Molecular Development - Epigenetics

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Introduction

Epigenetics mechanisms[1]

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.


Molecular Links: molecular | genetics | epigenetics | mitosis | meiosis | X Inactivation | Signaling | Factors | Mouse Knockout | microRNA | Mechanisms | Developmental Enhancers | Protein | Genetic Abnormal | Category:Molecular

Some Recent Findings

FMR1 gene silencing
FMR1 developmental gene silencing[2]
Mouse zygote paternal genome reprogramming[3]
Chromosome structure
  • Review - Germline epigenetic inheritance: Challenges and opportunities for linking human paternal experience with offspring biology and health[4] "Recently, novel experimental approaches and molecular techniques have demonstrated that a male's experiences can be transmitted through his germline via epigenetic processes. These findings suggest that paternal exposures influence phenotypic variation in unexposed progeny-a proposal that runs counter to canonical ideas about inheritance developed during the 20th century. Nevertheless, support for paternal germline epigenetic inheritance (GEI) in nonhuman mammals continues to grow and the mechanisms underlying this phenomenon are becoming clearer. To what extent do similar processes operate in humans, and if so, what are their implications for understanding human phenotypic variation, health, and evolution? Here, we review evidence for GEI in human and nonhuman mammals and evaluate these findings in relation to historical conceptions of heredity."
  • DNA methylation in Schwann cells and in oligodendrocytes[5] "DNA methylation is one of many epigenetics marks, which directly modifies base residues, usually cytosines, in a multiple-step cycle. It has been linked to the regulation of gene expression and alternative splicing in several cell types, including during cell lineage specification and differentiation processes. DNA methylation changes have also been observed during aging, and aberrant methylation patterns have been reported in several neurological diseases. We here review the role of DNA methylation in Schwann cells and oligodendrocytes, the myelin-forming glia of the peripheral and central nervous systems, respectively. We first address how methylation and demethylation are regulating myelinating cells' differentiation during development and repair. We then mention how DNA methylation dysregulation in diseases and cancers could explain their pathogenesis by directly influencing myelinating cells' proliferation and differentiation capacities."
  • The role and mechanisms of DNA methylation in the oocyte[6] "Epigenetic information in the mammalian oocyte has the potential to be transmitted to the next generation and influence gene expression; this occurs naturally in the case of imprinted genes. Therefore, it is important to understand how epigenetic information is patterned during oocyte development and growth. Here, we review the current state of knowledge of de novo DNA methylation mechanisms in the oocyte: how a distinctive gene-body methylation pattern is created, and the extent to which the DNA methylation machinery reads chromatin states. Recent epigenomic studies building on advances in ultra-low input chromatin profiling methods, coupled with genetic studies, have started to allow a detailed interrogation of the interplay between DNA methylation establishment and chromatin states; however, a full mechanistic description awaits."
  • Review - Reevaluation of FMR1 Hypermethylation Timing in Fragile X Syndrome[2] "Fragile X syndrome (FXS) is one of the most common heritable forms of cognitive impairment. It results from a fragile X mental retardation protein (FMRP) protein deficiency caused by a CGG repeat expansion in the 5'-UTR of the X-linked FMR1 gene. Whereas in most individuals the number of CGGs is steady and ranges between 5 and 44 units, in patients it becomes extensively unstable and expands to a length exceeding 200 repeats (full mutation). Interestingly, this disease is exclusively transmitted by mothers who carry a premutation allele (55-200 CGG repeats). When the CGGs reach the FM range, they trigger the spread of abnormal DNA methylation, which coincides with a switch from active to repressive histone modifications. This results in epigenetic gene silencing of FMR1 presumably by a multi-stage, developmentally regulated process. The timing of FMR1 hypermethylation and transcription silencing is still hotly debated. There is evidence that hypermethylation varies considerably between and within the tissues of patients as well as during fetal development, thus supporting the view that FMR1 silencing is a post-zygotic event that is developmentally structured. On the other hand, it may be established in the female germ line and transmitted to the fetus as an integral part of the mutation. This short review summarizes the data collected to date concerning the timing of FMR1 epigenetic gene silencing and reassess the evidence in favor of the theory that gene inactivation takes place by a developmentally regulated process around the 10th week of gestation." Fragile X
  • Maintenance of Mest imprinted methylation in blastocyst-stage mouse embryos is less stable than other imprinted loci following superovulation or embryo culture[7] "Assisted reproductive technologies are fertility treatments used by subfertile couples to conceive their biological child. Although generally considered safe, these pregnancies have been linked to genomic imprinting disorders, including Beckwith-Wiedemann and Silver-Russell Syndromes. Silver-Russell Syndrome is a growth disorder characterized by pre- and post-natal growth retardation. The Mest imprinted domain is one candidate region on chromosome 7 implicated in Silver-Russell Syndrome. We have previously shown that maintenance of imprinted methylation was disrupted by superovulation or embryo culture during pre-implantation mouse development. For superovulation, this disruption did not originate in oogenesis as a methylation acquisition defect. However, in comparison to other genes, Mest exhibits late methylation acquisition kinetics, possibly making Mest more vulnerable to perturbation by environmental insult. In this study, we present a comprehensive evaluation of the effects of superovulation and in vitro culture on genomic imprinting at the Mest gene. Superovulation resulted in disruption of imprinted methylation at the maternal Mest allele in blastocysts with an equal frequency of embryos having methylation errors following low or high hormone treatment. This disruption was not due to a failure of imprinted methylation acquisition at Mest in oocytes. For cultured embryos, both the Fast and Slow culture groups experienced a significant loss of maternal Mest methylation compared to in vivo-derived controls. This loss of methylation was independent of development rates in culture. These results indicate that Mest is more susceptible to imprinted methylation maintenance errors compared to other imprinted genes." Chromosome 7
More recent papers  
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Search term: Development Epigenetics | Epigenetics | Oocyte Epigenetics | Spermatozoa Epigenetics

