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Molecular mechanisms of a disease susceptibility variant of SIRT1: Genotoxic stress‐induced, CTCF‐dependent activation of SIRT1 gene expression
Author(s) -
Song Xiaoyuan,
Cho Miook,
Han Jeehae,
Hazuda Helen,
Duggirala Ravindranath,
Blangero John,
Rosenfeld Michael G.,
Suh Yousin
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.833.23
Subject(s) - ctcf , repressor , biology , gene , genetics , regulation of gene expression , promoter , epigenetics , dna methylation , gene expression , microbiology and biotechnology , enhancer
SIRT1 is an evolutionarily conserved protein deacetylase that modulates life span and stress resistance in model organisms. While increased expression of SIRT1 has been shown to provide protection from various diseases and aging effects in many invertebrate and vertebrate organ systems, surprisingly, the link between SIRT1 and human diseases and aging is not well understood. Here, we report identification of functional sequence variants in the human SIRT1 promoter that are associated with myocardial infarction. These variants have led to the identification of a pathway through which genotoxic stress results in demethylation of a DNA binding site for CCCTC‐binding factor (CTCF) in the promoter of the SIRT1 gene. We show that the wild‐type SIRT1 gene is a stress‐induced transcriptional target of CTCF, while a variant SIRT1 gene promoter is not bound by CTCF in response to genotoxic stress and hence SIRT1 gene expression does not increase with stress. We hypothesize that changes in DNA methylation of the wild‐type SIRT1 promoter may be due to recruitment of the Activation‐Induced cytidine Deaminase (AID) and concurrent dismissal of polycomb repressor complexes in response to genotoxic stress. This initial example of stress‐induced binding of CTCF suggests the possibility that regulated demethylation of CTCF response elements represents a more widely‐used strategy for activation of gene expression.