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Published on: June 3, 2018
PHD Finger Protein 19 Promotes Cardiac Hypertrophy via Epigenetically Regulating SIRT2
Wei Gu1, Yutong Cheng1, Su Wang1
1Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University and Beijing Institute of Heart Lung and Blood Vessel Diseases, 2 Anzhen Road, Beijing, China.
Insights
PHD finger protein 19 (PHF19) promotes cardiac hypertrophy by epigenetically suppressing SIRT2. PHF19 knockdown protects against angiotensin II-induced heart enlargement and dysfunction in mice.
Area of Science:
- Cardiovascular Biology
- Epigenetics
- Molecular Cardiology
Background:
- Cardiac hypertrophy is driven by epigenetic mechanisms.
- The role of polycomb protein PHF19 in cardiac hypertrophy is unknown.
- PHF19 regulates histone methylation marks H3K36me3 and H3K27me3.
Purpose of the Study:
- To investigate the role of PHF19 in cardiac hypertrophy.
- To elucidate the molecular mechanism by which PHF19 affects cardiac hypertrophy.
- To determine the relationship between PHF19, SIRT2, and hypertrophic markers in human hearts.
Main Methods:
- Adenovirus-mediated knockdown and overexpression of Phf19 in vitro and in vivo.
- Assessment of cardiomyocyte size, protein synthesis, and hypertrophic gene expression (Anp, Bnp).
- Measurement of cardiac function (fraction shortening, ejection fraction) and heart weight.
- Chromatin immunoprecipitation to assess PHF19 binding and histone modifications at the SIRT2 promoter.
- Analysis of PHF19 and SIRT2 expression in human hypertrophic heart samples.
Main Results:
- Phf19 knockdown reduced Angiotensin II (Ang II)-induced cardiomyocyte hypertrophy, repressed hypertrophic markers, and inhibited protein synthesis.
- Phf19 overexpression exacerbated Ang II-induced hypertrophy in vitro.
- In vivo Phf19 knockdown improved cardiac function and reduced heart weight and cardiomyocyte size in Ang II-treated mice.
- PHF19 epigenetically suppressed SIRT2 expression by regulating H3K27me3 and H3K36me3 at the SIRT2 promoter.
- Human hypertrophic hearts showed PHF19 overexpression and SIRT2 downregulation, with PHF19 positively correlating with hypertrophic markers and negatively with SIRT2.
Conclusions:
- PHF19 promotes cardiac hypertrophy through epigenetic regulation of SIRT2.
- PHF19 acts as a key epigenetic regulator in the development of cardiac hypertrophy.
- Targeting PHF19 may offer a therapeutic strategy for cardiac hypertrophy.
Abstract:
Epigenetic regulations essentially participate in the development of cardiomyocyte hypertrophy. PHD finger protein 19 (PHF19) is a polycomb protein that controls H3K36me3 and H3K27me3. However, the roles of PHF19 in cardiac hypertrophy remain unknown. Here in this work, we observed that PHF19 promoted cardiac hypertrophy via epigenetically targeting SIRT2. In angiotensin II (Ang II)-induced cardiomyocyte hypertrophy, adenovirus-mediated knockdown of Phf19 reduced the increase in cardiomyocyte size, repressed the expression of hypertrophic marker genes Anp and Bnp, as well as inhibited protein synthesis. By contrast, Phf19 overexpression promoted Ang II-induced cardiomyocyte hypertrophy in vitro. We also knocked down Phf19 expression in mouse hearts in vivo. The results demonstrated that Phf19 knockdown reduced Ang II-induced decline in cardiac fraction shortening and ejection fraction. Phf19 knockdown also inhibited Ang II-mediated increase in heart weight, reduced cardiomyocyte size, and repressed the expression of hypertrophic marker genes in mouse hearts. Further mechanism studies showed that PHF19 suppressed the expression of SIRT2, which contributed to the function of PHF19 during cardiomyocyte hypertrophy. PHF19 bound the promoter of SIRT2 and regulated the balance between H3K27me3 and H3K36me3 to repress the expression of SIRT2 in vitro and in vivo. In human hypertrophic hearts, the overexpression of PHF19 and downregulation of SIRT2 were observed. Of importance, PHF19 expression was positively correlated with hypertrophic marker genes ANP and BNP but negatively correlated with SIRT2 in human hypertrophic hearts. Therefore, our findings demonstrated that PHF19 promoted the development of cardiac hypertrophy via epigenetically regulating SIRT2.
