Comparative DNA-methylome and transcriptome analysis reveals heterosis-and polyploidy-associated epigenetic changes in rice

Heterosis and polyploidy have an overwhelming influence on plant evolution.Recently,polyploid rice hybrids have been used to breed new rice varieties because they combine the advantages of both heterosis and polyploidy.In this study,we generated six rice lines:autotetraploid rice hybrids and their autotetraploid parents,diploid donors,and hybrids of the diploid donors.To investigate the molecular mechanism controlling the effects of both hybridization and polyploidization,we performed bisulfite and RNA sequencing on young panicles at the pollen meiosis stage to compare the DNA metabolomes and transcriptomes among the six rice lines.The hybrids lines were hypermethylated compared to their corresponding parents and the autotetraploid lines showed globally increased DNA methylation of their transposable elements compared to the diploid donors.The alteration in DNA methylation level corresponded to the differential gene expressions among the rice genotypes,suggesting that methylation changes induced by polyploidization and hybridization may affect gene expression.Groups of gene candidates were identified that may be associated with heterosis and polyploidy.Our results provide DNA information that can be used to investigate epigenetic modification during heterosis and polyploidy in rice.

Generality and characteristics of genetic and epigenetic changes in newly synthesized allotetraploid wheat lines

Previous studies have shown rapid and extensive genomic However, these studies are based on either a few pre-selected instability associated with early stages of allopolyploidization in wheat. genomic loci or genome-wide analysis of a single plant individual for a given cross combination, thus making the extent and generality of the changes uncertain. To further study the generality and characteristics of allopolyploidization-induced genomic instability in wheat, we investigated genetic and epigenetic changes from a genome-wide perspective （by using the AFLP and MSAP markers） in four sets of newly synthesized allotetraploid wheat lines with various genome constitutions, each containing three randomly chosen individual plants at the same generation. We document that although general chromosomal stability was characteristic of all four sets of allotetraploid wheat lines, genetic and epigenetic changes at the molecular level occurred in all these plants, with both kinds of changes classifiable into two distinct categories, i.e., stochastic and directed. The abundant type of genetic change is loss of parental bands while the prevalent cytosine methylation pattern alteration is hypermethylation at the CHG sites. Our results have extended previous studies regarding allopolyploidization-induced genomic dynamics in wheat by demonstrafing the generality of both genetic and epigenetic changes associated with multiple nascent allotetraploid wheat lines, and providing novel insights into the characteristics of the two kinds of induced genomic instabilities.

Genetic heterogeneity of colorectal cancer and the microbiome

In 2020,the International Agency for Research on Cancer and the World Health Organization's GLOBOCAN database ranked colorectal cancer(CRC)as the third most common cancer in the world.Most cases of CRC(>95%)are sporadic and develop from colorectal polyps that can progress to intramucosal carcinoma and CRC.Increasing evidence is accumulating that the gut microbiota can play a key role in the initiation and progression of CRC,as well as in the treatment of CRC,acting as an important metabolic and immunological regulator.Factors that may determine the microbiota role in CRC carcinogenesis include inflammation,changes in intestinal stem cell function,impact of bacterial metabolites on gut mucosa,accumulation of genetic mutations and other factors.In this review,I discuss the major mechanisms of the development of sporadic CRC,provide detailed characteristics of the bacteria that are most often associated with CRC,and analyze the role of the microbiome and microbial metabolites in inflammation initiation,activation of proliferative activity in intestinal epithelial and stem cells,and the development of genetic and epigenetic changes in CRC.I consider longterm studies in this direction to be very important,as they open up new opportunities for the treatment and prevention of CRC.

Hepatocellular carcinoma risk after viral response in hepatitis C virus-advanced fibrosis: Who to screen and for how long?

Hepatitis C virus(HCV)chronic infection is associated with fibrosis progression,end-stage liver complications and HCC.Not surprisingly,HCV infection is a leading cause of liver-related morbidity and mortality worldwide.After sustained virological response(SVR),the risk of developing hepatocellular carcinoma is not completely eliminated in patients with established cirrhosis or with advanced fibrosis.Therefore,lifelong surveillance is currently recommended.This strategy is likely not universally cost-effective and harmless,considering that not all patients with advanced fibrosis have the same risk of developing HCC.Factors related to the severity of liver disease and its potential to improve after SVR,the molecular and epigenetic changes that occur during infection and other associated comorbidities might account for different risk levels and are likely essential for identifying patients who would benefit from screening programs after SVR.Efforts to develop predictive models and risk calculators,biomarkers and genetic panels and even deep learning models to estimate the individual risk of HCC have been made in the direct-acting antiviral agents era,when thousands of patients with advanced fibrosis and cirrhosis have reached SVR.These tools could help to identify patients with very low HCC risk in whom surveillance might not be justified.In this review,factors affecting the probability of HCC development after SVR,the benefits and risks of surveillance,suggested strategies to estimate individualized HCC risk and the current evidence to recommend lifelong surveillance are discussed.

