Fig 1: The differentially methylated enhancer at IGF2 in major psychosis targets the dopamine synthesis enzyme tyrosine hydroxylase (TH). a Higher-order chromatin interactions of the differentially-methylated enhancer at IGF2 with the TH gene in the human prefrontal cortex90; interactions within ±100 kb are shown. Blue arcs show all interactions from the location, and red arcs highlight those to the TH gene. Enh: Chromatin states reflecting enhancers in adult frontal lobe91 (blue rectangles). b Reduced DNA methylation at the IGF2 enhancer in major psychosis correlates with increased TH protein levels in the prefrontal cortex (R = −0.32, p < 0.05; linear regression; n = 17 controls (blue circles) and n = 22 cases (red circles)). TH protein levels are normalized to NeuN, INA, and actin. c DNA methylation at the IGF2 enhancer is associated with differing TH protein levels between cases and controls (same data as b). Low, mid, or high DNA methylation ( < 50%, 50–60%, and > 60%, respectively). Left to right: n = 8, 11, 3, 9, and 8 samples for cases (red boxplots) and controls (blue boxplots). Main effect of DNA methylation by two-way ANOVA F(2, 35) = 3.5, p < 0.05; *p = 0.05 by Tukey post-hoc test. Boxplot center indicates median; box bounds indicate 25th and 75th percentile, and whiskers mark 1.5 times the interquartile range. d, e Effect of Igf2 enhancer deletion knockout in mice. Schema shows deletion of the 4.9 kb Igf2 enhancer alongside mouse forebrain enhancers (ENCODE92, pink). d TH protein levels in striatum of adult wild-type (+/+; n = 19 mice; green circles) and Igf2enh−/− (n = 11 mice; purple circles) mice (normalized to NeuN and actin). Data points shown along with mean±standard deviation. e Dopamine levels in striatum of adult wild-type and Igf2enh−/− mice measured by HPLC (n = 20 and 9 mice, respectively). Data normalized to wild-type levels. *p < 0.05 by one-way ANOVA
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