Polyploidy and Myc Proto-Oncogenes Promote Stress Adaptation via Epigenetic Plasticity and Gene Regulatory Network Rewiring

Abstract

Polyploid cells demonstrate biological plasticity and stress adaptation in evolution; development; and pathologies, including cardiovascular diseases, neurodegeneration, and cancer. The nature of ploidy-related advantages is still not completely understood. Here, we summarize the literature on molecular mechanisms underlying ploidy-related adaptive features. Polyploidy can regulate gene expression via chromatin opening, reawakening ancient evolutionary programs of embryonality. Chromatin opening switches on genes with bivalent chromatin domains that promote adaptation via rapid induction in response to signals of stress or morphogenesis. Therefore, stress-associated polyploidy can activate Myc proto-oncogenes, which further promote chromatin opening. Moreover, Myc proto-oncogenes can trigger polyploidization de novo and accelerate genome accumulation in already polyploid cells. As a result of these cooperative effects, polyploidy can increase the ability of cells to search for adaptive states of cellular programs through gene regulatory network rewiring. This ability is manifested in epigenetic plasticity associated with traits of stemness, unicellularity, flexible energy metabolism, and a complex system of DNA damage protection, combining primitive error-prone unicellular repair pathways, advanced error-free multicellular repair pathways, and DNA damage-buffering ability. These three features can be considered important components of the increased adaptability of polyploid cells. The evidence presented here contribute to the understanding of the nature of stress resistance associated with ploidy and may be useful in the development of new methods for the prevention and treatment of cardiovascular and oncological diseases.

The Transcriptome and Proteome Networks of Malignant Tumours Reveal Atavistic Attractors of Polyploidy-Related Asexual Reproduction

“…Polyploidy as such (in normal mammalian tissues) induces a similar epigenetic shift favouring upregulation of unicellular and early multicellular genes (phylogenetic strata 1–5, from Prokaryotes to Eumetazoa), accompanied by downregulation of the genes of complex multicellularity, responsible for apoptosis, differentiation, immunity, and cell communication [ 72 ]. This shift towards unicellularity is aided by the ploidy-upregulated key proto-oncogene c-myc (originated in Opisthokonta) opening the chromatin for reprogramming [ 73 ], leading to epithelial-mesenchymal transition (EMT) [ 72 , 74 , 75 , 76 ] and hubbing the network nest of upregulated bivalent genes (in the same phylogenetic strata 1–5). The latter enable a critically rapid switch of the gene promoter activity from a suppressed to an active state.…”

“…The latter enable a critically rapid switch of the gene promoter activity from a suppressed to an active state. Moreover, cancer gene ontology (GO) modules embracing the c-MYC-HRAS axis and EGFR nest become activated by polyploidy [ 72 , 74 , 75 , 76 ].…”

Long-Term Transcriptomic Changes and Cardiomyocyte Hyperpolyploidy after Lactose Intolerance in Neonatal Rats

“…In accordance, the MCODE complex investigation found complexes implicated in RNA transport, mRNA and tRNA processing, basal transcription (regulated by Taf8, Taf2, Gtf2B and Gtf2E1), and ribosome biogenesis (regulated by Brix1, Pes1, Mak16). The activation of transcription and ribosome biogenesis may be the consequence of the transcriptionally permissive chromatin state originating from polyploidy, genetic instability, and other factors related to stress [ 79 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 ]. This suggestion is confirmed by the GO biological process “Negative regulation of chromosome organization” ( Figure 7 A).…”

“…Our data also identified the traits of open chromatin, such as the upregulation of the gene module “Negative regulation of chromosome organization” and modules related to active transcription and ribosome biogenesis. The association between polyploidy, chromatin opening, ribosome biogenesis, and active transcription was previously described in several studies performed with mammalian and plant cells in normal and pathologic states [ 91 , 145 , 146 , 147 ].…”

Systemic Alterations of Cancer Cells and Their Boost by Polyploidization: Unicellular Attractor (UCA) Model

“…Polyploidization makes cancer cells even worse because of chromosomal instability caused by difficulties with chromosome pairing and segregation [ 58 , 59 , 60 , 61 , 63 ]. Another recently recognized factor of gene expression changes in polyploid cells is the opening of chromatin owing to a decrease in surface/volume ratio, which relaxes chromatin architecture because of the loss of interactions of nuclear lamina with lamina-associated domains [ 90 ]. Chromatin opening may also cause cell dedifferentiation.…”