodeling of CD8 during the generation of CD3+ CD4- CD8- T cells.
Publication TypeJournal Article
Year of Publication2014
AuthorsHedrich, C. M., Crispín J. C., Rauen T., Ioannidis C., Koga T., Rodriguez N. Rodriguez, Apostolidis S. A., Kyttaris V. C., & Tsokos G. C.
JournalJ Biol Chem
Volume289
Issue4
Pagination2361-70
Date Published2014 Jan 24
ISSN1083-351X
KeywordsAnimals, Antigens, CD3, Antigens, CD8, Chromatin Assembly and Disassembly, Cyclic AMP Response Element Modulator, DNA (Cytosine-5-)-Methyltransferase, Female, Gene Silencing, Histocompatibility Antigens, Histone-Lysine N-Methyltransferase, Humans, Lupus Erythematosus, Systemic, Male, Mice, Mice, Inbred MRL lpr, T-Lymphocytes
Abstract

TCR-αβ(+)CD3(+)CD4(-)CD8(-) "double negative" T cells are expanded in the peripheral blood of patients with systemic lupus erythematosus (SLE) and lupus-prone mice. Double negative T cells have been claimed to derive from CD8(+) cells that down-regulate CD8 co-receptors and acquire a distinct effector phenotype that includes the expression of proinflammatory cytokines. This, along with the fact that double negative T cells have been documented in inflamed organs, suggests that they may contribute to disease expression and tissue damage. We recently linked the transcription factor cAMP responsive element modulator (CREM) α, which is expressed at increased levels in T cells from SLE patients and lupus prone MRL/lpr mice, with trans-repression of a region syntenic to the murine CD8b promoter. However, the exact molecular mechanisms that result in a stable silencing of both CD8A and CD8B genes remain elusive. Here, we demonstrate that CREMα orchestrates epigenetic remodeling of the CD8 cluster through the recruitment of DNA methyltransferase (DNMT) 3a and histone methyltransferase G9a. Thus, we propose that CREMα is essential for the expansion of double negative T cells in SLE. CREMα blockade may have therapeutic value in autoimmune disorders with DN T cell expansion.

DOI10.1074/jbc.M113.523605
Alternate JournalJ. Biol. Chem.
PubMed ID24297179
PubMed Central IDPMC3900979
Grant ListP30 DK043351 / DK / NIDDK NIH HHS / United States
R01 AI085567 / AI / NIAID NIH HHS / United States
R01 AI42269 / AI / NIAID NIH HHS / United States
R01 AI49954 / AI / NIAID NIH HHS / United States
R01 AI85567 / AI / NIAID NIH HHS / United States
R37 AI049954 / AI / NIAID NIH HHS / United States

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