Novel insight into the establishment of sex-specific epigenetic modifications in the germline

Sex-specific histone modifications in mouse fetal and neonatal germ cells

These findings – published online: 22 January 2019 – suggest that histone modifications play a critical role in regulating gene expression in FGCs following DNA methylation erasure, leading to their differentiation into fFGCs and mFGCs. These findings provide a novel insight into the establishment of sex-specific epigenetic modifications in the germline, which is required for functional germ cell development. However, further study is needed to elucidate whether and how the various types of modifications interact.

Abstract

Aims:
Epigenetic signatures of germline cells are dynamically reprogrammed to induce appropriate differentiation, development and sex specification. We investigated sex-specific epigenetic changes in mouse fetal germ cells (FGCs) and neonatal germ cells.

Materials & methods:
Six histone marks in mouse E13.5 FGCs and P1 neonatal germ cells were analyzed by chromatin immunoprecipitation and sequencing. These datasets were compared with transposase-accessible chromatin sites, DNA methylation and transcriptome.

Results:
Different patterns of each histone mark were detected in female and male FGCs, and H3K4me3/H3K27me3 bivalent marks were enriched in different chromosomal regions of female and male FGCs.

Conclusion:
Our results suggest that histone modifications may affect FGC gene expression following DNA methylation erasure, contributing to the differentiation into female and male germ cells.

The exposome : can we measure of all the exposures of an individual in a lifetime and how they relate to health ?

Development of exposome correlation globes to map out environment-wide associations

Success in mapping the human genome has fostered the complementary concept of the “exposome“.

The exposome can be defined as the measure of all the exposures of an individual in a lifetime and how those exposures relate to health. An individual’s exposure begins before birth and includes insults from environmental and occupational sources. Understanding how exposures from our environment, diet, lifestyle, etc. interact with our own unique characteristics such as genetics, physiology, and epigenetics impact our health is how the exposome will be articulated.

Exposomics is the study of the exposome and relies on the application of internal and external exposure assessment methods.

2016 Paper Abstract

The exposome concept was defined in 2005 as encompassing all environmental exposures from conception onwards, as a new strategy to evidence environmental disease risk factors. Although very appealing, the exposome concept is challenging in many respects. In terms of assessment, several hundreds of time-varying exposures need to be considered, but increasing the number of exposures assessed should not be done at the cost of increased exposure misclassification. Accurately assessing the exposome currently requires numerous measurements, which rely on different technologies; resulting in an expensive set of protocols. In the future, high-throughput ‘omics technologies may be a promising technique to integrate a wide range of exposures from a small numbers of biological matrices. Assessing the association between many exposures and health raises statistical challenges. Due to the correlation structure of the exposome, existing statistical methods cannot fully and efficiently untangle the exposures truly affecting the health outcome from correlated exposures. Other statistical challenges relate to accounting for exposure misclassification or identifying synergistic effects between exposures. On-going exposome projects are trying to overcome technical and statistical challenges. From a public health perspective, a better understanding of the environmental risk factors should open the way to improved prevention strategies.

2015 Paper Abstract

The environment plays a major role in influencing diseases and health. The phenomenon of environmental exposure is complex and humans are not exposed to one or a handful factors but potentially hundreds factors throughout their lives. The exposome, the totality of exposures encountered from birth, is hypothesized to consist of multiple inter-dependencies, or correlations, between individual exposures. These correlations may reflect how individuals are exposed. Currently, we lack methods to comprehensively identify robust and replicated correlations between environmental exposures of the exposome. Further, we have not mapped how exposures associated with disease identified by environment-wide association studies (EWAS) are correlated with other exposures. To this end, we implement methods to describe a first “exposome globe”, a comprehensive display of replicated correlations between individual exposures of the exposome. First, we describe overall characteristics of the dense correlations between exposures, showing that we are able to replicate 2,656 correlations between individual exposures of 81,937 total considered (3%). We document the correlation within and between broad a priori defined categories of exposures (e.g., pollutants and nutrient exposures). We also demonstrate utility of the exposome globe to contextualize exposures found through two EWASs in type 2 diabetes and all-cause mortality, such as exposure clusters putatively related to smoking behaviors and persistent pollutant exposure. The exposome globe construct is a useful tool for the display and communication of the complex relationships between exposure factors and between exposure factors related to disease status.

