Molecular Development - Epigenetics

Embryology - 24 Apr 2024        Expand to Translate
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Introduction

Epigenetics mechanisms

In terms of molecular mechanisms, the field of epigenetics has begun to florish with some recent important findings. Epigenetics as the name implies, is the inheritance mechanisms that lie outside the DNA sequence of our genes and include DNA methylation, histone modification, and those of the microRNA machinery. One of the initial discoveries was the effects of DNA methylation upon gene expression and then modifications of nucleosomal histones. DNA methylation is usually associated with 5-methylcytosine (m5C) and leads to transcriptional silencing in vertebrates. Epigenetic modifications can be transmitted from one cell generation to the next (mitotic inheritance) and can also be transmitted down organismal generations (meiotic inheritance). Recently the term “methylome” has been coined to refer to the methylation profile of the whole genome.

Molecular mechanisms of development is an exciting research area and requires a variety of different skills. This page introduces only a few examples and should give you a feel for the topic. Note that each section of system notes has a page covering molecular development in that system.

Mouse zygote paternal genome reprogramming

Some Recent Findings

Chromosome structure

The DNA methylation landscape of human early embryos "DNA methylation is a crucial element in the epigenetic regulation of mammalian embryonic development.We show that the major wave of genome-wide demethylation is complete at the 2-cell stage, contrary to previous observations in mice. Moreover, the demethylation of the paternal genome is much faster than that of the maternal genome, and by the end of the zygotic stage the genome-wide methylation level in male pronuclei is already lower than that in female pronuclei. DNA methylation dynamics of the human preimplantation embryo "In mammals, cytosine methylation is predominantly restricted to CpG dinucleotides and stably distributed across the genome, with local, cell-type-specific regulation directed by DNA binding factors. ...We present genome-scale DNA methylation maps of human preimplantation development and embryonic stem cell derivation, confirming a transient state of global hypomethylation that includes most CpGs, while sites of residual maintenance are primarily restricted to gene bodies. Together, our data confirm that paternal genome demethylation is a general attribute of early mammalian development that is characterized by distinct modes of epigenetic regulation." Maternal genome-wide DNA methylation patterns and congenital heart defects"The majority of congenital heart defects (CHDs) are thought to result from the interaction between multiple genetic, epigenetic, environmental, and lifestyle factors. Epigenetic mechanisms are attractive targets in the study of complex diseases because they may be altered by environmental factors and dietary interventions. ...We present preliminary evidence that alterations in maternal DNA methylation may be associated with CHDs. Our results suggest that further studies involving maternal epigenetic patterns and CHDs are warranted. Multiple candidate processes and pathways for future study have been identified." Epigenetics 2010 "This collection brings together twenty Research Articles published in five PLoS journals in the area of epigenetics during 2010, along with a Research in Translation article and two Primers. They reflect a range of model systems and organisms, and variously offer phenotypic, mechanistic, and chromatin-based insights." Epigenetic memory in induced pluripotent stem cells. "Our data indicate that nuclear transfer is more effective at establishing the ground state of pluripotency than factor-based reprogramming, which can leave an epigenetic memory of the tissue of origin that may influence efforts at directed differentiation for applications in disease modelling or treatment." (More? Stem Cells) NIH Roadmap Epigenomics Program

More recent papers

This table allows an automated computer search of the external PubMed database using the listed "Search term" text link. This search now requires a manual link as the original PubMed extension has been disabled. The displayed list of references do not reflect any editorial selection of material based on content or relevance. References also appear on this list based upon the date of the actual page viewing. References listed on the rest of the content page and the associated discussion page (listed under the publication year sub-headings) do include some editorial selection based upon both relevance and availability. More? References | Discussion Page | Journal Searches | 2019 References | 2020 References Search term: Xist <pubmed limit=5>Xist</pubmed> Search term: Epigenetics <pubmed limit=5>Epigenetics</pubmed>

DNA Methylation

Enzymes that lead to DNA methylation are described as methyltransferases (DNMTs) and fall into two categories.

