title: Lack of global epigenetic methylation defects in CBS deficient mice.
abstract: Cystathionine β-synthase (CBS) deficiency is a recessive inborn error of metabolism in which patients have extremely elevated plasma total homocysteine and have clinical manifestations in the vascular, visual, skeletal, and nervous systems. Homocysteine is an intermediary metabolite produced from the hydrolysis of S-adenosylhomocysteine (SAH), which is a by-product of methylation reactions involving the methyl-donor S-adenosylmethionine (SAM). Here, we have measured SAM, SAH, DNA and histone methylation status in an inducible mouse model of CBS deficiency to test the hypothesis that homocysteine-related phenotypes are caused by inhibition of methylation due to elevated SAH and reduced SAM/SAH ratio. We found that mice lacking CBS have elevated cellular SAH and reduced SAM/SAH ratios in both liver and kidney, but this was not associated with alterations in the level of 5-methylcytosine or various histone modifications. Using methylated DNA immunoprecipitation in combination with microarray, we found that of the 241 most differentially methylated promoter probes, 89 % were actually hypermethylated in CBS deficient mice. In addition, we did not find that changes in DNA methylation correlated well with changes in RNA expression in the livers of induced and uninduced CBS mice. Our data indicates that reduction in the SAM/SAH ratio, due to loss of CBS activity, does not result in overall hypomethylation of either DNA or histones.
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USA.
authors.forename: Hyung-Ok
authors.initials: HO
authors.lastname: Lee
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USA.
authors.forename: Liqun
authors.initials: L
authors.lastname: Wang
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USA.
authors.forename: Yin-Ming
authors.initials: YM
authors.lastname: Kuo
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USA.
authors.forename: Sapna
authors.initials: S
authors.lastname: Gupta
authors.affiliation: Biostatisitics Program, Fox Chase Cancer Center, Philadelphia, PA, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Slifker
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USA.
authors.forename: Yue-Sheng
authors.initials: YS
authors.lastname: Li
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Andrews
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USA. warren.kruger@fccc.edu.
authors.forename: Warren D
authors.initials: WD
authors.lastname: Kruger
mesh_terms: D000818:Animals; D003541:Cystathionine beta-Synthase / Q000235:genetics* / Q000378:metabolism; D004247:DNA / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic / Q000235:genetics*; D057890:Epigenomics / Q000379:methods; D006710:Homocysteine / Q000235:genetics / Q000378:metabolism; D006712:Homocystinuria / Q000235:genetics* / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D012435:S-Adenosylhomocysteine / Q000378:metabolism; D012436:S-Adenosylmethionine / Q000378:metabolism
chemical_list: D006710:Homocysteine; D012436:S-Adenosylmethionine; D004247:DNA; D012435:S-Adenosylhomocysteine; D003541:Cystathionine beta-Synthase