Fig. 1.
Permissive epigenetic regulation at the cldn5 promoter is associated with stress resilience. (A) Experimental timeline and (B) behavioral profile of unstressed CTRL, SS, SI ratio <1, and RES, SI ratio >1 (one-way ANOVA: F2,14 = 1,084; ***P < 0.0001, n = 10 to 12 mice/group). (C) Stress resilience is associated with higher permissive pan-acetylation on histone 3 (pan-acH3, two-way ANOVA: phenotype effect F2,168 = 168; ***P < 0.0001) and lower repressive methylation on H3K27me3 (two-way ANOVA: phenotype effect F2,168 = 32.05; ***P < 0.0001) on cldn5 gene promoter in the NAc of mice. Lower acetylation is also observed in SS mice when compared to CTRL (two-way ANOVA: phenotype effect F1,108 = 13.68; ***P = 0.0003). (D) Repressive histone methylation at CLDN5 promoter is reduced in the NAc of major depressive disorder (MDD) subjects under antidepressant (AD+) treatment at time of death when compared to healthy CTRL or MDD subjects without treatment (MDD, AD−) (500 bp, one-way ANOVA: F2,24 = 6.119; **P = 0.0071; 2,700 bp, one-way ANOVA: F2,24 = 4.513; *P = 0.0217; n = 5 to 15 subjects/group). If one- or two-way ANOVA statistical test was significant, Bonferroni posttests were performed with *P < 0.05; **P < 0.01; ***P < 0.001. See SI Appendix, Tables S1 and S3 for primers and detailed demographic data.