Transcriptional noise is proposed to participate in cell fate changes, but contributions to mammalian cell differentiation systems, including cancer, remain associative. Cancer evolution is driven by genetic variability, with modulatory or contributory participation of epigenetic variants. Accumulation of epigenetic variants enhances transcriptional noise, which can facilitate cancer cell fate transitions. Acute myeloid leukaemia (AML) is an aggressive cancer with strong epigenetic dependencies, characterized by blocked differentiation. It constitutes an attractive model to probe links between transcriptional noise and malignant cell fate regulation. Gcn5/KAT2A is a classical epigenetic transcriptional noise regulator. Its loss increases transcriptional noise and modifies cell fates in stem and AML cells. By reviewing the analysis of KAT2A-depleted pre-leukaemia and leukaemia models, I discuss that the net result of transcriptional noise is diversification of cell fates secondary to alternative transcriptional programmes. Cellular diversification can enable or hinder AML progression, respectively, by differentiation of cell types responsive to mutations, or by maladaptation of leukaemia stem cells. KAT2A-dependent noise-responsive genes participate in ribosome biogenesis and KAT2A loss destabilizes translational activity. I discuss putative contributions of perturbed translation to AML biology, and propose KAT2A loss as a model for mechanistic integration of transcriptional and translational control of noise and fate decisions. This article is part of a discussion meeting issue \'Causes and consequences of stochastic processes in development and disease\'.

Objective: The clinical and genetic characteristics of a child with inherited bone marrow failure syndrome as prominent clinical manifestations and special facial features were analyzed, and the etiology and mechanism were explored in, combination with clinical practice. Methods: Blood samples and clinical information were collected separately from the proband and their biological parents. The pathogenic variant was verified using next-generation sequencing technology screening, and the candidate variable sites were confirmed by using Sanger sequencing among all members of the family. Results: A heterozygous nonsense mutation in exon 17 of KAT6A (NM_006766), c.4177G > T (p.E1393*) predicted to cause truncation within the acidic domain of the protein was identified. Pedigree analysis did not reveal any variation in this locus between the proband\'s father and mother. No report of this pathogenic variant was found in a literature search of domestic and foreign databases, indicating that it is a newly discovered mutation. According to the guidelines of the American College of Medical Genetics, the variation was preliminarily determined to be a pathogenic. The newly discovered heterozygous mutation in KAT6A may be the cause of the disease in this child. Additionally, inherited bone marrow failure syndrome is a prominent manifestation. Conclusion: This study not only provides us with an in-depth understanding of this rare syndrome but also deepens our understanding of the function of KAT6A.

暂无摘要。

Background and Aims: Previous work has shown the association between blood-based methylation of coagulation factor II receptor-like 3 gene (F2RL3) and cardiovascular mortality in Caucasians. However, the diagnostic value of F2RL3 methylation for CHD is still unknown. The aim of our study was to evaluate the association between blood-based F2RL3 methylation and the risk of CHD in the Chinese population. Methods: The methylation level of F2RL3 was quantified by mass spectrometry in a case-control study with 180 CHD cases and 184 controls. The association between F2RL3 methylation intensity and CHD was assessed by logistic regression models, controlling confounding factors. Results: The hypomethylation in F2RL3_A amplicon was significantly associated with CHD (odds ratio (ORs) per -10% methylation: 1.22-1.42, p < 0.035 for six out of seven CpG loci). Specifically, this significant association was observed in elderly CHD patients (≥60 years), myocardial infarction (MI) patients, heart failure patients and the patients with minor to medium cardiac function impairment (NYHA Ⅰ&Ⅱ CHD cases) (ORs per -10% methylation: 1.35-1.58, 1.32-2.00, 1.29-1.43, 1.25-1.44; p < 0.024, 0.033, 0.035, 0.025, respectively). However, F2RL3_B CpG sites showed no or very weak association with CHD. The combination of F2RL3_A_CpG_1 and F2RL3_A_CpG_3 methylation levels could efficiently discriminate CHD, MI, heart failure, NYHA I&II CHD, and elderly CHD patients from controls (area under curve (AUC) = 0.75, 0.79, 0.75, 0.76, and 0.82, respectively). Conclusion: We propose blood-based F2RL3 methylation as a potential biomarker for CHD, especially for people with older age or with the status of MI. The combination of F2RL3 methylation and conventional risk factors might be an approach to evaluate CHD at early stage.

