Non-coding RNAs and chromatin: key epigenetic factors from spermatogenesis to transgenerational inheritance

Cellular fate and gene expression patterns are modulated by different epigenetic factors including non-coding RNAs (ncRNAs) and chromatin organization. Both factors are dynamic throughout male germ cell differentiation on the seminiferous tubule, despite the transcriptional inactivation in the last stages of spermatogenesis. Sperm maturation during the caput-to-cauda transit on the epididymis involves changes in chromatin organization and the soma-to-germ line transference of ncRNAs that are essential to obtain a functional sperm for fertilization and embryo development. Here, the male environment (diseases, drugs, mental stress) is crucial to modulate these epigenetic factors throughout sperm maturation, affecting the corresponding offspring. Paternal transgenerational inheritance has been directly related to sperm epigenetic changes, most of them associated with variations in the ncRNA content and chromatin marks. Our aim is to give an overview about how epigenetics, focused on ncRNAs and chromatin, is pivotal to understand spermatogenesis and sperm maturation, and how the male environment impacts the sperm epigenome modulating the offspring gene expression pattern.

Epigenetics recording varied environment and complex cell events represents the origin of cellular aging / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

Although a relationship between epigenetics and aging phenotypic changes has been established, a theoretical explanation of the intrinsic connection between the epigenetics and aging is lacking. In this essay, we propose that epigenetic recording of varied cell environment and complex history could be an origin of cellular aging. Through epigenetic modifications, the environment and historical events can induce the chromatin template into an activated or repressive accessible structure, thereby shaping the DNA template into a spectrum of chromatin states. The inner nature of diversity and conflicts born by the cell environment and its historical events are hence recorded into the chromatin template. This could result in a dissipated spectrum of the chromatin state and chaos in overall gene expression. An unavoidable degradation of epigenome entropy, similar to Shannon entropy, would be consequently induced. The resultant disorder in epigenome, characterized by corrosion of epigenome entropy as reflected in chromatin template, can be stably memorized and propagated through cell division. Furthermore, the hysteretic nature of epigenetics responding to the emerging environment could exacerbate the degradation of epigenome entropy. As well as stochastic errors, we propose that outside entropy (or chaos) derived from the varied environment and complex cell history, gradually input and imprinted into the chromatin via epigenetic modifications, would lead inevitably to cellular aging, the extent of which could be aggravated by hysteresis of epigenetics without error erasing and correction.

Epigenetics recording varied environment and complex cell events represents the origin of cellular aging / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

Although a relationship between epigenetics and aging phenotypic changes has been established, a theoretical explanation of the intrinsic connection between the epigenetics and aging is lacking. In this essay, we propose that epigenetic recording of varied cell environment and complex history could be an origin of cellular aging. Through epigenetic modifications, the environment and historical events can induce the chromatin template into an activated or repressive accessible structure, thereby shaping the DNA template into a spectrum of chromatin states. The inner nature of diversity and conflicts born by the cell environment and its historical events are hence recorded into the chromatin template. This could result in a dissipated spectrum of the chromatin state and chaos in overall gene expression. An unavoidable degradation of epigenome entropy, similar to Shannon entropy, would be consequently induced. The resultant disorder in epigenome, characterized by corrosion of epigenome entropy as reflected in chromatin template, can be stably memorized and propagated through cell division. Furthermore, the hysteretic nature of epigenetics responding to the emerging environment could exacerbate the degradation of epigenome entropy. As well as stochastic errors, we propose that outside entropy (or chaos) derived from the varied environment and complex cell history, gradually input and imprinted into the chromatin via epigenetic modifications, would lead inevitably to cellular aging, the extent of which could be aggravated by hysteresis of epigenetics without error erasing and correction.

Comparison of the phenolic contents and epigenetic and genetic variability of wild and cultivated watercress (Rorippa nasturtium var. aquaticum L.)