More Information

  • The exposome concept: a challenge and a potential driver for environmental health research, ersjournals, 2016.
  • Development of exposome correlation globes to map out environment-wide associations, ncbi, PMC4299925, 2015.
  • Exposome and Exposomics, cdc, niosh.
  • humanexposomeproject website.

Could prenatal test results decide for treatments to help reduce the effects of a genetic disorder?

Universal Haplotype-Based Noninvasive Prenatal Testing for Single Gene Diseases

Together, single-gene disorders are more common than Down’s syndrome. A fast test for genetic disorders means parents could learn about the future health of their baby as early as six weeks into pregnancy.

November 2016 Study Abstract

Background
Researchers have developed approaches for the noninvasive prenatal testing of single gene diseases. One approach that allows for the noninvasive assessment of both maternally and paternally inherited mutations involves the analysis of single nucleotide polymorphisms (SNPs) in maternal plasma DNA with reference to parental haplotype information. In the past, parental haplotypes were resolved by complex experimental methods or inferential approaches, such as through the analysis of DNA from other affected family members. Recently, microfluidics-based linked-read sequencing technology has become available and allows the direct haplotype phasing of the whole genome rapidly. We explored the feasibility of applying this direct haplotyping technology in noninvasive prenatal testing.

Simple blood test can detect genetic diseases early in pregnancy, New Scientist, Magazine issue 3107, 7 January 2017.

Universal Haplotype-Based Noninvasive Prenatal Testing for Single Gene Diseases, American Association for Clinical Chemistry, DOI: 10.1373/clinchem.2016.268375, December 2016.

Icarus (Henri Matisse,1947) credit doomsteaddiner.

Methods
We first resolved the haplotypes of parental genomes with the use of linked-read sequencing technology. Then, we identified SNPs within and flanking the genes of interest in maternal plasma DNA by targeted sequencing. Finally, we applied relative haplotype dosage analysis to deduce the mutation inheritance status of the fetus.

Results
Haplotype phasing and relative haplotype dosage analysis of 12 out of 13 families were successfully achieved. The mutational status of these 12 fetuses was correctly classified.

Conclusions
High-throughput linked-read sequencing followed by maternal plasma-based relative haplotype dosage analysis represents a streamlined approach for noninvasive prenatal testing of inherited single gene diseases. The approach bypasses the need for mutation-specific assays and is not dependent on the availability of DNA from other affected family members. Thus, the approach is universally applicable to pregnancies at risk for the inheritance of a single gene disease.

High genetic correlations found between six psychiatric disorders

Personality Traits and Psychiatric Disorders Linked to Specific Genomic Locations

A meta-analysis of genome-wide association studies (GWAS) has identified six loci or regions of the human genome that are significantly linked to personality traits, report researchers at University of California San Diego School of Medicine in this week’s advance online publication of Nature Genetics. The findings also show correlations with six psychiatric disorders.

Abstract

Personality is influenced by genetic and environmental factors1 and associated with mental health. However, the underlying genetic determinants are largely unknown.

We identified six genetic loci, including five novel loci2, 3, significantly associated with personality traits in a meta-analysis of genome-wide association studies (N = 123,132–260,861). Of these genome-wide significant loci, extraversion was associated with variants in WSCD2 and near PCDH15, and neuroticism with variants on chromosome 8p23.1 and in L3MBTL2. We performed a principal component analysis to extract major dimensions underlying genetic variations among five personality traits and six psychiatric disorders (N = 5,422–18,759).

Some genetic variants linked to extraversion and neuroticism personality traits have been identified.

The first genetic dimension separated personality traits and psychiatric disorders, except that neuroticism and openness to experience were clustered with the disorders. High genetic correlations were found between extraversion and attention-deficit–hyperactivity disorder (ADHD) and between openness and schizophrenia and bipolar disorder. The second genetic dimension was closely aligned with extraversion–introversion and grouped neuroticism with internalizing psychopathology (e.g., depression or anxiety).

In addition, there were high genetic correlations between extraversion and attention deficit hyperactivity disorder (ADHD) and between openness and schizophrenia and bipolar disorder. Neuroticism was genetically correlated with internalized psychopathologies, such as depression and anxiety.

Study and Press Release

Can Phthalates program your Baby to be Obese?

Phthalates may cause fat accumulation and program the stem cell to become obese via an epigenetic balance

Benzyl butyl phthalate (BBP), a chemical commonly used in the food manufacturing process, can increase fat stores in the body even before we’re born.

