B lymphoma Moloney murine leukemia virus insertion region 1 homolog: the Janus-faced polycomb protein that will break your heart

Pathological remodeling characterized by excessive deposition of extracellular matrix proteins and fibrosis is a hallmark of heart disease. While cardiac fibroblasts comprise an essential cell type in the heart that is responsible for homeostasis of the extracellular matrix, on insult these cells transform to a myofibroblast phenotype, secreting elevated levels of matrix proteins. Ultimately, this profibrotic environment reduces myocardial compliance and accelerates the progression to heart failure via pathophysiological adaptations that culminate in chamber dilatation, cardiac myocyte hypertrophy, and apoptosis.

Given the broad and deleterious impact cardiac fibrosis has on heart physiology, understanding the molecular mechanisms underlying the phenotypic switch of cardiac fibroblasts from homeostatic role players to pathophysiological mediators has been the subject of much investigation. In a recent article published in the American Journal of Physiology-Heart and Circulatory Physiology, Yang and colleagues (8) performed a mechanistic study hypothesizing that B lymphoma Moloney murine leukemia virus insertion region 1 homolog (BMI1) is an important mediator of cardiac fibrosis induced by myocardial infarction. Using RNA lentivirus vectors and intramyocardial injections, the authors elegantly observed that BMI1 downregulation ameliorates the infarct phenotype and subsequently delays the onset of heart failure. On the other hand, BMI1 overexpression exacerbated the infarct phenotype. The authors went on to show that these changes occur due to BMI1 regulation of cardiac fibroblast proliferation and migration. Finally, the authors elucidated that phosphatase and tensin homolog (PTEN) inhibition and subsequent phosphatidylinositol 3-kinase (PI3K)-Akj-mammalian target of rapamycin (mTOR) activation is the cellular signaling cascade downstream of BMI1-induced myocardial fibrosis (Fig. 1).

Fig. 1.

Proposed mechanism of B lymphoma Moloney murine leukemia virus insertion region 1 homolog (BMI1)-mediated cardiac fibrosis. During myocardial infarction, hypoxia stimulates BMI1, promoting transcriptional repression. BMI1 acts on the phosphatase and tensin homolog (PTEN) gene and inhibits its transcription. Alleviation of the suppressive action of PTEN, phosphatidylinositol 3-kinase (PI3K), Akt, and mammalian target of rapamycin (mTOR) are free to signal. Collectively, these kinases promote proliferation and migration in cardiac fibroblasts and subsequently unregulated extracellular matrix deposition and fibrosis.

BMI1 is a member of the polycomb group of proteins. Polycomb group proteins constitute a conserved gene silencing system (1). Organized within polycomb repressive complex (PRC)1 and PRC2, they induce chromatin modifications that primarily regulate developmental genes in multiple cell types and tissues, including embryonic and adult stem cells, and are essential for cell fate transitions and proper development (1). BMI1 is a key protein partner in PRC1 that helps in maintaining the integrity of the complex. It is also a key player in ubiquitination of histone H2A, which affects the gene expression pattern involved in various cellular processes, such as cell proliferation, growth, DNA repair, apoptosis, and senescence (2). On the other hand, BMI1 deficiency has been reported to present neurological abnormalities, postnatal depletion of stem cells, oxidative stress, reduced lifespan, and premature aging phenotypes (2). Collectively, these findings indicate that BMI1 activity is enormously important, and any uncontrolled disturbances can promote a transition from normal developmental physiology to diverse and potentially terminal pathophysiology (e.g., cancer).

Recently, the pathophysiological significance of BMI1 has been extended beyond gene regulation per se. Specifically, it was observed that BMI1 binds and stabilizes the androgen receptor, resulting in sustained signaling in prostate cancer cells (10). Importantly, this was independent of PRC1. These data reveal that BMI1 is not only a transcriptional repressor but also a transcriptional activator through its binding partners (in this case, the androgen receptor). Nonetheless, it remains to be seen whether BMI1 can modulate the activity of other (nuclear) receptors to promote normal physiology and/or disease.

In the context of cardiovascular and cardiorenal fibrosis, it appears that BMI1 overexpression promotes deleterious remodeling (3, 8). Similarly, downregulation of BMI1 significantly enhances the induction of beating cardiomyocytes from neonatal and adult fibroblasts (9). Nonetheless, these results may be cell type (i.e., fibroblast) specific, as BMI1-expressing cardiac progenitor cells promote the de novo generation of cardiac myocytes and neovascularization after acute myocardial infarction (5, 7). On the other hand, genetic ablation of BMI-expressing cardiac progenitor cells postmyocardial infarction substantially deteriorated both angiogenesis and ejection fraction, resulting in an ischemic dilated cardiac phenotype (5).

A possible limitation of the present work by Yang et al. (8) was the lack of clarification as to why BMI1 was upregulated postmyocardial infarction. Certainly, it is plausible to speculate that hypoxia/ischemia stimulates BMI1, as hypoxia has been observed to be the stimulus for BMI1-mediated mesenchymal transition and renal fibrosis in renal tubular epithelial cells (3). However, the proinflammatory milieu postmyocardial infarction could give rise to any number of possible activators. Furthermore, confirmation as to how BMI1 mechanistically regulates PTEN inhibition and PI3K-Akt-mTOR activation in cardiac fibroblasts was not empirically tested in the present investigation. It was Song et al. (6), in 2009, who first observed that BMI1 transcriptionally represses PTEN through direct association with the PTEN locus and, therefore, the negative regulation PI3K/Akt pathway. Nonetheless, the signaling relationship between BMI1, PTEN, PI3K, and Akt has been corroborated consistently throughout the literature (3, 6).

In addition to this canonical mechanism of BMI1 signal transduction, it is interesting to speculate other potential mechanisms for the profibrotic effects of BMI1. One novel possibility could be BMI1-dependent modulation of receptors that promote fibrosis (e.g., the angiotensin II receptor), similar to what has been reported for the androgen receptor (10). Another potential mechanism could be BMI1 interactions with non-protein-coding regions of the genome (i.e., independent of PTEN transcript suppression). Recent studies have indicated that noncoding RNA (i.e., long noncoding RNA, microRNA, and circular RNA) have been implicated in coordinated gene silencing through polycomb group proteins, and noncoding RNAs have been reported to contribute to myocardial fibrosis and heart failure (4). Therefore, it is plausible to hypothesize that BMI1 could interact with long noncoding RNA to regulate gene expression associated with cardiac fibrosis.

In summary, results from the work by Yang and colleagues have suggested that BMI1 could be a novel therapeutic to combat pathological cardiac remodeling and fibrosis postmyocardial infarction. However, further analysis of the literature has revealed that BMI1 has diverse mechanisms of action (i.e., epigenetic as well as receptor mediated) that may expand the therapeutic potential of this polycomb group protein. On the other hand, however, the therapeutic potential of BMI1 may also be hindered by coexisting developmental cues within the patient, the (patho)physiological context of its activation or inhibition, and the cell type in which it needs to act. Nonetheless, given that cardiac fibrosis is a consistent feature across almost all forms of heart disease, BMI1 inhibition certainly appears to have appealing therapeutic potential.

GRANTS

This work was supported by American Heart Association Grant 18POST34060003 and National Institutes of Health Grants K99-GM-118885 and R01-HL-143082.

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

C.G.M. and C.F.W. prepared figures; C.G.M. drafted manuscript; C.G.M., C.F.W., and B.J. edited and revised manuscript; C.G.M., C.F.W., and B.J. approved final version of manuscript.