Hypermethylation of CpG island in O^6-methylguanine-DNA methyltransferase gene was associated with K-rasG to A mutation in colorectal tumor

AIM: To investigate the functions of promoter hypermethylation of O6-methylguanine-DNA methyltransferase (MGMT) gene in colorectal tumorigenesis and progression.METHODS: The promoter hypermethylation of MGMT gene was detected in 27 sporadic colorectal adenomas,62 sporadic colorectal carcinomas and 20 normal colorectal mucosa tissues by methylation-specific PCR. At the same time, the expression of MGMT protein was carried out in the same samples using immunohistochemistry. Mutantallele-specific amplification was used to detect K-rasG to A point mutation in codon 12.RESULTS: None of the normal colorectal mucosa tissues showed methylated bands. Promoter hypermethylation was detected in 40.7% (11 of 27) of adenomas and 43.5% (27 of 62) of carcinomas. MGMT proteins were expressed in nucleus and cytoplasm of normal colorectal mucosa tissues. Loss of MGMT expression was found in 22.2% (6 of 27) of adenomas and 45.2% (28 of 62) of carcinomas. The difference between them was significant (P = 0.041). In the 6 adenomas and 28 carcinomas losing MGMT expression, 5 and 24 cases presented methylation,respectively (P = 0.027, P＜0.001). Thirteen of the 19 colorectal tumors with K-rasG to A point mutation in codon 12 had methylated MGMT(P = 0.011). The frequencies of K-rasG to A point mutation were 35.3% (12 of 34) and 12.7% (7 of 55) in tumors losing MGMT expression and with normal expression, respectively.CONCLUSION: Promoter hypermethylation and loss of expression of MGMT gene were common events in colorectal tumorigenesis, and loss of expression of MGMT occurs more frequently in carcinomas than in adenomas in sporadic patients. Hypermethylation of the CpG island of MGMT gene was associated with loss of MGMT expression and K-ras G to A point mutation in colorectal tumor. The frequency of K-ras G to A point mutation was increased in tumors losing MGMT expression. It suggests that epigenetic inactivation of MGMT plays an important role in colorectal neoplasia.

Why stem/progenitor cells lose their regenerative potential

Nowadays,it is clear that adult stem cells,also called as tissue stem cells,play a central role to repair and maintain the tissue in which they reside by their selfrenewal ability and capacity of differentiating into distinct and specialized cells.As stem cells age,their renewal ability declines and their capacity to maintain organ homeostasis and regeneration is impaired.From a molecular perspective,these changes in stem cells properties can be due to several types of cell intrinsic injury and DNA aberrant alteration(i.e epigenomic profile)as well as changes in the tissue microenviroment,both into the niche and by systemic circulating factors.Strikingly,it has been suggested that aging-induced deterioration of stem cell functions may play a key role in the pathophysiology of the various agingassociated disorders.Therefore,understanding how resident stem cell age and affects near and distant tissues is fundamental.Here,we examine the current knowledge about aging mechanisms in several kinds of adult stem cells under physiological and pathological conditions and the principal aging-related changes in number,function and phenotype that determine the loss of tissue renewal properties.Furthermore,we examine the possible cell rejuvenation strategies.Stem cell rejuvenation may reverse the aging phenotype and the discovery of effective methods for inducing and differentiating pluripotent stem cells for cell replacement therapies could open up new possibilities for treating age-related diseases.

Innate immune responses in RNA viral infection

RNA viruses cause a multitude of human diseases,including several pandemic events in the past century.Upon viral invasion,the innate immune system responds rapidly and plays a key role in activating the adaptive immune system.In the innate immune system,the interactions between pathogen-associated molecular patterns and host pattern recognition receptors activate multiple signaling pathways in immune cells and induce the production of pro-inflammatory cytokines and interferons to elicit antiviral responses.Macrophages,dendritic cells,and natural killer cells are the principal innate immune components that exert antiviral activities.In this review,the current understanding of innate immunity contributing to the restriction of RNA viral infections was briefly summarized.Besides the main role of immune cells in combating viral infection,the intercellular transfer of pathogen and host-derived materials and their epigenetic and metabolic interactions associated with innate immunity was discussed.This knowledge provides an enhanced understanding of the innate immune response to RNA viral infections in general and aids in the preparation for the existing and next emerging viral infections.

Three-dimensional regulation of transcription

Cells can adapt to environment and development by reconstructing their transcriptional networks to regulate diverse cellular processes without altering the underly- ing DNA sequences. These alterations, namely epige- netic changes, occur during cell division, differentiation and cell death. Numerous evidences demonstrate that epigenetic changes are governed by various types of determinants, including DNA methylation patterns, his- tone posttranslational modification signatures, histone variants, chromatin remodeling, and recently discovered chromosome conformation characteristics and non- coding RNAs （ncRNAs）. Here, we highlight recent efforts on how the two latter epigenetic factors participate in the sophisticated transcriptional process and describe emerging techniques which permit us to uncover and gain insights into the fascinating genomic regulation.