Older papers  
These papers originally appeared in the Some Recent Findings table, but as that list grew in length have now been shuffled down to this collapsible table.

See also the Discussion Page for other references listed by year and References on this current page.

  • The DNA methylation landscape of human early embryos[8] "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[9] "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[10] "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 [11] "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.[12] "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

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

Epigenetics - monozygous twins.jpg
DNA Methylation, young and old monozygous twins.[13]

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.[14] 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.[15]

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.[16]

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.[14]

Primordial Germ Cells

Mouse primordial germ cell DNA methylation[17]


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
 Primordial germ cell DNA methylation 01.jpg

DNA Demethylation

Activation-Induced cytidine Deaminase

Mammalian active DNA demethylation[14]

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.[14] 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.png Maternal and paternal resource allocation.png
Placenta potential imprinted genes[15] Maternal and paternal resource allocation[15]

X Inactivation

Macaque Xi at interphase
Macaque Xi at interphase[18]

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

  1. ↑ Qiu J. (2006). Epigenetics: unfinished symphony. Nature , 441, 143-5. PMID: 16688142 DOI.
  2. ↑ 2.0 2.1 Mor-Shaked H & Eiges R. (2018). Reevaluation ofFMR1Hypermethylation Timing in Fragile X Syndrome. Front Mol Neurosci , 11, 31. PMID: 29467618 DOI.
  3. ↑ Iqbal K, Jin SG, Pfeifer GP & Szabó PE. (2011). Reprogramming of the paternal genome upon fertilization involves genome-wide oxidation of 5-methylcytosine. Proc. Natl. Acad. Sci. U.S.A. , 108, 3642-7. PMID: 21321204 DOI.
  4. ↑ Ryan CP & Kuzawa CW. (2020). Germline epigenetic inheritance: Challenges and opportunities for linking human paternal experience with offspring biology and health. Evol. Anthropol. , , . PMID: 32196832 DOI.
  5. ↑ Arthur-Farraj P & Moyon S. (2020). DNA methylation in Schwann cells and in oligodendrocytes. Glia , , . PMID: 31958184 DOI.
  6. ↑ Sendžikaitė G & Kelsey G. (2019). The role and mechanisms of DNA methylation in the oocyte. Essays Biochem. , , . PMID: 31782490 DOI.
  7. ↑ Velker BAM, Denomme MM, Krafty RT & Mann MRW. (2017). Maintenance ofMestimprinted methylation in blastocyst-stage mouse embryos is less stable than other imprinted loci following superovulation or embryo culture. Environ Epigenet , 3, dvx015. PMID: 29492315 DOI.
