Contribution of Increased Expression of Yin Yang 2 to Development of Cardiomyopathy.

Yi Zhang,Yanlin Ma,Jun Wang,Yutao Xi,Jiang Chang,Ilimbek Beketaev,Ana Maria Segura,Wei Yu

doi:10.3389/fmolb.2020.00035

Abstract

Yin Yang 2 (YY2) is a member of the Yin Yang family of transcription factors. Although the bioactivity of YY2 has been previously studied, its role in cardiovascular diseases is not known. We observed the increased expression of YY2 in failing human hearts compared with control hearts, raising the question of whether YY2 is involved in the pathogenesis of cardiomyopathy. To investigate the potential contribution of YY2 to the development of cardiomyopathy, we crossed two independent transgenic (Tg) mouse lines, pCAG-YY2-Tg+and alpha-myosin heavy chain-cre (α-MHC-Cre), to generate two independent double transgenic (dTg) mouse lines in which the conditional cardiomyocyte-specific expression of YY2 driven by the α-MHC promoter was mediated by Cre recombinase, starting at embryonic day 9.0. In dTg mice, we observed partial embryonic lethality and hearts with defective cardiomyocyte proliferation. Surviving dTg mice from both lines developed cardiomyopathy and heart failure that occurred with aging, showing different degrees of severity that were associated with the level of transgene expression. The development of cardiomyopathy was accompanied by increased levels of cardiac disease markers, apoptosis, and cardiac fibrosis. Our studies further revealed that the Cre-mediated cardiomyocyte-specific increase in YY2 expression led to increased levels of Beclin 1 and LC3II, indicating that YY2 is involved in mediating autophagic activity in mouse hearts in vivo. Also, compared with control hearts, dTg mouse hearts showed increased JNK activity. Because autophagy and JNK activity are important for maintaining cardiac homeostasis, the dysregulation of these signaling pathways may contribute to YY2-induced cardiomyopathy and heart failure in vivo.

Highlights

The Yin Yang family member protein Yin Yang 2 (YY2) shares 56% amino acid sequence identity and 86% similarity in the zinc finger domain with YY1 (Nguyen et al, 2004)
The role of YY1 in cardiomyocyte differentiation, cardiac development, and cardiomyopathy has been previously explored (Sucharov et al, 2003; Morikawa et al, 2013; Beketaev et al, 2015), studies of the involvement of YY2 in cardiovascular development and diseases have been limited, albeit that YY2 expression was detected in mouse hearts during both embryogenesis and postnatal stages (Drews et al, 2009)
We found that the expression of YY2 induced by a-MHC-Cre, which was activated at ∼E9.0, caused partial prenatal lethality

Summary

Introduction

The Yin Yang family member protein Yin Yang 2 (YY2) shares 56% amino acid sequence identity and 86% similarity in the zinc finger domain with YY1 (Nguyen et al, 2004). YY2 and Cardiomyopathy to bind to a similar DNA sequence [i.e., A/CCAT (Yant et al, 1995)] and share multiple common targets, as revealed by the genome-wide analysis of human YY1 and YY2 shRNA knockdown cell lines (Kim et al, 2007; Chen et al, 2010). Others have shown that YY2 antagonizes YY1’s effects on the promoters of interleukin 4 (IL-4) and interferon beta (INF-b) genes (Klar and Bode, 2005; Lee et al, 2016), suggesting that YY1 and YY2 may have distinctly different activities. Most studies of YY2 activity have involved in vitro approaches. One study showed that the increased expression of YY2 impairs primary neuron differentiation and triggers cell death (Klar et al, 2015). The methylation of lysine 247 of YY2 (K247) has been shown to mediate cell proliferation and is potentially involved in cancer growth (Wu et al, 2017)

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Conclusion