Abstract

Benzyl butyl phthalate induces epigenetic stress to enhance adipogenesis in mesenchymal stem cells, Molecular and Cellular Endocrinology, sciencedirect, 2016.04.

Endocrine disruptors, phthalates, may have contributed to recent global obesity health crisis. Our study investigated the potential of benzyl butyl phthalate (BBP) to regulate the mesenchymal stem cell epigenome to drive adipogenesis.

BBP exposure enhanced lipid accumulation and adipogenesis in a dose-dependent manner compared to control (P < 0.001).

Can Plastic Program Your Baby To Be Obese?, vitalrecord, May 17, 2016.

Babies by Aimee Ray.

  • Adipogenesis markers, PPARγ (P < 0.001), C/EBPα (P < 0.01), and aP2 (P < 0.001) were significantly upregulated by increasing concentrations of BBP when compared to DMSO.
  • BBP enhanced H3K9 acetylation while decreasing H3K9 dimethylation. Fifty μM BBP increased histone acetyltransferases, p300 (P < 0.05) and GCN5 (P < 0.01) gene expression.
  • Furthermore, histone deacetylases (HDACs), HDAC3 (P < 0.01) and HDAC10 (P < 0.01, 10 μM BBP; P < 0.001, 50 μM BBP) and histone methyltransferases, SETDB1 (P < 0.01) and G9a (P < 0.01), were significantly downregulated by BBP exposure.
  • BBP acts, in part, through PPARγ, as PPARγ knockdown led to decreased H3K9ac and rescued H3K9me2 during BBP exposure.

In conclusion, BBP regulated MSCs towards adipogenesis by tipping the epigenomic balance.

HGP-Write: Testing Large Synthetic Genomes in Cells

Scientists want to synthesize the human genome. What does that mean?

Scientists Talk Privately About Creating a Synthetic Human Genome, nytimes, MAY 13, 2016.

Scientists met at Harvard University recently to discuss the fabrication of a human genome, meaning they would use chemicals to manufacture all the DNA contained in human chromosomes.

The project, called HGP-Write, is spurring both intrigue and concern in the scientific communities because it may become possible, such as through cloning, to use a synthetic genome to create human beings without biological parents.

Scientists Want To Synthesize The Human Genome. What Does That Mean?, newsy, May 15, 2016.

Image James King-Holmes/Science Source.

The Human Genome Project was aimed at reading the sequence of the three billion chemical letters in the DNA blueprint of human life. The new HGP-Write project would involve writing the human genome – synthesizing all the three billion units data from chemicals – and could have a big “scientific payoff“…

Investigating Causes of Epigenomic and Genomic Errors

Germline Exposures March3, 2016 Webinar

Untitled-2

Upcoming webinar, March 3, 2016, 1-3pm EST: “Environmental Exposures and the Germline: Investigating Causes of Epigenomic and Genomic ErrorsRegister here.

As evidence mounts that some forms of autism are driven by “de novo” errors in the germline (genomic glitches not present in either parent), the question arises: what environmental factors might contribute to this phenomenon? Leading researchers will delve into questions of germline plasticity, genotoxic exposures, and molecular events that affect DNA.

Presenters:

  • Dana Dolinoy, PhD, University of Michigan
    “Heritable epigenetic effects of germline exposure to toxicants”
    • Watch webinar with Dr. Dolinoy on Epigenie
  • Carole Yauk, PhD, Health Canada
    “Analysis of chemical exposures and life stage factors that contribute to genetic disease”. Read Yauk et al: “Approaches for Indentifying Germ Cell Mutagens
  • With commentary by: Cathrine Hoyo, PhD, UNC, and Lisa Chadwick, PhD, NIEHS

This 2-hour webinar, open to researchers and the public, is free, but you must pre-register. Spaces are limited. Register here.

Sources Germline Exposures.

U.K. researcher receives approval to genetically modify human embryos

HFEA approval for new “gene editing” techniques

Scientists in Britain have been give the go-ahead to edit the genes of human embryos for research purposes, using a technique that some say could eventually be used to create “designer babies”.

The Human Fertilisation and Embryology Authority (HFEA) has approved a research application from the Francis Crick Institute to use new “gene editing” techniques on human embryos (see Licence Committee – minutes).

