Cancer development is driven by the accumulation of alterations affecting the structure and function of the genome. Whereas genetic changes disrupt the DNA sequence, epigenetic alterations contribute to the acquisition of hallmark tumor capabilities by regulating gene expression programs that promote tumorigenesis. Shifts in DNA methylation and histone mark patterns, the two main epigenetic modifications, orchestrate tumor progression and metastasis. These cancer‐specific events have been exploited as useful tools for diagnosis, monitoring, and treatment choice to aid clinical decision making. Moreover, the reversibility of epigenetic modifications, in contrast to the irreversibility of genetic changes, has made the epigenetic machinery an attractive target for drug development. This review summarizes the most advanced applications of epigenetic biomarkers and epigenetic drugs in the clinical setting, highlighting commercially available DNA methylation‐based assays and epigenetic drugs already approved by the US Food and Drug Administration.

Cancer epigenetics in clinical practice

Cartilage oligomeric matrix protein acts as a molecular biomarker in multiple cancer types

Single-cell profiling to explore pancreatic cancer heterogeneity, plasticity and response to therapy

Epigenetics has transformed our understanding of the molecular basis of complex diseases, including cardiovascular and metabolic disorders. This review offers a comprehensive overview of the current state of knowledge on epigenetic processes implicated in cardiovascular and metabolic diseases, highlighting the potential of DNA methylation as a precision medicine biomarker and examining the impact of social determinants of health, gut bacterial epigenomics, noncoding RNA, and epitranscriptomics on disease development and progression. We discuss challenges and barriers to advancing cardiometabolic epigenetics research, along with the opportunities for novel preventive strategies, targeted therapies, and personalized medicine approaches that may arise from a better understanding of epigenetic processes. Emerging technologies, such as single-cell sequencing and epigenetic editing, hold the potential to further enhance our ability to dissect the complex interplay between genetic, environmental, and lifestyle factors. To translate research findings into clinical practice, interdisciplinary collaborations, technical and ethical considerations, and accessibility of resources and knowledge are crucial. Ultimately, the field of epigenetics has the potential to revolutionize the way we approach cardiovascular and metabolic diseases, paving the way for precision medicine and personalized health care, and improving the lives of millions of individuals worldwide affected by these conditions. 

https://www.ahajournals.org/doi/pdf/10.1161/CIRCRESAHA.123.322135

Epigenetics of Early Cardiometabolic Disease: Mechanisms and Precision Medicine

DNA methylation is an epigenetic mechanism that plays important roles in various biological processes including transcriptional and post-transcriptional regulation, genomic imprinting, aging, and stress response to environmental changes and disease. Consistent with thermodynamic principles acting within living systems and the application of maximum entropy principle, we propose a theoretical framework to understand and decode the DNA methylation process. A central tenet of this argument is that the probability density function of DNA methylation information-divergence summarizes the statistical biophysics underlying spontaneous methylation background and implicitly bears on the channel capacity of molecular machines conforming to Shannon's capacity theorem. On this theoretical basis, contributions from the molecular machine (enzyme) logical operations to Gibb entropy (S) and Helmholtz free energy (F) are intrinsic. Application to the estimations of S on datasets from Arabidopsis thaliana suggests that, as a thermodynamic state variable, individual methylome entropy is completely determined by the current state of the system, which in biological terms translates to a correspondence between estimated entropy values and observable phenotypic state. In patients with different types of cancer, results suggest that a significant information loss occurs in the transition from differentiated (healthy) tissues to cancer cells. This type of analysis may have important implications for early-stage diagnostics. The analysis of entropy fluctuations on experimental datasets revealed existence of restrictions on the magnitude of genome-wide methylation changes originating by organismal response to environmental changes. Only dysfunctional stages observed in the Arabidopsis mutant met1 and in cancer cells do not conform to these rules. 

/pdf/on-the-thermodynamics-of-dna-methylation-process-2iactivz.pdf

On the thermodynamics of DNA methylation process

Bulk sequencing methodologies have allowed us to make great progress in cancer research. Unfortunately, these techniques lack the resolution to fully unravel the epigenetic mechanisms that govern tumor heterogeneity. Consequently, many novel single cell-sequencing methodologies have been developed over the past decade, allowing us to explore the epigenetic components that regulate different aspects of cancer heterogeneity, namely: clonal heterogeneity, tumor microenvironment (TME), spatial organization, intratumoral differentiation programs, metastasis, and resistance mechanisms. In this review, we explore the different sequencing techniques that enable researchers to study different aspects of epigenetics (DNA methylation, chromatin accessibility, histone modifications, DNA-protein interactions, and chromatin 3D architecture) at the single cell level, their potential applications in cancer, and their current technical limitations. 

Single cell cancer epigenetics.


