BAF155 promotes cardiac hypertrophy and fibrosis through inhibition of WWP2-mediated PARP1 ubiquitination
Naijin Zhang, Ying Zhang, Yong Chen, Hao Qian, Boquan Wu, Saien Lu, Shilong You, Wancheng Xu, Yuanming Zou, Xinyue Huang, Wenbin Wang, Jingwei Liu, Da Li, Liu Cao, Yingxian Sun
Abstract
BAF155 is a subunit of the SWI/SNF chromatin remodeling complexes, which increase DNA accessibility by remodeling nucleosomes during gene transcription 1 . BAF155 plays an important role in development and disease. For instance, the BAF155-containing BAF complex is required to maintain self-renewal and pluripotency of embryonic stem cells through regulation of Oct4/Sox2-dependent transcription 2 . BAF155 has also been shown to promote breast cancer progression and metastasis by regulating the expression of c-Myc pathway genes 3 , 4 . However, the roles and mechanisms of BAF155 in cardiovascular disease remain unknown. Here, we found that BAF155 expression was notably upregulated in cardiac tissues of patients and mice with heart failure and in angiotensin II (Ang II)-treated cardiomyocytes (Fig. 1a ; Supplementary Fig. S1a, b ). Fig. 1: BAF155 restrains WWP2-mediated PARP1 ubiquitination to promote cardiac hypertrophy and fibrosis. a Immunohistochemical staining of BAF155 and BNP proteins in heart tissues from healthy donors and patients with heart failure ( n = 5). b Schematic of Ang II-induced mouse model of cardiac hypertrophy and fibrosis. BAF155 -cWT and BAF155 -cKO mice were administered with saline or Ang II (1.5 mg/kg/day) through a subcutaneously implanted osmotic minipump (0.5 µL/h) for 2 weeks. c EF% and FS% of BAF155 -cWT and BAF155 -cKO mice ( n = 6). d H&E staining, TRITC-labeled WGA staining, and Masson’s trichrome staining of BAF155 -cWT and BAF155 -cKO hearts ( n = 6). e Schematic of Ang II-induced mouse model of cardiac hypertrophy and fibrosis. BAF155 -WT and BAF155 -TG mice were administered with saline or Ang II (1.5 mg/kg/day) through a subcutaneously implanted osmotic minipump (0.5 µL/h) for 2 weeks. f EF% and FS% of BAF155 -WT and BAF155 -TG mice ( n = 6). g H&E staining, TRITC-labeled WGA staining, and Masson’s trichrome staining of BAF155 -WT and BAF155 -TG hearts ( n = 6). h Schematic showing workflow for quantitative proteome analysis. i Heatmaps of differentially expressed proteins among BAF155 -cWT, BAF155 -cKO, BAF155 -WT, and BAF155 -TG hearts ( n = 3). j , k Volcano plots showing foldchanges of all detected proteins between BAF155 -cWT and BAF155 -cKO hearts ( j ), and BAF155 -WT and BAF155 -TG hearts ( k ). l Co-IP assay showing the interaction between WWP2 and PARP1 in BAF155 -cWT and BAF155 -cKO hearts. m Ubiquitination levels of PARP1 in BAF155 -cWT and BAF155 -cKO hearts. n Co-IP assay showing the interaction between WWP2 and PARP1 in BAF155 -WT and BAF155 -TG hearts. o Ubiquitination levels of PARP1 in BAF155 -WT and BAF155 -TG hearts. p , q Immunoblotting showing expression of PARP1 and levels of total PARylation in BAF155 -cWT and BAF155 -cKO hearts ( p ), and BAF155 -WT and BAF155 -TG hearts ( q ) ( n = 6). r Working model showing the role of BAF155 in regulating cardiac homeostasis. Data represent means ± SD. * P < 0.05, ** P < 0.01, *** P < 0.001. Two-way ANOVA with Bonferroni multiple comparisons test ( a , c , d , f , g , p , q ). Full size image