The aim of the research, led by Dr Kathy Niakan, a group leader at the Crick, is to understand the genes human embryos need to develop successfully.

The work carried out at the Crick will be for research purposes and will look at the first seven days of a fertilised egg’s development (from a single cell to around 250 cells).

The knowledge acquired from the research will be important for understanding how a healthy human embryo develops.

This knowledge may improve embryo development after in vitro fertilisation (IVF) and might provide better clinical treatments for infertility, using conventional medical methods.

Paul Nurse, director of the Crick, said:

“I am delighted that the HFEA has approved Dr Niakan’s application. Dr Niakan’s proposed research is important for understanding how a healthy human embryo develops and will enhance our understanding of IVF success rates, by looking at the very earliest stage of human development – one to seven days.”

In line with HFEA regulations, any donated embryos will be used for research purposes only and cannot be used in treatment. These embryos will be donated by patients who have given their informed consent to the donation of embryos which are surplus to their IVF treatment.

The genome editing research now needs to gain ethical approval and, subject to that approval, the research programme will begin within the next few months.

Press releases

  • Britain gives scientist go-ahead to genetically modify human embryos, reuters, Feb 1, 2016.
  • CRISPR Editing of Human Embryos Approved in the U.K., genengnews, Feb 1, 2016.
  • In a world first, UK scientists just got approval to edit human embryos, vox, February 1, 2016.
  • U.K. Approves First Studies of New Gene Editing Technique CRISPR on Human Embryos, time, Feb 1, 2016.
  • UK researcher gets go-ahead to create embryos using CRISPR, siliconrepublic, Feb 1, 2016.

The Human Genome: a New Picture of Disease Genetics

“High risk” cell populations may be playing important roles in human disorders and diseases

Research in the University of Utah Gregg Lab is focused on understanding genetic and epigenetic pathways and neuronal circuits that influence motivated behaviors and susceptibility to mental illness.

Mental illnesses are extremely complex and involve both genetic and environmental factors that alter brain functions and behavioral drives.

The NIMH estimates that about one in four Americans suffer from a diagnosable mental disorder with nearly 6% suffering serious disabilities as a result, and that the total cost of serious mental illness in the US exceeds $317 billion per year.

THE UNIVERSITY OF UTAH

Human Gene Editing important issues and need for appropriate regulatory oversight

Scientists urge caution on human gene editing

image of statue Human-Gene-Editing
The 2015 International Summit on Human Gene Editing concluded that it would be “irresponsible” to use a powerful tool for editing human genes until more is known about the consequences and ethics of passing genetic changes to future generations.

Abstract – 2015 International Summit Statement

Clinical Use: Germline.

Gene editing might also be used, in principle, to make genetic alterations in gametes or embryos, which will be carried by all of the cells of a resulting child and will be passed on to subsequent generations as part of the human gene pool. Examples that have been proposed range from avoidance of severe inherited diseases to ‘enhancement’ of human capabilities. Such modifications of human genomes might include the introduction of naturally occurring variants or totally novel genetic changes thought to be beneficial.

Germline editing poses many important issues, including:

  1. the risks of inaccurate editing (such as off-target mutations) and incomplete editing of the cells of early-stage embryos (mosaicism);
  2. the difficulty of predicting harmful effects that genetic changes may have under the wide range of circumstances experienced by the human population, including interactions with other genetic variants and with the environment;
  3. the obligation to consider implications for both the individual and the future generations who will carry the genetic alterations;
  4. the fact that, once introduced into the human population, genetic alterations would be difficult to remove and would not remain within any single community or country;
  5. the possibility that permanent genetic ‘enhancements’ to subsets of the population could exacerbate social inequities or be used coercively;
  6. and the moral and ethical considerations in purposefully altering human evolution using this technology.

It would be irresponsible to proceed with any clinical use of germline editing unless and until

  1. the relevant safety and efficacy issues have been resolved, based on appropriate understanding and balancing of risks, potential benefits, and alternatives,
  2. and there is broad societal consensus about the appropriateness of the proposed application.

Moreover, any clinical use should proceed only under appropriate regulatory oversight. At present, these criteria have not been met for any proposed clinical use: the safety issues have not yet been adequately explored; the cases of most compelling benefit are limited; and many nations have legislative or regulatory bans on germline modification. However, as scientific knowledge advances and societal views evolve, the clinical use of germline editing should be revisited on a regular basis.

Sources and More information