Background: Epigenetic modifications are key factors modulating the expression of genes involved in the synthesis of phytochemicals. The knowledge of plant epigenetic and genetic variations can contribute to enhance the production of bioactive compounds. These issues have been little explored thus far in Rorippa nasturtium var. aquaticum L. (watercress), an edible and medicinal plant. The aim of the current study was to determine and compare the phenolic composition and epigenetic and genetic variations between wild and cultivated watercress. Results: Significant differences were found in the quantitative phenolic composition between wild and cultivated watercress. The eight primer combinations used in the methylation-sensitive amplification polymorphism (MSAP) method revealed different epigenetic status for each watercress type, the cultivated one being the most epigenetically variable. The genetic variability revealed by the EcoRI/MspI amplification profile and also by eight inter-simple sequence repeat (ISSR) primers was different between the two types of watercress. The results of the Mantel test showed that the correlation between genetic and epigenetic variations has diminished in the cultivated type. Cluster analyses showed that the epigenetic and genetic characterizations clearly discriminated between wild and cultivated watercress. Conclusions: Relevant chemical, epigenetic, and genetic differences have emerged between wild and cultivated watercress. These differences can contribute to fingerprint and develop quality control tools for the integral and safety use and the commercialization of watercress. The richness of epialleles could support the development of tools to manipulate the watercress epigenome to develop high bioproduct­producing cultivars

Finding clues to the riddle of sex determination in zebrafish.

How sex is determined has been one of the most intriguing puzzles in biology since antiquity. Although a fundamental process in most metazoans, there seems to be myriad of ways in which sex can be determined – from genetic to environmental sex determination. This variation is limited mainly to upstream triggers with the core of sex determination pathway being conserved. Zebrafish has gained prominence as a vertebrate model system to study development and disease. However, very little is known about its primary sex determination mechanism. Here we review our current understanding of the sex determination in zebrafish. Zebrafish lack identifiable heteromorphic sex chromosomes and sex is determined by multiple genes, with some influence from the environment. Recently, chromosome 4 has been identified as sex chromosome along with few sex-linked loci on chromosomes 5 and 16. The identities of candidate sex-linked genes, however, have remained elusive. Sex in zebrafish is also influenced by the number of meiotic oocytes in the juvenile ovary, which appear to instruct retention of the ovarian fate. The mechanism and identity of this instructive signal remain unknown. We hypothesize that sex in zebrafish is a culmination of combinatorial effects of the genome, germ cells and the environment with inputs from epigenetic factors translating the biological meaning of this interaction.

Genomics in Alzheimer’s disease / 国际药学研究杂志

Alzheimer’s disease AD is a major form of neurodegenerative disease. Due to the lack of effective treatment for AD, drug discovery is imminent, and genomics has become a driving force for the drug discovery. Genomic studies of AD involve several aspects, such as large-scale studies on the genetic risk, brain transcriptome studies, and epigenetic studies. Notable progress has been made in genomic studies of AD, which has facilitated the drug discovery. In the meantime, biomarkers for early diagnosis including those from peripheral blood have emerged as a major research topic because early detection and intervention are the prominent task for the moment. Research progress in this field will be briefly reviewed. Because of the vast heterogeneity in AD pathogenesis, genomics will also provide strong support for precision medicine in the future.

Genomics in Alzheimer′s disease / 国际药学研究杂志

Alzheimer′s disease(AD)is a major form of neurodegenerative disease. Due to the lack of effective treatment for AD,drug discovery is imminent,and genomics has become a driving force for the drug discovery. Genomic studies of AD involve sever?al aspects,such as large-scale studies on the genetic risk,brain transcriptome studies,and epigenetic studies. Notable progress has been made in genomic studies of AD,which has facilitated the drug discovery. In the meantime,biomarkers for early diagnosis includ?ing those from peripheral blood have emerged as a major research topic because early detection and intervention are the prominent task for the moment. Research progress in this field will be briefly reviewed. Because of the vast heterogeneity in AD pathogenesis ,genom?ics will also provide strong support for precision medicine in the future.