UNASSIGNED: THE CASE FOR EPIGENETIC ALTERATIONS The mechanisms of the long-term impacts of exposure to chemical substances remain poorly understood. While genotoxic and mutagenic effects have been well characterized, epigenetic mechanisms such as DNA methylation could also account for the delayed effects of exposures. It is in the case of tobacco that the strongest arguments for a role of these mechanisms have been obtained in human populations. This text presents recent data on this issue demonstrating the plausibility of epigenetic mechanisms to explain the persistence of biological signals long after stopping exposure.
TABAC ET MÉTHYLATION DE L’ADN : UN EXEMPLE D’ALTÉRATION ÉPIGÉNÉTIQUE Les mécanismes des impacts à long terme des expositions à des substances chimiques demeurent assez mal connus. Si les effets génotoxiques et mutagènes ont été bien caractérisés, les mécanismes épigénétiques, comme la méthylation de l’ADN, pourraient aussi rendre compte des effets différés des expositions : dans les populations humaines, les arguments les plus solides ont été obtenus dans le cas du tabac. Les données récentes sur ce sujet démontrent la plausibilité des mécanismes épigénétiques pour expliquer la persistance de signaux biologiques longtemps après l’arrêt de l’exposition.

Autosomal dominant pseudohypoparathyroidism 1B (AD-PHP1B) is a rare endocrine and imprinted disorder. The objective of this study is to clarify the imprinted regulation of the guanine nucleotide binding-protein α-stimulating activity polypeptide 1 (GNAS) cluster in the occurrence and development of AD-PHP1B based on animal and clinical patient studies. The methylation-specific multiples ligation-dependent probe amplification (MS-MLPA) was conducted to detect the copy number variation in syntaxin-16 (STX16) gene and methylation status of the GNAS differentially methylated regions (DMRs). Long-range PCR was used to confirm deletion at STX16 gene. In the first family, DNA analysis of the proband and proband\'s mother revealed an isolated loss of methylation (LOM) at exon A/B and a 3.0 kb STX16 deletion. The patient\'s healthy grandmother had the 3.0 kb STX16 deletion but no epigenetic abnormality. The patient\'s healthy maternal aunt showed no genetic or epigenetic abnormality. In the second family, the analysis of long-range PCR revealed the 3.0 kb STX16 deletion for the proband but not her children. In this study, 3.0 kb STX16 deletion causes isolated LOM at exon A/B in two families, which is the most common genetic mutation of AD-PHP1B. The deletion involving NESP55 or AS or genomic rearrangements of GNAS can also result in AD-PHP1B, but it\'s rare. LOM at exon A/B DMR is prerequisite methylation defect of AD-PHP1B. STX16 and NESP55 directly control the imprinting at exon A/B, while AS controls the imprinting at exon A/B by regulating the transcriptional level of NESP55.

Over the last several decades, several lines of evidence have shown that epigenetic modifications modulate phenotype and mediate an organism\'s response to environmental stimuli. Plant DNA is normally highly methylated, although notable differences exist between species. Many biomolecular techniques based on PCR have been developed to analyse DNA methylation status, however a qualitative leap was made with the advent of next-generation sequencing (NGS). In the case of large, repetitive, or not-yet-sequenced genomes characterised by a high level of DNA methylation, the NGS analysis of bisulphite pre-treated DNA is expensive and time consuming, and moreover, in some cases data analysis is a major challenge. Methylation-sensitive amplification polymorphism (MSAP) analysis is a highly effective method to study DNA methylation. The method is based on the comparison of double DNA digestion profiles (EcoRI-HpaII and EcoRI-MspI) to reveal methylation pattern variations. These are often attributable to pedoclimatic and stress conditions which affect all organisms during their lifetime. In our study, five white poplar (Populus alba L.) specimens were collected from different monoclonal stands in the Maltese archipelago, and their DNA was processed by means of an innovative approach where MSAP analysis was followed by NGS. This allowed us to identify genes that were differentially methylated among the different specimens and link them to specific biochemical pathways. Many differentially methylated genes were found to encode transfer RNAs (tRNAs) related to photosynthesis or light reaction pathways. Our results clearly demonstrate that this combinatorial method is suitable for epigenetic studies of unsequenced genomes like P. alba (at the time of study), and to identify epigenetic variations related to stress, probably caused by different and changing pedoclimatic conditions, to which the poplar stands have been exposed.

