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Challenges and Opportunities in Epigenetics

Challenges and Opportunities in Epigenetics

Deichmann, U. (2023)

Abstract

The concept of chromatin as a complex of nucleic acid and proteins in the cell nucleus was developed by cytologists and biochemists in the late 19th century. It was the starting point for biochemical research on DNA and nuclear proteins. Interest in chromatin declined rapidly at the beginning of the 20th century, but a few decades later a new focus on chromatin emerged, which was not only related to its structure, but also to its function in gene regulatory processes in the development of higher organisms. Since the late 20th century, research on chromatin modifications as well as DNA methylation that emerged in the 1970s have also been conducted under the label epigenetics, a term originally introduced for the complex processes between genotype and phenotype during development. These processes – in particular gene regulation – were subsequently scrutinized by molecular biologists.

Research termed epigenetics remained marginal until the end of the 20th century but experienced a rapid rise when heritability was added to its definition. This was accompanied by an increasing diversity in researchers’ understanding and definitions of epigenetics. Epigenetics now includes research on histone and DNA-modifying enzymes, nucleosome remodelers, histone chaperones, chromatin-binding proteins to facilitate transcription factor and polymerase action, and the role of long non-coding RNA and small interfering RNA in transcriptional regulation.

This article highlights the major phases of chromatin and epigenetics research until the present time and illuminates how different scientific contexts changed the relevance and meaning of chromatin from the 19th century. The paper also points to misconceptions and media hype about epigenetics, for example unsupported claims about transgenerational inheritance in humans or questioning of the basic biological principles of gene regulation based on specific regulatory sequences of the genome.

Mehdipour, P. (2023)

Abstract

Successful cancer evolution (CE) relies on the sequential molecular and functional events including 1) telomere; 2) sub-telomere; 3) epigenetic; 4-6) hit-episodes; 7) an innovative cell cycle machinery, as the multi-phase, and 8) chromosomal abnormalities. In this regard, eight available, fundamental/evolutionary and strategic key information (Evolutionary- ID) presented.

Telomere length (TL), has the fundamental role in cancer development, with serious challenges in the clinical managements. Breast cancer and brain tumor are an unresolved problem in Science and Medicine. Besides, an early and translatable diagnostic- prognostic-predictive platform, by considering the targets-ID, is required. Diverse TL in two cases affected with astrocytoma with grade IV, revealed to be 12500 and 15000 bp in tumor, and 10000 and 9000 bp at genomic level. Interestingly, TL is declined in the lymph node, i.e., occurrence of evolution.

Sub-telomeres (STs) through the cellular journey, are the neighboring destination at genomic and somatic level. The evolutionary pattern of STs has not been, routinely, decoded to the personalized clinical managements. The STsequences, are diversely predisposed to variety of environmental factors and play influential role in healthy individuals and the patients. An early detection is available by analysis of the ST- hybridized signals in the biopsy of auxiliary lymph nodes (ALN), and/or by circulating tumor cells (CTCs) into the blood stream. Diverse pattern of signal frequency and intensity in individual chromosomes at both somatic (ALN) and genomic (lymphocytes) levels were remarkable. The most common involved targets included chromosomes 5 and 9, 16 and 19; with diverse intensity at p and q chromosomal arms respectively. These findings have the predisposing, and an initial influence through the patients’ course of disease.

ST- signals, by providing the STs-ID, offer periodical and predictive, indices in cancer screening and therapy.

Furthermore, the complementary, cell cycle protein expression (PE) including Ki67, cyclin D1, and cyclin E, accelerates an early clinical management through the period of disease based on the CTCs.

Epigenetics is the next molecular destination by focusing on the genomic/somatic index, as an evolutionary Epigenetics-ID with its impact on the cancer management. The target panel is Ataxia Telangiectasia mutated gene (ATM) as the molecular marker and an initiator of different cancers.

