Talk:Molecular Development - Epigenetics
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Cite this page: Hill, M.A. (2019, September 22) Embryology Molecular Development - Epigenetics. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Talk:Molecular_Development_-_Epigenetics
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A Unique Gene Regulatory Network Resets the Human Germline Epigenome for Development
Cell. 2015 Jun 4;161(6):1453-67. doi: 10.1016/j.cell.2015.04.053.
Tang WW1, Dietmann S2, Irie N1, Leitch HG2, Floros VI3, Bradshaw CR4, Hackett JA1, Chinnery PF3, Surani MA5.
Resetting of the epigenome in human primordial germ cells (hPGCs) is critical for development. We show that the transcriptional program of hPGCs is distinct from that in mice, with co-expression of somatic specifiers and naive pluripotency genes TFCP2L1 and KLF4. This unique gene regulatory network, established by SOX17 and BLIMP1, drives comprehensive germline DNA demethylation by repressing DNA methylation pathways and activating TET-mediated hydroxymethylation. Base-resolution methylome analysis reveals progressive DNA demethylation to basal levels in week 5-7 in vivo hPGCs. Concurrently, hPGCs undergo chromatin reorganization, X reactivation, and imprint erasure. Despite global hypomethylation, evolutionarily young and potentially hazardous retroelements, like SVA, remain methylated. Remarkably, some loci associated with metabolic and neurological disorders are also resistant to DNA demethylation, revealing potential for transgenerational epigenetic inheritance that may have phenotypic consequences. We provide comprehensive insight on early human germline transcriptional network and epigenetic reprogramming that subsequently impacts human development and disease. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved. Comment in Forget the Parents: Epigenetic Reprogramming in Human Germ Cells. [Cell. 2015]
© 2015 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
DNA Demethylation Dynamics in the Human Prenatal Germline
Cell. 2015 Jun 4;161(6):1425-36. doi: 10.1016/j.cell.2015.05.012. Epub 2015 May 21.
Gkountela S1, Zhang KX2, Shafiq TA1, Liao WW3, Hargan-Calvopiña J1, Chen PY4, Clark AT5.
Global DNA demethylation in humans is a fundamental process that occurs in pre-implantation embryos and reversion to naive ground state pluripotent stem cells (PSCs). However, the extent of DNA methylation reprogramming in human germline cells is unknown. Here, we performed whole-genome bisulfite sequencing (WGBS) and RNA-sequencing (RNA-seq) of human prenatal germline cells from 53 to 137 days of development. We discovered that the transcriptome and methylome of human germline is distinct from both human PSCs and the inner cell mass (ICM) of human blastocysts. Using this resource to monitor the outcome of global DNA demethylation with reversion of primed PSCs to the naive ground state, we uncovered hotspots of ultralow methylation at transposons that are protected from demethylation in the germline and ICM. Taken together, the human germline serves as a valuable in vivo tool for monitoring the epigenome of cells that have emerged from a global DNA demethylation event. Copyright © 2015 Elsevier Inc. All rights reserved.
Epigenetic reprogramming in the germline resets genomic potential and erases epigenetic memory. Three studies by Gkountela et al., Guo et al., and Tang et al. analyze the transcriptional and epigenetic landscape of human primordial germ cells, revealing a unique transcriptional network and progressive and conserved global erasure of DNA methylation.
Notes on the role of dynamic DNA methylation in mammalian development
Proc Natl Acad Sci U S A. 2015 Jun 2;112(22):6796-9. doi: 10.1073/pnas.1415301111. Epub 2014 Nov 3.
Bestor TH1, Edwards JR2, Boulard M3.
