Abstract 39: Telomerase Reverse Transcriptase Mediates Vascular Smooth Muscle Cell Proliferation and Cell Cycle Progression Through Epigenetic Regulation of E2F Target Genes
INTRODUCTION: By maintaining the stability of telomeres, DNA-protein complexes that protect the ends of chromosomes, telomerase is rate limiting for tissue renewal and cell proliferation. In addition to this telomere maintenance function, mounting evidence suggests that the telomerase reverse transcriptase (TERT) exhibits a direct regulatory role in the activation of mitotic gene expression without apparent involvement of its well-established function in telomere homeostasis. In the present study, we investigated the role of TERT in vascular remodeling and the hypothesis that TERT regulates vascular smooth muscle cell (VSMC) proliferation through an epigenetic activation of an S Phase gene expression program.
METHODS AND RESULTS: We first demonstrate high levels of TERT expression in replicating SMC of the developing neointima of human atherosclerosis. Studies in VSMC isolated from genetically engineered TERT-deficient mice with normal telomere length establish that TERT is necessary for cell proliferation. Conversely, overexpression of TERT induces cell proliferation without extending telomere length. Although TERT-deficient VSMC are not senescent, decreased proliferation is associated with stable and irreversible silencing of S phase gene expression, including target genes of the S Phase transcription factor E2F. Chromatin immunoprecipitation assays confirm that TERT is recruited to E2F target sites and promotes chromatin accessibility by facilitating the acquisition of permissive histone modifications. Finally, using a model of guide-wire induced arterial injury, we demonstrate these observations are applicable in vivo and identify decreased neointima formation in TERT-deficient mice.
CONCLUSIONS: These data indicate a previously unrecognized role for TERT in the epigenetic regulation of proliferative gene expression in VSMC.
Author Disclosures: J. Aono: None. E.B. Heywood: None. H. Qing: None. K.L. Jones: None. D. Bruemmer: None.
- © 2014 by American Heart Association, Inc.