ATM has remarkable roles, including: 1) in DNA double strand break (DSB), 2) to initiate different types of neoplastic disorders, including cancer, and 3), polymorphism, D1853N as a peridisposing marker by initiating the hit process. The influential characteristics include: family history of neoplastic disorders through the pedigree, the key role of ATM promoter methylation, cooperation of ATM/Rb protein expression, D1853N- marker, telomere length (TL) and the clinico-pathological characteristics in different types of brain tumors, and the environmental factors. Interestingly, TL has an independent influence on the progressive cancer evolution. An early detection by CTCs based on the D1853N/Sub-TL/Cell cycle checkpoints based on the PE assay and molecular test facilitate an early detection and therapy, based on the personalized approach.

By highlighting the preventive insight in Medicine, a brief record on the “Methylation in Chorionic villus samples (CVS)” with aim of an early detective strategy is provided. All nine CVS samples were methylated for the MCPH1 gene. An early detection is possible either through CV sampling or by the circulating CV cells in the maternal blood.


Evolutionary Hit includes: presence of D1853N polymorphism of ATM, as the hit-initiator through an evolutionary and progressive molecular based sequential alterations led to discovery of three-hit hypothesis in a patient affected with astrocytoma. More hits include five, and eight- hit hypotheses in primary breast cancer patients. Such platforms are considered as the individualized model in cancer. The pedigrees and details at the molecular follow-up studies and functional alteration at protein level are available in the provided sections.

Novel strategy of Cell cycle phases in breast cancer is the major intersection for cancer therapy.

The novel cell cycle hypothesis (CCH) highlights the mosaic based of dual and/or multi-phases, as minor clones at single cell level in the breast cancer (BC) -patients, escorted by the normal cell population. Such mosaicism provided an archetypal, unique diagnostic and therapeutic model, by applying different mosaic patterns (MPs) as well as “G1/S, S/G2 and G1/S/G2, and accompanied by normal phases, as a sole including G1, S, and G2 at the single cells level.  

Diagnosis is based on the mode of signal copy numbers (SCN) and the related PE. Interestingly MPs were also unmasked in patients with chronic myelogeneous leukemia and other solid tumors.

Finally, the predisposing/predictive/prognostic/preventive square provides an innovate CDKs inhibitor-based therapy in BC and other cancers.

Personalized base cancer therapy is the confusing procedure and requires the pedigree-based data, personalized, evolutionary based information including molecular and functional at both genomic and somatic, at single cell levelThe target territories comprise cell cycle phases, proteins, Telomere length, telomerase, sub-telomere, and Epigenetics. The aim is directing the cell cycle fundamental forces back to normal, by performing:

1) Applying personalized, single cell-based approach, at molecular, functional level, pedigree analysis, and balancing the micro-/macro-environmental factors, including nutrition.

2) Satisfactory high single cell enumeration based on the FISH and protein expression assays;

3) Decoding the required dosage and combined therapeutic regimens accordingly,

4) Unmasking the cell cycle combined (mosaic) phases including different Cyclins; and

5) Bilateral cooperation between Pharmacology, Medicine, and Cancer Genetics/cell biology.


 Let’s combine the evolutionary-based strategy by translating the personalized data at molecular/ Functional/ Informative, and pedigree-based level to the personalized therapy.

Risso, C., Tsai, D. F., Montoya, S., Jahn, J., & Taylor, J. (2022)

