Phosphorylation of the chromatin remodeling factor DPF3a induces cardiac hypertrophy through releasing HEY repressors from DNA

Abstract

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.

EBF2 transcriptionally regulates brown adipogenesis via the histone reader DPF3 and the BAF chromatin remodeling complex

“…Elegant work from the Sperling laboratory (Lange et al 2008;Cui et al 2016) has highlighted different functions for the short isoform Dpf3a, which recruits BAF through interactions with tissue-specific transcription factors, and the long isoform Dpf3b, which can directly bind histones through its tandem PHD finger. Both Dpf3 splice isoforms are expressed in BAT; however, augmenting DPF3A levels in brown adipocytes repressed Ucp1 expression (Fig.…”

“…A naturally occurring C-terminal splice variant of DPF3 (DPF3A) is identical to DPF3B from amino acids 1-261 but contains a truncated PHD finger (Fig. 7A); this variant is unable to bind histones and instead can exert its function through interaction with sequence-specific transcription factors (Lange et al 2008;Cui et al 2016). We used retrovirus to express Flag-tagged versions of the truncated (DPF3A) and full-length (DPF3B) isoforms of DPF3 into brown adipocytes, with the reasoning that ectopic expression of these different DPF3 isoforms would disrupt the natural stoichiometry of the BAF complex.…”

The epigenetic landscape related to reactive oxygen species formation in the cardiovascular system

“…Similarly, in cardiac hypertrophy, CK2 phosphorylated the BAF45c subunit double plant homeodomain (PHD) finger protein 3a (DPF3a), thereby releasing it from the transcriptional repressor HEY. This allowed BRG1 to bind to DPF3a and to promote expression of HEY genomic targets such as natriuretic peptide precursor A and GATA binding protein 4 (Cui et al , ). While a role of ROS has not been explicitly investigated in this setting, ROS have been shown to activate CK2 leading to Nrf2 activation and HO‐1 induction (Kim et al , ) further suggesting an important role of BRG1 in the adaptation to oxidative stress in the heart.…”

Beyond Family: Modeling Non-hereditary Heart Diseases With Human Pluripotent Stem Cell-Derived Cardiomyocytes

“…Chronic adrenergic activation is one of the pathogenic triggers of maladaptive hypertrophy, and the effects of prolonged exposure to isoproterenol or phenylephrine have been studied in hPSC-CMs in regard to hypertrophy-inhibiting effects of several active compounds (Foldes et al, 2011;Martin et al, 2014;Gesmundo et al, 2017). Nevertheless, the reliability of this approach is hindered by hPSC-CM immature adrenergic signaling (Jung et al, 2016;Uzun et al, 2016;Trieschmann et al, 2019), which generates highly variable and aberrant stress-responses (Foldes et al, 2014) often failing to produce representative pathological phenotypes in vitro (Tanaka et al, 2014;Cui et al, 2016;Naftali-Shani et al, 2018). Hormonal stimulation has been shown to be more effective for maladaptive hypertrophy modeling purposes, with angiotensin-II and especially endothelin-1 treatments successfully recapitulating hypertrophic phenotypes in terms of expression/secretion of natriuretic peptides A and B (Carlson et al, 2013), myofibrillar disarray (Tanaka et al, 2014) and mRNA/miRNA profiling (Aggarwal et al, 2014).…”