  8. ↑ Guo H, Zhu P, Yan L, Li R, Hu B, Lian Y, Yan J, Ren X, Lin S, Li J, Jin X, Shi X, Liu P, Wang X, Wang W, Wei Y, Li X, Guo F, Wu X, Fan X, Yong J, Wen L, Xie SX, Tang F & Qiao J. (2014). The DNA methylation landscape of human early embryos. Nature , 511, 606-10. PMID: 25079557 DOI.
  9. ↑ Smith ZD, Chan MM, Humm KC, Karnik R, Mekhoubad S, Regev A, Eggan K & Meissner A. (2014). DNA methylation dynamics of the human preimplantation embryo. Nature , 511, 611-5. PMID: 25079558 DOI.
  10. ↑ Chowdhury S, Erickson SW, MacLeod SL, Cleves MA, Hu P, Karim MA & Hobbs CA. (2011). Maternal genome-wide DNA methylation patterns and congenital heart defects. PLoS ONE , 6, e16506. PMID: 21297937 DOI.
  11. ↑ PLoS Collection - Epigenetics 2010
  12. ↑ Kim K, Doi A, Wen B, Ng K, Zhao R, Cahan P, Kim J, Aryee MJ, Ji H, Ehrlich LI, Yabuuchi A, Takeuchi A, Cunniff KC, Hongguang H, McKinney-Freeman S, Naveiras O, Yoon TJ, Irizarry RA, Jung N, Seita J, Hanna J, Murakami P, Jaenisch R, Weissleder R, Orkin SH, Weissman IL, Feinberg AP & Daley GQ. (2010). Epigenetic memory in induced pluripotent stem cells. Nature , 467, 285-90. PMID: 20644535 DOI.
  13. ↑ Fraga MF, Ballestar E, Paz MF, Ropero S, Setien F, Ballestar ML, Heine-Suñer D, Cigudosa JC, Urioste M, Benitez J, Boix-Chornet M, Sanchez-Aguilera A, Ling C, Carlsson E, Poulsen P, Vaag A, Stephan Z, Spector TD, Wu YZ, Plass C & Esteller M. (2005). Epigenetic differences arise during the lifetime of monozygotic twins. Proc. Natl. Acad. Sci. U.S.A. , 102, 10604-9. PMID: 16009939 DOI.
  14. ↑ 14.0 14.1 14.2 14.3 Sanz LA, Kota SK & Feil R. (2010). Genome-wide DNA demethylation in mammals. Genome Biol. , 11, 110. PMID: 20236475 DOI.
  15. ↑ 15.0 15.1 15.2 Frost JM & Moore GE. (2010). The importance of imprinting in the human placenta. PLoS Genet. , 6, e1001015. PMID: 20617174 DOI.
  16. ↑ Popp C, Dean W, Feng S, Cokus SJ, Andrews S, Pellegrini M, Jacobsen SE & Reik W. (2010). Genome-wide erasure of DNA methylation in mouse primordial germ cells is affected by AID deficiency. Nature , 463, 1101-5. PMID: 20098412 DOI.
  17. ↑ Abe M, Tsai SY, Jin SG, Pfeifer GP & Szabó PE. (2011). Sex-specific dynamics of global chromatin changes in fetal mouse germ cells. PLoS ONE , 6, e23848. PMID: 21886830 DOI.
  18. ↑ McLaughlin CR & Chadwick BP. (2011). Characterization of DXZ4 conservation in primates implies important functional roles for CTCF binding, array expression and tandem repeat organization on the X chromosome. Genome Biol. , 12, R37. PMID: 21489251 DOI.

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Cite this page: Hill, M.A. (2023, December 2) Embryology Molecular Development - Epigenetics. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Molecular_Development_-_Epigenetics

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