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Nutrient-Gene Interactions

Vitamin A Status in Mice Affects the Histone Code of the Phosphoenolpyruvate Carboxykinase Gene in Liver¹

Departments of Nutritional Sciences and Molecular and Cellular Biology, The University of Connecticut, Storrs, CT 06269

³To whom correspondence should be addressed. E-mail: mmcgrane{at}canr.uconn.edu.

ABSTRACT

Vitamin A deficiency decreases hepatic phosphoenolpyruvate carboxykinase (PEPCK) gene expression in mice, and expression is restored with retinoic acid (RA) treatment in vivo. In the studies reported here, we examined changes in histone modification and coregulator association with the regulatory domains of the PEPCK gene in response to alterations in vitamin A status. We identified nuclear receptors that bind to retinoic acid response elements (RAREs) in the PEPCK promoter by electrophoretic mobility shift assay and verified these in vivo using chromatin immunoprecipitation in mouse liver. Hypothetically, nuclear receptors at PEPCK RAREs recruit specific coactivator molecules that contribute to the acetylation of core histones and/or serve as bridging molecules between nuclear receptors and basal transcription factors at the transcription start site. We identified 3 coactivator molecules, cAMP-response element binding protein (CBP), steroid receptor coactivator (SRC)-1, and peroxisome-proliferator activated receptor (PPAR)--coactivator (PGC)-1, that bound in association with the PEPCK RAREs in vivo. Furthermore, there was differential binding of these coactivators in vitamin A–deficient mice. Related to this, specific lysine residues were acetylated on histones H3 and H4 at the 3 RAREs of the PEPCK promoter, consistent with the action of the above coactivators, and acetylation of certain lysines was significantly decreased with vitamin A deficiency. These results demonstrate the associated changes that occur in nuclear receptor binding, coactivator recruitment, and histone acetylation in response to vitamin A status, identified at specific RAREs in the PEPCK gene in vivo.

KEY WORDS: • vitamin A • phosphoenolpyruvate carboxykinase gene • histone acetylation • coactivators

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