Higher rates of autism and attention deficit/hyperactivity disorder in American children:Are food quality issues impacting epigenetic inheritance?

In the United States,schools offer special education services to children who are diagnosed with a learning or neurodevelopmental disorder and have difficulty meeting their learning goals.Pediatricians may play a key role in helping children access special education services.The number of children ages 6-21 in the United States receiving special education services increased 10.4%from 2006 to 2021.Children receiving special education services under the autism category increased 242%during the same period.The demand for special education services for children under the developmental delay and other health impaired categories increased by 184%and 83%respectively.Although student enrollment in American schools has remained stable since 2006,the percentage distribution of children receiving special education services nearly tripled for the autism category and quadrupled for the developmental delay category by 2021.Allowable heavy metal residues remain persistent in the American food supply due to food ingredient manufacturing processes.Numerous clinical trial data indicate heavy metal exposures and poor diet are the primary epigenetic factors responsible for the autism and attention deficit hyperactivity disorder epidemics.Dietary heavy metal exposures,especially inorganic mercury and lead may impact gene behavior across generations.In 2021,the United States Congress found heavy metal residues problematic in the American food supply but took no legislative action.Mandatory health warning labels on select foods may be the only way to reduce dietary heavy metal exposures and improve child learning across generations.

Mechanisms of chromatin-based epigenetic inheritance

Multi-cellular organisms such as humans contain hundreds of cell types that share the same genetic information(DNA sequences),and yet have different cellular traits and functions.While how genetic information is passed through generations has been extensively characterized,it remains largely obscure how epigenetic information encoded by chromatin regulates the passage of certain traits,gene expression states and cell identity during mitotic cell divisions,and even through meiosis.In this review,we will summarize the recent advances on molecular mechanisms of epigenetic inheritance,discuss the potential impacts of epigenetic inheritance during normal development and in some disease conditions,and outline future research directions for this challenging,but exciting field.

Nucleosome assembly and epigenetic inheritance

In eukaryotic cells,histones are packaged into octameric core particles with DNA wrapping around to form nucleosomes,which are the basic units of chromatin(Kornberg and Thomas,1974).Multicellular organisms utilise chromatin marks to translate one single genome into hundreds of epigenomes for their corresponding cell types.Inheritance of epigenetic status is critical for the maintenance of gene expression profile during mitotic cell divisions(Allis et al.,2006).During S phase,canonical histones are deposited onto DNA in a replication-coupled manner(Allis et al.,2006).To understand how dividing cells overcome the dilution of epigenetic marks after chromatin duplication,DNA replication coupled(RC)nucleosome assembly has been of great interest.In this review,we focus on the potential influence of RC nucleosome assembly processes on the maintenance of epigenetic status.

DNA replication components as regulators of epigenetic inheritance---lesson from fission yeast centromere

Genetic information stored in DNA is accurately copied and transferred to subsequent generations through DNA replication. This process is accomplished through the concerted actions of highly conserved DNA replication components. Epigenetic information stored in the form of histone modifications and DNA methylation, constitutes a second layer of regulatory information important for many cellular processes, such as gene expression regulation, chromatin organization, and genome stabil- ity. During DNA replication, epigenetic information must also be faithfully transmitted to subsequent generations. How this monumental task is achieved remains poorly understood. In this review, we will discuss recent advances on the role of DNA replication components in the inheritance of epigenetic marks, with a particular focus on epigenetic regulation in fission yeast. Based on these findings, we propose that specific DNA replication components function as key regulators in the replication of epigenetic information across the genome.

Paternal environmental exposure-induced spermatozoal small noncoding RNA alteration meditates the intergenerational epigenetic inheritance of multiple diseases

Studies of human and mammalian have revealed that environmental exposure can affect paternal health conditions as well as those of the offspring.However,studies that explore the mechanisms that meditate this transmission are rare.Recently,small noncoding RNAs(sncRNAs)in sperm have seemed crucial to this transmission due to their alteration in sperm in response to environmental exposure,and the methodology of microinjection of isolated total RNA or sncRNAs or synthetically identified sncRNAs gradually lifted the veil of sncRNA regulation during intergenerational inheritance along the male line.Hence,by reviewing relevant literature,this study intends to answer the following research concepts:(1)paternal environmental factors that can be passed on to offspring and are attributed to spermatozoal sncRNAs,(2)potential role of paternal spermatozoal sncRNAs during the intergenerational inheritance process,and(3)the potential mechanism by which spermatozoal sncRNAs meditate intergenerational inheritance.In summary,increased attention highlights the hidden wonder of spermatozoal sncRNAs during intergenerational inheritance.Therefore,in the future,more studies should focus on the origin of RNA alteration,the target of RNA regulation,and how sncRNA regulation during embryonic development can be sustained even in adult offspring.