Embedding the Future of Regenerative Medicine into the Open Epigenomic Landscape of Pluripotent Human Embryonic Stem Cells.

It has been recognized that pluripotent human embryonic stem cells (hESCs) must be transformed into fate-restricted derivatives before use for cell therapy. Realizing the therapeutic potential of pluripotent hESC derivatives demands a better understanding of how a pluripotent cell becomes progressively constrained in its fate options to the lineages of tissue or organ in need of repair. Discerning the intrinsic plasticity and regenerative potential of human stem cell populations reside in chromatin modifications that shape the respective epigenomes of their derivation routes. The broad potential of pluripotent hESCs is defined by an epigenome constituted of open conformation of chromatin mediated by a pattern of Oct-4 global distribution that corresponds genome-wide closely with those of active chromatin modifications. Dynamic alterations in chromatin states correlate with lossof- Oct4-associated hESC differentiation. The epigenomic transition from pluripotence to restriction in lineage choices is characterized by genome-wide increases in histone H3K9 methylation that mediates global chromatin-silencing and somatic identity. Human stem cell derivatives retain more open epigenomic landscape, therefore, more developmental potential for scale-up regeneration, when derived from the hESCs in vitro than from the CNS tissue in vivo. Recent technology breakthrough enables direct conversion of pluripotent hESCs by small molecule induction into a large supply of lineage-specific neuronal cells or heart muscle cells with adequate capacity to regenerate neurons and contractile heart muscles for developing safe and effective stem cell therapies. Nuclear translocation of NAD-dependent histone deacetylase SIRT1 and global chromatin silencing lead to hESC cardiac fate determination, while silencing of pluripotenceassociated hsa-miR-302 family and drastic up-regulation of neuroectodermal Hox miRNA hsa-miR-10 family lead to hESC neural fate determination. These recent studies place global chromatin dynamics as central to tracking the normal pluripotence and lineage progression of hESCs. Embedding lineage-specific genetic and epigenetic developmental programs into the open epigenomic landscape of pluripotent hESCs offers a new repository of human stem cell therapy derivatives for the future of regenerative medicine.

Novel insights into the genetic and epigenetic paternal contribution to the human embryo

The integrity of the sperm genome and epigenome are critical for normal embryonic development. The advent of assisted reproductive technology has led to an increased understanding of the role of sperm in fertilization and embryogenesis. During fertilization, the sperm transmits not only nuclear DNA to the oocyte but also activation factor, centrosomes, and a host of messenger RNA and microRNAs. This complex complement of microRNAs and other non-coding RNAs is believed to modify important post-fertilization events. Thus, the health of the sperm genome and epigenome is critical for improving assisted conception rates and the birth of healthy offspring.

The central role of RNA in the genetic programming of complex organisms

Notwithstanding lineage-specific variations, the number and type of protein-coding genes remain relatively static across the animal kingdom. By contrast there has been a massive expansion in the extent of genomic non-proteincoding sequences with increasing developmental complexity. These non-coding sequences are, in fact, transcribed in a regulated manner to produce large numbers of large and small non-protein-coding RNAs that control gene expression at many levels including chromatin architecture, post-transcriptional processing and translation. Moreover, many RNAs are edited, especially in the nervous system, which may be the basis of epigenome-environment interactions and the function of the brain.

Apesar das variações linhagem-específicas, o número e tipo de genes codificadores de proteínas permanecem relativamente estáticos no reino animal. Em contraste, houve uma expansão maciça da quantidade de sequências genômicas não-codificadoras de proteínas com o aumento da complexidade do desenvolvimento. Essas sequências não codificadoras são, de fato, transcritas de maneira regulada para produzirem numerosos RNAs grandes e pequenos não-codificadores de proteínas que controlam a expressão de genes em vários níveis, incluindo a arquitetura da cromatina, o processamento pós-transcricional e a tradução. Além disso, muitos RNAs são editados, especialmente no sistema nervoso, o que pode ser a base de interações epigenoma-ambiente e a função do cérebro.