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Publication
Wilson Disease: Intersecting DNA Methylation and Histone Acetylation Regulation
of Gene Expression in a Mouse Model of Hepatic Copper Accumulation.
Authors Sarode GV, Neier K, Shibata NM, Shen Y, Goncharov DA, Goncharova EA, Mazi TA,
Joshi N, Settles ML, LaSalle JM, Medici V
Submitted By Submitted Externally on 12/3/2021
Status Published
Journal Cellular and molecular gastroenterology and hepatology
Year 2021
Date Published
Volume : Pages 12 : 1457 - 1477
PubMed Reference 34098115
Abstract The pathogenesis of Wilson disease (WD) involves hepatic and brain copper
accumulation resulting from pathogenic variants affecting the ATP7B gene and
downstream epigenetic and metabolic mechanisms. Prior methylome investigations
in human WD liver and blood and in the Jackson Laboratory (Bar Harbor, ME)
C3He-Atp7btx-j/J (tx-j) WD mouse model revealed an epigenetic signature of WD,
including changes in histone deacetylase (HDAC) 5. We tested the hypothesis that
histone acetylation is altered with respect to copper overload and aberrant DNA
methylation in WD., We investigated class IIa HDAC4 and HDAC5 and H3K9/H3K27
histone acetylation in tx-j mouse livers compared with C3HeB/FeJ (C3H) control
in response to 3 treatments: 60% kcal fat diet, D-penicillamine (copper
chelator), and choline (methyl group donor). Experiments with copper-loaded
hepatoma G2 cells were conducted to validate in vivo studies., In 9-week tx-j
mice, HDAC5 levels increased significantly after 8 days of a 60% kcal fat diet
compared with chow. In 24-week tx-j mice, HDAC4/5 levels were reduced 5- to
10-fold compared with C3H, likely through mechanisms involving HDAC
phosphorylation. HDAC4/5 levels were affected by disease progression and
accompanied by increased acetylation. D-penicillamine and choline partially
restored HDAC4/5 and H3K9ac/H3K27ac to C3H levels. Integrated RNA and chromatin
immunoprecipitation sequencing analyses revealed genes regulating energy
metabolism and cellular stress/development, which, in turn, were regulated by
histone acetylation in tx-j mice compared with C3H mice, with Ppara and Ppar?
among the most relevant targets., These results suggest dietary modulation of
class IIa HDAC4/5, and subsequent H3K9/H3K27 acetylation/deacetylation can
regulate gene expression in key metabolic pathways in the pathogenesis of WD.




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