Cancer heterogeneity and drug resistance remain pivotal obstacles in effective cancer treatment and management. One major contributor to these challenges is epigenetic modifications - gene regulation that does not involve changes to the DNA sequence itself but significantly impacts gene expression. As we elucidate these phenomena, we underscore the pivotal role of epigenetic modifications in regulating gene expression, contributing to cellular diversity, and driving adaptive changes that can instigate therapeutic resistance. This review dissects essential epigenetic modifications - DNA methylation, histone modifications, and chromatin remodeling - illustrating their significant yet complex contributions to cancer biology. While these changes offer potential avenues for therapeutic intervention due to their reversible nature, the interplay of epigenetic and genetic changes in cancer cells presents unique challenges that must be addressed to harness their full potential. By critically analyzing the current research landscape, we identify knowledge gaps and propose future research directions, exploring the potential of epigenetic therapies and discussing the obstacles in translating these concepts into effective treatments. This comprehensive review aims to stimulate further research and aid in developing innovative, patient-centered cancer therapies. Understanding the role of epigenetic modifications in cancer heterogeneity and drug resistance is critical for scientific advancement and paves the way towards improving patient outcomes in the fight against this formidable disease. 

Epigenetic modifications: Key players in cancer heterogeneity and drug resistance.

Breast tumors are highly vascularized and dependent on angiogenesis for growth, progression and metastasis. Like other solid tumors, vasculature in breast tumors also display leaky and tortuous phenotype and hence inhibit immune cell infiltration, show reduced efficacy to anticancer drugs and radiotherapy. Epigenetic reprogramming including significant alterations in DNA methylation in tumor and stromal cells generate an imbalance in expression of pro- and anti-angiogenic factors and subsequently lead to disordered angiogenesis. Hence, understanding DNA methylation-based regulation of angiogenesis in breast tumors may open new avenues for designing therapeutic targets. Our present review manuscript summarized contemporary knowledge of influence of DNA methylation in regulating angiogenesis. Further, we identified novel set of pro-angiogenic genes enriched in endothelial cells which are coregulated with DNMT isoforms in breast tumors and harboring CpG islands. Our analysis revealed promoters of pro-angiogenic genes were hypomethylated and anti-angiogenic genes were hypermethylated in tumors and further reflected on their expression patterns. Interestingly, promoter DNA methylation intensities of novel set of pro-angiogenic genes significantly correlated to patient survival outcome. 

Novel insights into DNA methylation-based epigenetic regulation of breast tumor angiogenesis

Obesity, characterised by the accumulation of excess fat, is a complex condition resulting from the combination of genetic and epigenetic factors. Recent studies have found correspondence between DNA methylation and cell differentiation, suggesting a role of the former in cell fate determination. There is a lack of comprehensive understanding concerning the underpinnings of preadipocyte differentiation, specifically when cells are undergoing terminal differentiation (TD). To gain insight into dynamic genome-wide methylation, 3T3 L1 preadipocyte cells were differentiated by a hormone cocktail. The genomic DNA was isolated from undifferentiated cells and 4 hrs (4H), 2 days (2D) post-differentiated cells, and 15 days (15D) TD cells. We employed whole-genome bisulfite sequencing (WGBS) to ascertain global genomic DNA methylation alterations at single base resolution as preadipocyte cells differentiate. The genome-wide distribution of DNA methylation showed similar overall patterns in pre- and post- and terminally differentiated adipocytes, according to WGBS analysis. DNA methylation decreases at 4H after differentiation initiation, followed by methylation gain as cells approach TD. Studies revealed novel differentially methylated regions (DMRs) associated with adipogenesis. DMR analysis suggested that though DNA methylation is global, noticeable changes are observed at specific sites known as ‘hotspots.’ Hotspots are genomic regions rich in transcription factor (TF) binding sites and exhibit methylation-dependent TF binding. Subsequent analysis indicated hotspots as part of DMRs. The gene expression profile of key adipogenic genes in differentiating adipocytes is context-dependent, as we found a direct and inverse relationship between promoter DNA methylation and gene expression.