 Epigenetic alterations, such as DNA methylation aberrations, are a hallmark of human cancer. This observation has led to the assessment of hypomethylating agents (HMAs) as potential drugs to treat oncological patients, being considered the clinical approval of these pharmacological compounds in the therapy of myeloid malignancies as one of the main achievements of this scientific field. A good example is myelodysplastic syndrome (MDS), a pre-leukemia disorder that can evolve into acute myeloid leukemia (AML), where very few therapeutic options were available until the introduction of HMAs. However, it remains unsolved how we can predict if an MDS patient will response or not to the epigenetic drug and for how long. Using the great analytical power of the newly developed single-cell technologies, we have herein tackled this issue. To study the evolution of the clonal molecular and cellular architecture MDS upon the treatment with HMAs, we performed single-cell DNA sequencing (scDNA-seq) of an amplicon panel for 53 genes commonly mutated in myeloid malignancies and single-cell protein sequencing (scProt-seq) of 45 cell-surface proteins to provide a simultaneous landscape of the genetic setting and immunophenotype. We sequenced hundreds of thousands of cells from these MDS patients where paired bone marrow samples were obtained at the time of diagnosis and at the end of at least six cycles of azacitidine treatment. Our study has unveiled that the co-occurrence of particular truncating or stop codon mutations in the same myeloid progenitor cell; the multibranched dynamics of the mutant clones; and the persistence of particular cell lineages with distinct mutational profiles (such as non-classical monocytes and CD8+ effector T-cells) can predict the clinical response of MDS patients to HMA therapy.
 Citation Format: Ignacio Campillo-Marcos, Marta Casado-Pelaez, Veronica Davalos, Gerardo Ferrer, Caterina Mata, Elisabetta Mereu, David Valcarcel, Antonieta Molero, Lurdes Zamora, Laura Palomo, Pamela Acha, Ana Manzanares, Francesc Solé, Manel Esteller. Single-cell multiomics analysis of myelodysplastic syndrome predicts clinical response to DNA methylation inhibitor therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB130.

Abstract LB130: Single-cell multiomics analysis of myelodysplastic syndrome predicts clinical response to DNA methylation inhibitor therapy

Abstract Skin aging is characterized by structural and functional changes that contribute to age-associated frailty. This probably depends on synergy between alterations in the local niche and stem cell-intrinsic changes, underscored by proinflammatory microenvironments that drive pleotropic changes. The nature of these age-associated inflammatory cues, or how they affect tissue aging, is unknown. Based on single-cell RNA sequencing of the dermal compartment of mouse skin, we show a skew towards an IL-17-expressing phenotype of T helper cells, γδ T cells and innate lymphoid cells in aged skin. Importantly, in vivo blockade of IL-17 signaling during aging reduces the proinflammatory state of the skin, delaying the appearance of age-related traits. Mechanistically, aberrant IL-17 signals through NF-κB in epidermal cells to impair homeostatic functions while promoting an inflammatory state. Our results indicate that aged skin shows signs of chronic inflammation and that increased IL-17 signaling could be targeted to prevent age-associated skin ailments. 

/pdf/targeting-lymphoid-derived-il-17-signaling-to-delay-skin-30ertz2n.pdf

Targeting lymphoid-derived IL-17 signaling to delay skin aging

Recent findings are challenging the classical hematopoietic model in which long-term hematopoietic stem cells (LT-HSC) are the base of the hematopoietic system. Clonal dynamics analysis of the hematopoietic system indicate that LT-HSC are not the main contributors of normal hemapoiesis in physiological conditions and the hematopoietic system is mainly maintained by multipotent progenitors (MPPs, hereafter HPC) and LT-HSCs are mostly in a non-active state. The first HSCs emerge from the aorta-gonad and mesonephros (AGM) region along with hematopoietic progenitors (HPC) within hematopoietic clusters. Molecular pathways that determine the HSC fate instead of HPC are still unknown, although inflammatory signaling, including NF-κB has been implicated in the development of HSCs. Here, we identify a chromatin binding function for IκBα (also known as the inhibitor of NF-κB) that is Polycomb repression complex 2 (PRC2)-dependent and specifically determines dormant vs proliferating HSCs from the onset of their emergence in the AGM. We find a specific reduction of LT-HSCs in the IκBα knockout new-born pups. This defect is manifested at the FL stage already, and traceable to the first emerging HSCs in the E11.5 AGM, without affecting the general HPC population. IκBα deficient LT-HSCs express dormancy signature genes, are less proliferative and can robustly respond to activation stimuli such as in vitro culture and serial transplantation. At the molecular level, we find decreased PRC2-dependent H3K27me3 at the promoters of several retinoic acid signaling elements in the IκBα - deficient aortic endothelium and E14.5 FL LT-HSCs. Additionally, IκBα binding itself is found in the promoters of retinoic acid receptors rarα in the AGM, and rarγ in the LT-HSC of FL. Overall, we demonstrate that the retinoic acid pathway is over-activated in the hematopoietic clusters of IκBα-deficient AGMs leading to premature dormancy of LT-HSCs that persists in the FL LT-HSCs.

/pdf/ikba-controls-dormancy-induction-in-hematopoietic-stem-cell-lxraoijg.pdf

Marta Casado-Pelaez

Papers

Single cell cancer epigenetics.

Abstract LB130: Single-cell multiomics analysis of myelodysplastic syndrome predicts clinical response to DNA methylation inhibitor therapy

Targeting lymphoid-derived IL-17 signaling to delay skin aging

IκBα controls dormancy induction in Hematopoietic stem cell development via retinoic acid