Environmentally Induced Paternal Epigenetic Inheritance and Its Effects on Offspring Health

Increasing evidences indicate that chronic diseases in offspring may be the result of ancestral environmental exposures. Exposures to environmental compounds in windows of epigenetic susceptibility have been shown to promote epigenetic alterations that can be inherited between generations. DNA methylation, histone modifications, and noncoding RNAs are sound mechanistic candidates for the delivery of environmental information from gametes to zygotes. This review focuses mainly on paternal exposures and assesses the risk of epigenetic alterations in the development of diseases, providing insights into relationships between aberrant sperm epigenetic patterns and offspring health. Elucidation of the mechanisms underlying environmental epigenetic information that survive from epigenetic reprogramming and its transmission to future generations may hold a great promise for providing therapeutic targets for epigenetic diseases associated with environmental exposures.

Transgenerational analysis of H3K4me3 and H3K27me3 by ChIP-Seq links epigenetic inheritance to metabolism

Histone methylation is a kind of important epigenetic modification which occurs on the lysine residue or arginine residue of histone tails（Zhang and Reinberg,2001）.It takes part in multiple biological processes,including gene expression,genomic stability,stem cell maturity,genetic imprinting,mitosis and development（Fischle et al.,2005）.

Harnessing male germline epigenomics for the genetic improvement in cattle

Sperm is essential for successful artificial insemination in dairy cattle,and its quality can be influenced by both epi-genetic modification and epigenetic inheritance.The bovine germline differentiation is characterized by epigenetic reprogramming,while intergenerational and transgenerational epigenetic inheritance can influence the offspring’s development through the transmission of epigenetic features to the offspring via the germline.Therefore,the selec-tion of bulls with superior sperm quality for the production and fertility traits requires a better understanding of the epigenetic mechanism and more accurate identifications of epigenetic biomarkers.We have comprehensively reviewed the current progress in the studies of bovine sperm epigenome in terms of both resources and biological discovery in order to provide perspectives on how to harness this valuable information for genetic improvement in the cattle breeding industry.

Inheritance of social dominance is associated with global sperm DNA methylation in inbred male mice

Dominance relationships between males and their associated traits are usually heritable and have implications for sexual selection in animals.In particular,social dominance and its related male pheromones are heritable in inbred mice;thus,we wondered whether epigenetic changes due to altered levels of DNA methylation determine inheritance.Here,we used C57BL/6 male mice to establish a social dominance-subordination relationship through chronic dyadic encounters,and this relationship and pheromone covariation occurred in their offspring,indicative of heritability.Through transcriptome sequencing and whole-genome DNA methylation profiling of the sperm of both generations,we found that differential methylation of many genes was induced by social dominance-subordination in sires and could be passed on to the offspring.These methylated genes were mainly related to growth and development processes,neurodevelopment,and cellular transportation.The expression of the genes with similar functions in whole-genome methylation/bisulfite sequencing was also differentiated by social dominance-subordination,as revealed by RNA-seq.In particular,the gene Dennd1a,which regulates neural signaling,was differentially methylated and expressed in the sperm and medial prefrontal cortex in paired males before and after dominance-subordination establishment,suggesting the potential epigenetic control and inheritance of social dominance-related aggression.We suggest that social dominance might be passed on to male offspring through sperm DNA methylation and that the differences could potentially affect male competition in offspring by affecting the development of thenervous system.

The patterns and participants of parental histone recycling during DNA replication in Saccharomyces cerevisiae

Epigenetic information carried by histone modifications not only reflects the state of gene expression,but also participates in the maintenance of chromatin states and the regulation of gene expression.Recycling of parental histones to daughter chromatin after DNA replication is vital to mitotic inheritance of epigenetic information and the maintenance of cell identity,because the locus-specific modifications of the parental histones need to be maintained.To assess the precision of parental histone recycling,we developed a synthetic local label-chasing system in budding yeast Saccharomyces cerevisiae.Using this system,we observed that parental histone H3 can be recycled to their original position,thereby recovering their position information after DNA replication at all tested loci,including heterochromatin boundary,non-transcribed region,and actively transcribed regions.Moreover,the recycling rate appears to be affected by local chromatin environment.We surveyed a number of potential regulatory factors and observed that histone H3-H4 chaperon Asf1 contributed to parental histone recycling,while the eukaryotic replisome-associated components Mcm2 and Dpb3 displayed compounding effects in this process.In addition,the FACT complex also plays a role in the recycling of parental histones and helps to stabilize the nucleosomes.

Split decision:why it matters?

The establishment and faithful maintenance of epigenetic information in the context of chromatin are crucial for a great number of biologic phenomena,including position effect variegation,Polycomb silencing,X-chromosome inactivation and genomic imprinting.However,mechanisms by which that the correct histone modification patterns propagate into daughter cells during mitotic divisions remain to be elucidated.The partitioning pattern of parental histone H3-H4 tetramers is a critical question toward our understanding of the epigenetic inheritance.In this review,we discuss why the histone H3-H4 tetramer split decision matters.