WGBS of Differentiating Adipocytes Reveals Variations in DMRs and Context-Dependent Gene Expression

Abstract Obesity, characterised by the accumulation of excess fat, is a complex condition resulting from the combination of genetic and epigenetic factors. Recent studies have found correspondence between DNA methylation and cell differentiation, suggesting a role of the former in cell fate determination. There is a lack of comprehensive understanding concerning the underpinnings of preadipocyte differentiation, specifically when cells are undergoing terminal differentiation (TD). To gain insight into dynamic genome-wide methylation, 3T3 L1 preadipocyte cells were differentiated by a hormone cocktail. The genomic DNA was isolated from undifferentiated cells and 4 hrs (4H), 2 days (2D) post-differentiated cells, and 15 days (15D) TD cells. We employed whole-genome bisulfite sequencing (WGBS) to ascertain global genomic DNA methylation alterations at single base resolution as preadipocyte cells differentiate. The genome-wide distribution of DNA methylation showed similar overall patterns in pre- and post- and terminally differentiated adipocytes, according to WGBS analysis. DNA methylation decreases at 4H after differentiation initiation, followed by methylation gain as cells approach TD. Studies revealed novel differentially methylated regions (DMRs) associated with adipogenesis. DMR analysis suggested that though DNA methylation is global, noticeable changes are observed at specific sites known as ‘hotspots.’ Hotspots are genomic regions rich in transcription factor (TF) binding sites and exhibit methylation-dependent TF binding. Subsequent analysis indicated hotspots as part of DMRs. The gene expression profile of key adipogenic genes in differentiating adipocytes is context-dependent, as we found a direct and inverse relationship between promoter DNA methylation and gene expression. 

Genome-wide Methylation Dynamics and Context-dependent Gene Expression Variability in Differentiating Preadipocytes

Stem cells are undifferentiated cells characterized by their self-renewal capacity and pluripotency. The multipotent differentiation potential of stem cells grants them significant promise in clinical therapies for tissue injury and organ regeneration. Therefore, the molecular mechanisms underlying the maintenance of stem cell self-renewal and pluripotency have been a major focus of research in the field. In recent years, increasing evidence suggests that cell cycle is not only a central driver of cell division but also participate in controlling stem cell self-renewal and differentiation fate through various pathways. Stem cells, especially embryonic stem cells (ESCs), exhibit unique cell cycle features, with a notably short overall cycle duration, a significantly shortened G1 phase, and a prolonged S phase. This rapid cell cycle not only results in increased cell numbers but is also closely associated with the maintenance of their self-renewal capacity. Pluripotency states (such as naïve, formative, and primed) are tightly linked to specific cell cycle patterns, and this association exhibits species specificity. Elucidating the molecular mechanisms coupling the cell cycle with stemness maintenance is of great significance for the clinical application of stem cells. This review focuses on the cell cycle regulatory network centered around Cyclins and their inhibitors in stem cells, as well as the molecular mechanisms by which core pluripotency factors and cell cycle proteins influence stem cell fate determination. We discuss signaling pathways such as Jak1/Stat3, PI3K/Akt, and Hippo/YAP, and the role of epigenetic regulation, particularly histone modifications, in modulating the expression of differentiation-related and cell cycle-associated genes. Additionally, a brief overview is provided of the unique glycolytic metabolic mode and one-carbon metabolism in stem cells, along with their relationship with epigenetic modifications and rapid proliferative characteristics. Moreover, we analyze the regulatory functions of cell cycle regulators such as Cyclins and checkpoint protein p53 in somatic cell reprogramming and the fate determination of adult stem cells including neural and hematopoietic stem cells (HSCs). Practical strategies based on cell cycle regulation are discussed, along with prospects and challenges for their applications in regenerative medicine. 

pdf/coupling-of-stemness-maintenance-with-cell-cycle-control-in-iuvn86thyztg.pdf

Coupling of stemness maintenance with cell cycle control in stem cells

The molecular mechanisms that regulate stem cell pluripotency and differentiation has shown the crucial role that methylation plays in this process. DNA methylation has been shown to be important in the context of developmental pathways, and the role of histone methylation in establishment of the bivalent state of genes is equally important. Recent studies have shed light on the role of RNA methylation changes in stem cell biology. The dynamicity of these methylation changes not only regulates the effective maintenance of pluripotency or differentiation, but also provides an amenable platform for perturbation by cellular stress pathways that are inherent in immune responses such as inflammation or oncogenic programs involving cancer stem cells. We summarize the recent research on the role of methylation dynamics and how it is reset during differentiation and de-differentiation.

Resetting the epigenome: Methylation dynamics in cancer stem cells

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Resetting the epigenome: Methylation dynamics in cancer stem cells