Abstract

The B-cell antigen receptor signaling pathway has been a primary focus in the targeted treatment of B-cell malignancies for the past decade. When aberrantly activated, this pathway initiates a cascade of phosphorylation mediated by several tyrosine kinases, with Bruton’s tyrosine kinase (BTK) being essential among them. Multiple generations of covalent and non-covalent BTK inhibitors have revolutionized therapeutic options for several B-cell lymphomas. However, the use of continuous BTK inhibition is limited by development of resistance resulting from acquired point mutations that allow persistent B-cell receptor signaling. Genomic sequencing of patient samples at disease progression has recently led to the discovery of novel resistance mutations in BTK that result in diminished or absent BTK kinase activity (termed kinase-deficient). However, the mechanisms underlying the potential advantage of kinase-deficient BTK mutations are incompletely understood and still under investigation. In this review, we provide a background of the pathway leading to the development of current therapies that target BTK and review the literature describing kinase-deficient BTK mutations. We propose that BTK inactivating mutations provide an advantage to neoplastic B-lymphocytes in patients with BTK inhibitor resistant B-cell malignancies and highlight potential mechanisms through which BTK kinase-deficient mutations could be acting, either due to differential protein conformation or by behaving as a scaffold for other signaling molecules. Due to the novelty of these mutations and their increasing rate of incidence over the last decade, it is imperative to continue studying BTK kinase deficient mutations across B-cell malignancies and to propose alternate therapies that could target them.

Dubey, S., Dubey, M. J., Ghosh, R., Mitchell, A. J., Chatterjee, S., Das, S., Pandit, A., Ray, B. K., Das, G., & León, J. (2022)

Abstract

Epigenetics, hypothalamic-pituitary axes, environmental and metabolic influences, and transgenerational plasticity govern social behavior. Cognitive research considers the brain’s default mode network (DMN) as a central hub that integrates various cognitive and social processing domains responsible for emotion perception, empathy, theory of mind, and morality. Hence, DMN is regarded as the “social brain.” Upsurge in social turmoil, social anxiety, panic, depression, post-traumatic stress, hoarding, herd behavior, substance and behavioral addictions, sexual abuse, and violence in the time of the COVID-19 pandemic are intricately related to personality traits resulting in disruptive social cognition and social behavior, conceptualized as the result of unsettling and disruption of the functional nexus of the DMN. Considering overt and conspicuous display of neuroticism during the current pandemic, its impact upon modulation of the DMN functional nexus and the DMN itself, and the potential to presage cognitive impairment in the future, the authors caution that an increase in the global burden of dementia may be one of the long-term ramifications of COVID-19. Social behavior, a functional derivative of the DMN, can strikingly affect the functional nexus of DMN and the DMN itself, in a centripetal way via the phenomenon called “Experience-Dependent Plasticity,” with long-term consequences. In this review, we intend to 1) decipher the association between social cognition and social behavior with the DMN, in time of COVID-19; and to 2) discuss the prospective aftermath of disrupted social behavior during the pandemic on modulation/alteration of functional connectomes of DMN or the DMN itself in the time ahead.

Uchiyama, T., Ohkido, I., Okabe, M., & Yamada, T. (2019)

Abstract

Chronic kidney disease (CKD) is a global epidemic and public health crisis, and one-tenth of the world’s population is affected by CKD. In particular, CKD related to cardiovascular disease; therefore, it is important to suppress the progression of CKD. CKD-mineral and bone disorder (CKD-MBD) is not limited to abnormalities in the serum parameters concerning mineral homeostasis; importantly, it is strongly associated with higher rates of both all-cause and cardiovascular-related mortality. Therefore, CKD-MBD immediate countermeasures.

Epigenetics has been recently recognized as an essential mechanism for pathogenesis in many diseases, including kidney diseases. Epigenetic modifications are inherited nuclear characteristics, or molecular changes that can affect gene expression without altering DNA sequences, including DNA methylation, histone modification, and non-coding RNAs. Epigenetic modifications in patients with acute kidney injury (AKI) or CKD are actively undergoing investigation; however, there have been few reports relating epigenetic changes to mineral homeostasis and CKD-MBD, particularly in the text of parathyroid diseases.

In this review, we first describe epigenetic modification and subsequently discuss the roles and mechanisms of epigenetic modification in the pathogeneses of AKI, AKI-to-CKD transition, CKD, and CKD-MBD.