1. DNMT1 - copies the pattern of DNA methylation during cell replication (methylation maintenance).
2. DNMT3a and DNMT3b - are responsible for the de novo DNA methylation.

DNA Methylation Changes with Age

DNA Methylation, young and old monozygous twins.

Developmental Methylation Changes

Within the embryonic genome DNA methylation occurs at regions of cytosine residues followed by guanines (CpG) and is a main epigenetic mechanism regulating early gene expression and later genomic imprinting, see review. There are extensive changes in DNA methylation state that occur during development and relate to imprinted genes, the total number of genes imprinted in currently unknown, with 100 identified imprinted genes in the mouse and about 50 known in the human. This imprinting will also differ between the embryo and the placenta.

Overall a developmental demethylation is followed by an eventual remethylation of about 70% of all CpGs, except for the primordial germ cell population. The primordial germ cells will form the germ line cell population in the embryo gonad. These cells appear to undergo epigenetic reprogramming through an independent genome-wide of erasure of imprints and epimutations through cytidine deaminases.

The zygote initially has a male and female pronucleus that will fuse to form the diploid nucleus. Each of the male and female pronuclei have different patterns of methylation and undergo different demethylation processes. The male pronucleus undergoes an extensive loss of DNA methylation, with imprinted genes resisting this process. The female pronucleus has less active demethylation requiring several mitotic rounds to complete this process.

Primordial Germ Cells

Mouse primordial germ cell DNA methylation Demethylation Global DNA demethylation occurs in primordial germ cells about the time when they colonize the genital ridges. Remethylation Male - prospermatogonia methylation occurs during fetal stages. Female - oocytes methylation occurs postnatally. Links: Primordial Germ Cell Development

DNA Demethylation

Activation-Induced cytidine Deaminase

Mammalian active DNA demethylation

Activation-Induced cytidine Deaminase (AID) is an enzyme required for demethylation (removal of CpG methylation). Within the genome, DNA methylation is associated with epigenetic mechanisms and occurs at cytosine residues that are followed by guanines. This enzyme is also found expressed in primordial germ cells.

Links: Primordial Germ Cell Development

Histone Modification

Histones are a family of proteins involved in the bundling of genomic DNA into chromatin. The unit size of chromatin DNA + associated histones is described as the nucleosome. A group of histone modifying enzymes can modify histone protein NH2-terminal tails by: acetylation, methylation, phosphorylation, sumoylation, or ubiquitination. These modifications of histone proteins can in turn determine the accessibility of the DNA to the transcription machinery.

Histone Acetylation

The lysine residues on histone tails can have acetyl groups either removed (by histone deacetyltransferases, HDACs) or added (by histone acetyl transferases, HATs).

• Normally the lysine residues on histone tails bear a positive charge that can bind negatively charged DNA to form a condensed structure with low transcriptional activity.
• Histone acetylation removes these positive charges allowing a less condensed structure with higher transcriptional activity.

Potential Imprinted Genes

Placenta potential imprinted genes	Maternal and paternal resource allocation

X Inactivation

Macaque Xi at interphase

As X inactivation is not an encoded genetic function and occurs randomly throughout female tissues, this represents a form of epigenetics. The presence in females of two X chromosome raises the issue of gene dosage, in the case of mammals this is regulated by inactivating one of the X chromosomes. To balance expression with the autosomal chromosomes the dosage imbalance is then adjusted by doubling expression of X-linked genes in both sexes. The process of inactivation relies on the Xist RNA, a 17 kb non-coding RNA, which accumulates on the future inactive X (Xi) chromosome.

Links: X Inactivation

References

Search Pubmed

June 2010 "epigenetics" - All (37097) Review (6256) Free Full Text (15778)

Search Pubmed Now: epigenetics

Glossary Links

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Cite this page: Hill, M.A. (2024, April 24) Embryology Molecular Development - Epigenetics. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Molecular_Development_-_Epigenetics

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© Dr Mark Hill 2024, UNSW Embryology ISBN: 978 0 7334 2609 4 - UNSW CRICOS Provider Code No. 00098G