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

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.

Biological roles of Yin Yang 2: Its implications in physiological and pathological events

“…Similar to the YY1 protein, as shown by Drews et al , the expression of YY2 might be ubiquitous as well since YY2 mRNA could be detected in the entire embryonic mice 19 . Indeed, YY2 is expressed in various types of tissues, including the cardiovascular, neuronal, breasts, muscle, eye, stomach, lung, brain and testis 1,7,9,19,20 …”

“…Recently Wu et al showed that YY2 suppresses the expression of MYPN , 23 which expression is needed for normal development of cardiac muscle and its abnormality is associated with cardiomyopathy 36 . On the other hand, Zhang et al reported that elevated levels of YY2 lead to partial embryonic death, while the surviving embryos have impaired proliferation of cardiomyocytes and develop cardiomyopathy 20 . These evidences suggest the importance of stringent YY2 regulation in the differentiation and development of the cardiovascular system.…”

Sumoylation-deficient phosphoglycerate mutase 2 impairs myogenic differentiation

“…The following pair of complementary oligos harboring 20-nucleotide guide RNA sequences was used to generate guide RNA (gRNA): forward 5′CAC​CGATC​GCA​CCT​AAG​ATT​AAG​GC3′ and reverse 5′AAA​CGCC​TTA​ATC​TTA​GGT​GCG​ATC3’. The guide oligo was subcloned into pX458 as previously described ( Zhang et al, 2020 ). Briefly, these two complementary oligos (100 μM) were phosphorylated by T4 polynucleotide kinase, annealed by boiling for 10 min, and left at room temperature overnight.…”

“…The following pair of complementary oligos harboring 20-nucleotide guide RNA sequences was used to generate guide RNA (gRNA): forward 5′CACCGATCGCA CCTAAGATTAAGGC3′ and reverse 5′AAACGCCTTAATC TTAGGTGCGATC3'. The guide oligo was subcloned into pX458 as previously described (Zhang et al, 2020)…”

A Complex Heterogeneous Network Model of Disease Regulated by Noncoding RNAs: A Case Study of Unstable Angina Pectoris

“…(1) Te target genes of hub miRNAs were validated for a new dataset (GSE60993) containing gene expression from unstable angina and healthy controls, using AUC and AUPR as evaluation metrics. (2) Transcription factors (TFs) are important proteins that regulate gene expression [56], and their dysregulation will cause abnormal gene expression, which is closely associated with the development and progression of complex diseases [57]. Te TF-Marker database [58] provides cell-and tissue-specifc TFs and related markers.…”