TY  - JOUR
A1  - Bernt, Alexander
A1  - Rangrez, Ashraf Y.
A1  - Eden, Matthias
A1  - Jungmann, Andreas
A1  - Katz, Sylvia
A1  - Rohr, Claudia
A1  - Müller, Oliver J.
A1  - Katus, Hugo A.
A1  - Sossalla, Samuel T.
A1  - Williams, Tatjana
A1  - Ritter, Oliver
A1  - Frank, Derk
A1  - Frey, Norbert
T1  - Sumoylation-independent activation of Calcineurin-NFAT-signaling via SUMO2 mediates cardiomyocyte hypertrophy
JF  - Scientific Reports
N2  - The objective of this study was to identify unknown modulators of Calcineurin (Cn)-NFAT signaling. Measurement of NFAT reporter driven luciferase activity was therefore utilized to screen a human cardiac cDNA-library (~10\(^{7}\) primary clones) in C2C12 cells through serial dilutions until single clones could be identified. This extensive screening strategy culminated in the identification of SUMO2 as a most efficient Cn-NFAT activator. SUMO2-mediated activation of Cn-NFAT signaling in cardiomyocytes translated into a hypertrophic phenotype. Prohypertrophic effects were also observed in mice expressing SUMO2 in the heart using AAV9 (Adeno-associated virus), complementing the in vitro findings. In addition, increased SUMO2-mediated sumoylation in human cardiomyopathy patients and in mouse models of cardiomyopathy were observed. To decipher the underlying mechanism, we generated a sumoylation-deficient SUMO2 mutant (ΔGG). Surprisingly, ΔGG replicated Cn-NFAT-activation and the prohypertrophic effects of native SUMO2, both in vitro and in vivo, suggesting a sumoylation-independent mechanism. Finally, we discerned a direct interaction between SUMO2 and CnA, which promotes CnA nuclear localization. In conclusion, we identified SUMO2 as a novel activator of Cn-NFAT signaling in cardiomyocytes. In broader terms, these findings reveal an unexpected role for SUMO2 in cardiac hypertrophy and cardiomyopathy, which may open the possibility for therapeutic manipulation of this pathway.
KW  - Calcineurin-NFATsignaling
KW  - activation
KW  - SUMO2
KW  - cardiac hypertrophy
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-167525
VL  - 6
IS  - 35758
ER  - 
TY  - JOUR
A1  - Cui, Huanhuan
A1  - Schlesinger, Jenny
A1  - Schoenhals, Sophia
A1  - Tonjes, Martje
A1  - Dunkel, Ilona
A1  - Meierhofer, David
A1  - Cano, Elena
A1  - Schulz, Kerstin
A1  - Berger, Michael F.
A1  - Haack, Timm
A1  - Abdelilah-Seyfried, Salim
A1  - Bulyk, Martha L.
A1  - Sauer, Sascha
A1  - Sperling, Silke R.
T1  - Phosphorylation of the chromatin remodeling factor DPF3a induces cardiac hypertrophy through releasing HEY repressors from DNA
JF  - Nucleic Acids Research
N2  - DPF3 (BAF45c) is a member of the BAF chromatin remodeling complex. Two isoforms have been described, namely DPF3a and DPF3b. The latter binds to acetylated and methylated lysine residues of histones. Here, we elaborate on the role of DPF3a and describe a novel pathway of cardiac gene transcription leading to pathological cardiac hypertrophy. Upon hypertrophic stimuli, casein kinase 2 phosphorylates DPF3a at serine 348. This initiates the interaction of DPF3a with the transcriptional repressors HEY, followed by the release of HEY from the DNA. Moreover, BRG1 is bound by DPF3a, and is thus recruited to HEY genomic targets upon interaction of the two components. Consequently, the transcription of downstream targets such as NPPA and GATA4 is initiated and pathological cardiac hypertrophy is established. In human, DPF3a is significantly up-regulated in hypertrophic hearts of patients with hypertrophic cardiomyopathy or aortic stenosis. Taken together, we show that activation of DPF3a upon hypertrophic stimuli switches cardiac fetal gene expression from being silenced by HEY to being activated by BRG1. Thus, we present a novel pathway for pathological cardiac hypertrophy, whose inhibition is a long-term therapeutic goal for the treatment of the course of heart failure.
KW  - phosphorylation
KW  - DPF3a
KW  - HEY repressors
KW  - DNA
KW  - cardiac hypertrophy
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166391
VL  - 44
IS  - 6
ER  -