Molecular Development - Epigenetics

From Embryology
Embryology - 15 Nov 2018    Facebook link Pinterest link Twitter link  Expand to Translate  
Google Translate - select your language from the list shown below (this will open a new external page)

العربية | català | 中文 | 中國傳統的 | français | Deutsche | עִברִית | हिंदी | bahasa Indonesia | italiano | 日本語 | 한국어 | မြန်မာ | Pilipino | Polskie | português | ਪੰਜਾਬੀ ਦੇ | Română | русский | Español | Swahili | Svensk | ไทย | Türkçe | اردو | ייִדיש | Tiếng Việt    These external translations are automated and may not be accurate. (More? About Translations)

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 - 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 Syndrome
  • Maintenance of Mest imprinted methylation in blastocyst-stage mouse embryos is less stable than other imprinted loci following superovulation or embryo culture[4] "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
  • The DNA methylation landscape of human early embryos[5] "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.
More recent papers  
Mark Hill.jpg
PubMed logo.gif

This table shows an automated computer PubMed search using the listed sub-heading term.

  • Therefore the list of references do not reflect any editorial selection of material based on content or relevance.
  • References appear in 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.

Links: References | Discussion Page | Pubmed Most Recent | Journal Searches


Search term: Epigenetics

Qingxia Xuan, Yunfeng Zhou, Binbin Tan, Zhongyue Xiao, Shizhen Dong, Faliang Dai, Lei Gao, Tengfei Guo, Pan Chen, Jie Sun, Dandan Feng, Jianjun Jin, Fong-Fong Chu, Qiang Gao Mice Deficient in Cyp4a14 Have An Increased Number of Goblet Cells and Attenuated Dextran Sulfate Sodium-Induced Colitis. Cell. Physiol. Biochem.: 2018, 50(6);2272-2282 PubMed 30423565

Fang Zhao, Wangjun Wu, Quanwei Wei, Ming Shen, Bojiang Li, Yi Jiang, Kaiqing Liu, Honglin Liu Exogenous adrenocorticotropic hormone affects genome-wide DNA methylation and transcriptome of corpus luteum in sows. FASEB J.: 2018;fj201801081RRR PubMed 30423262

Arshdeep Sekhon, Ritambhara Singh, Yanjun Qi DeepDiff: DEEP-learning for predicting DIFFerential gene expression from histone modifications. Bioinformatics: 2018, 34(17);i891-i900 PubMed 30423076

Florian Schmidt, Markus List, Engin Cukuroglu, Sebastian Köhler, Jonathan Göke, Marcel H Schulz An ontology-based method for assessing batch effect adjustment approaches in heterogeneous datasets. Bioinformatics: 2018, 34(17);i908-i916 PubMed 30423059

Older papers  
  • DNA methylation dynamics of the human preimplantation embryo[6] "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[7] "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 [8] "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.[9] "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.[10]

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.[11] 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.[12]

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.[13]

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.[11]

Primordial Germ Cells

Mouse primordial germ cell DNA methylation[14]


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[11]

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.[11] 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[12] Maternal and paternal resource allocation[12]

X Inactivation

Macaque Xi at interphase
Macaque Xi at interphase[15]

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. 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.
  5. 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.
  6. 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.
  7. 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.
  8. PLoS Collection - Epigenetics 2010
  9. 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.
  10. 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.
  11. 11.0 11.1 11.2 11.3 Sanz LA, Kota SK & Feil R. (2010). Genome-wide DNA demethylation in mammals. Genome Biol. , 11, 110. PMID: 20236475 DOI.
  12. 12.0 12.1 12.2 Frost JM & Moore GE. (2010). The importance of imprinting in the human placenta. PLoS Genet. , 6, e1001015. PMID: 20617174 DOI.
  13. 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.
  14. 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.
  15. 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.

Search Pubmed

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


Search Pubmed Now: epigenetics



Glossary Links

Glossary: A | B | C | D | E | F | G | H | I | J | K | L | M | N | O | P | Q | R | S | T | U | V | W | X | Y | Z | Numbers | Symbols | Term Link



Cite this page: Hill, M.A. (2018, November 15) Embryology Molecular Development - Epigenetics. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Molecular_Development_-_Epigenetics

What Links Here?
© Dr Mark Hill 2018, UNSW Embryology ISBN: 978 0 7334 2609 4 - UNSW CRICOS Provider Code No. 00098G