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Epigenetic dysregulation via regulator of calcineurin 1 (RCAN1) in Alzheimer's disease
Author(s) -
Wong Helen,
Levenga Josien,
Rothermel Beverly,
Klann Eric,
Hoeffer Charles A
Publication year - 2012
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.26.1_supplement.928.8
Subject(s) - epigenetics , creb , chromatin immunoprecipitation , biology , transcription factor , microbiology and biotechnology , histone , calcineurin , chromatin , gene expression , genetics , promoter , gene , medicine , transplantation
Alzheimer's disease (AD) is a neurodegenerative disease that is associated with epigenetic dysregulation. However, the mechanisms mediating epigenetic dysfunction in AD are unknown. Our objective was to determine if Regulator of Calcineurin 1 ( RCAN1 ) has a role in AD‐related epigenetic changes. RCAN1 is located on human chromosome 21, trisomy of which results in Down syndrome (DS), a disorder characterized with early onset AD. Moreover, RCAN1 is overexpressed in both DS and AD. RCAN1 modulates the activity of calcineurin (CaN), a calcium‐sensitive phosphatase that can in turn regulate the transcription factor cyclic AMP response element binding protein (CREB). CREB affects epigenetic modification by recruiting histone acetylase activity that promotes transcription at specific DNA sites. To test the idea that RCAN1 overexpression may mediate aberrant CaN/CREB signaling leading to epigenetic dysregulation in AD, we generated transgenic mice that selectively overexpress RCAN1 in the brain using the Cre/lox system. Using immunoblotting, enzymatic assays and chromatin immunoprecipitation of hippocampal tissue from these mice, we found altered CaN activity and trafficking to the nucleus, CREB activation and histone acetylation. Overall, this work provides critical new understanding of a role for RCAN1 in regulating epigenetic mechanisms and gene expression in AD. Supported by NS034007, NS047384 (E.K.)