Respiratory syncytial virus (RSV) is the leading viral pathogen associated with acute lower respiratory tract infection and hospitalization in children < 5 years of age worldwide. While there are known clinical risk factors for severe RSV infection, the majority of those hospitalized are previously healthy infants. There is consequently an unmet need to identify biomarkers that predict host response, disease severity, and sequelae. The primary objective is to identify biomarkers of severe RSV acute respiratory tract infection (ARTI) in infants. Secondary objectives include establishing biomarkers associated with respiratory sequelae following RSV infection and characterizing the viral load, RSV whole-genome sequencing, host immune response, and transcriptomic, proteomic, metabolomic and epigenetic signatures associated with RSV disease severity. Six hundred thirty infants will be recruited across 3 European countries: the Netherlands, Spain, and the United Kingdom. Participants will be recruited into 2 groups: (1) infants with confirmed RSV ARTI (includes upper and lower respiratory tract infections), 500 without and 50 with comorbidities; and (2) 80 healthy controls. At baseline, participants will have nasopharyngeal, blood, buccal, stool, and urine samples collected, plus complete a questionnaire and 14-day symptom diary. At convalescence (7 weeks ± 1 week post-ARTI), specimen collection will be repeated. Laboratory measures will be correlated with symptom severity scores to identify corresponding biomarkers of disease severity.
NCT03756766.

Recent studies implicate mitochondrial dysfunction in the development and progression of numerous chronic diseases, which may be partially due to modifications in mitochondrial DNA (mtDNA). There is also mounting evidence that epigenetic modifications to mtDNA may be an additional layer of regulation that controls mitochondrial biogenesis and function. Several environmental factors (eg, smoking, air pollution) have been associated with altered mtDNA methylation in a handful of mechanistic studies and in observational human studies. However, little is understood about other environmental contaminants that induce mtDNA epigenetic changes. Numerous environmental toxicants are classified as endocrine disrupting chemicals (EDCs). Beyond their actions on hormonal pathways, EDC exposure is associated with elevated oxidative stress, which may occur through or result in mitochondrial dysfunction. Although only a few studies have assessed the impacts of EDCs on mtDNA methylation, the current review provides reasons to consider mtDNA epigenetic disruption as a mechanism of action of EDCs and reviews potential limitations related to currently available evidence. First, there is sufficient evidence that EDCs (including bisphenols and phthalates) directly target mitochondrial function, and more direct evidence is needed to connect this to mtDNA methylation. Second, these and other EDCs are potent modulators of nuclear DNA epigenetics, including DNA methylation and histone modifications. Finally, EDCs have been shown to disrupt several modulators of mtDNA methylation, including DNA methyltransferases and the mitochondrial transcription factor A/nuclear respiratory factor 1 pathway. Taken together, these studies highlight the need for future research evaluating mtDNA epigenetic disruption by EDCs and to detail specific mechanisms responsible for such disruptions.

Chronic arsenic toxicity has become a global concern due to its adverse pathophysiological outcome and carcinogenic potential. It is already established that arsenic induced reactive oxygen species alters mitochondrial functionality. Major regulatory genes for mitochondrial biogenesis, i.e., PGC1α, Tfam, NRF1and NRF2 are located in the nucleus. As a result, mitochondria-nucleus crosstalk is crucial for proper mitochondrial function. This previous hypothesis led us to investigateinvolvement of epigenetic alteration behindenhanced mitochondrial biogenesis in chronic arsenic exposure. An extensive case-control study was conducted with 390 study participants (unexposed, exposed without skin lesion, exposed with skin lesion and exposed skin tumour) from highly arsenic exposed areas ofWest Bengal, India. Methylation specific PCRrevealed significant promoter hypomethylation oftwo key biogenesis regulatory genes, PGC1αandTfam in arsenic exposed individuals and also in skin tumour tissues. Linear regression analysis indicated significant negative correlation between urinary arsenic concentration and promoter methylation status. Increased expression of biogenesis regulatory genes wasobtained by quantitative real-time PCR analysis. Moreover, altered mitochondrial fusion-fission regulatory gene expression was also observed in skin tumour tissues. miR663, having tumour suppressor gene like function was known to be epigenetically regulated through mitochondrial retrograde signal. Promoter hypermethylation with significantly decreased expression of miR663 was found in skin cancer tissues compared to non-cancerous control tissue. In conclusion, results indicated crucial role of epigenetic alteration in arsenic induced mitochondrial biogenesis and arsenical skin carcinogenesis for the first time. However, further mechanistic studies are necessary for detailed understanding of mitochondria-nucleus crosstalk in arsenic perturbation.