TY - JOUR T1 - Epigenetic modulation in the pathogenesis and treatment of inherited aortic aneurysm conditions JF - bioRxiv DO - 10.1101/2021.02.12.431010 SP - 2021.02.12.431010 AU - Benjamin E. Kang AU - Rustam Bagirzadeh AU - Djahida Bedja AU - Jefferson J. Doyle AU - Elena G. MacFarlane AU - Harry C. Dietz Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/02/14/2021.02.12.431010.abstract N2 - Shprintzen-Goldberg syndrome (SGS) is a rare systemic connective tissue disorder characterized by craniofacial, skeletal, neurodevelopmental, cutaneous, and cardiovascular manifestations, including aortic root aneurysm. It has significant phenotypic overlap with both Marfan syndrome (MFS) and Loeys-Dietz syndrome (LDS). We previously reported that SGS is caused by heterozygous mutations in the Sloan-Kettering Institute proto-oncogene (SKI), which encodes a potent suppressor of transforming growth factor beta (TGFβ) target gene expression. Herein, we show that mouse lines harboring orthologous amino acid substitutions in Ski recapitulate multiple human SGS phenotypic manifestations, including skin collagen deposition, skeletal kyphosis, behavioral hypoactivity, and aortic root aneurysm. Furthermore, aortic root aneurysm in SGS mice is associated with both increased acetylation of histone H3 at lysine-27 (H3K27) and TGFβ target gene expression, all of which can be ameliorated by pharmacological CBP/P300 inhibition in vivo; similar findings were seen in cultured dermal fibroblast from SGS patients. Aortic root growth is also abrogated in a mouse model of MFS by selective CBP/P300 inhibition in association with blunted expression of TGFβ target genes. These data document excessive H3K27 acetylation and hence TGFβ target gene expression in the pathogenesis of inherited presentations of aortic root aneurysm and the therapeutic potential of pharmacological epigenetic modulation.Competing Interest StatementB.E.K. and H.C.D are inventors on a patent application entitled - Targeted Epigenetic Therapy For Inherited Aortic Aneurysm Condition, (no. PCT/US2018/49217), jointly filed on 31st August 2018 by the Johns Hopkins University School of Medicine. All other authors declare that they have no competing interests. ER -