It has been nearly 40 y since it was suggested that genomic methylation patterns could be transmitted via maintenance methylation during S phase and might play a role in the dynamic regulation of gene expression during development [Holliday R, Pugh JE (1975) Science 187(4173):226-232; Riggs AD (1975) Cytogenet Cell Genet 14(1):9-25]. This revolutionary proposal was justified by "... our almost complete ignorance of the mechanism for the unfolding of the genetic program during development" that prevailed at the time. Many correlations between transcriptional activation and demethylation have since been reported, but causation has not been demonstrated and to date there is no reasonable proof of the existence of a complex biochemical system that activates and represses genes via reversible DNA methylation. Such a system would supplement or replace the conserved web of transcription factors that regulate cellular differentiation in organisms that have unmethylated genomes (such as Caenorhaditis elegans and the Dipteran insects) and those that methylate their genomes. DNA methylation does have essential roles in irreversible promoter silencing, as in the monoallelic expression of imprinted genes, in the silencing of transposons, and in X chromosome inactivation in female mammals. Rather than reinforcing or replacing regulatory pathways that are conserved between organisms that have either methylated or unmethylated genomes, DNA methylation endows genomes with the ability to subject specific sequences to irreversible transcriptional silencing even in the presence of all of the factors required for their expression, an ability that is generally unavailable to organisms that have unmethylated genomes. KEYWORDS: DNA methylation; development; differentiation Comment in Reply to Wilkinson: Minor role of programmed methylation and demethylation in mammalian development. [Proc Natl Acad Sci U S A. 2015] Evidence that DNA methylation engenders dynamic gene regulation. [Proc Natl Acad Sci U S A. 2015]
The DNA methylation landscape of human early embryos
Nature. 2014 Jul 31;511(7511):606-10. doi: 10.1038/nature13544. Epub 2014 Jul 23.
Guo H1, Zhu P2, Yan L3, Li R3, Hu B4, Lian Y5, Yan J5, Ren X5, Lin S5, Li J5, Jin X5, Shi X5, Liu P5, Wang X6, Wang W6, Wei Y6, Li X4, Guo F4, Wu X4, Fan X4, Yong J7, Wen L4, Xie SX7, Tang F8, Qiao J5.
DNA methylation is a crucial element in the epigenetic regulation of mammalian embryonic development. However, its dynamic patterns have not been analysed at the genome scale in human pre-implantation embryos due to technical difficulties and the scarcity of required materials. Here we systematically profile the methylome of human early embryos from the zygotic stage through to post-implantation by reduced representation bisulphite sequencing and whole-genome bisulphite sequencing. 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. The inverse correlation between promoter methylation and gene expression gradually strengthens during early embryonic development, reaching its peak at the post-implantation stage. Furthermore, we show that active genes, with the trimethylation of histone H3 at lysine 4 (H3K4me3) mark at the promoter regions in pluripotent human embryonic stem cells, are essentially devoid of DNA methylation in both mature gametes and throughout pre-implantation development. Finally, we also show that long interspersed nuclear elements or short interspersed nuclear elements that are evolutionarily young are demethylated to a milder extent compared to older elements in the same family and have higher abundance of transcripts, indicating that early embryos tend to retain higher residual methylation at the evolutionarily younger and more active transposable elements. Our work provides insights into the critical features of the methylome of human early embryos, as well as its functional relation to the regulation of gene expression and the repression of transposable elements.
DNA methylation dynamics of the human preimplantation embryo
Nature. 2014 Jul 31;511(7511):611-5. doi: 10.1038/nature13581. Epub 2014 Jul 23.
Smith ZD1, Chan MM2, Humm KC3, Karnik R4, Mekhoubad S5, Regev A6, Eggan K7, Meissner A4.
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. This comparatively static landscape is in marked contrast with the events of fertilization, during which the paternal genome is globally reprogrammed. Paternal genome demethylation includes the majority of CpGs, although methylation remains detectable at several notable features. These dynamics have been extensively characterized in the mouse, with only limited observations available in other mammals, and direct measurements are required to understand the extent to which early embryonic landscapes are conserved. 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. Although most features share similar dynamics to those in mouse, maternally contributed methylation is divergently targeted to species-specific sets of CpG island promoters that extend beyond known imprint control regions. Retrotransposon regulation is also highly diverse, and transitions from maternally to embryonically expressed elements. 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.
Fine-tuning evolution: germ-line epigenetics and inheritance
Reproduction. 2013 Apr 30. [Epub ahead of print]
Stringer J, Barrand S, Western P. Source J Stringer, Centre for Reproduction and Development, Monash Institute of Medical Research, Clayton, Australia. Abstract In mice, epiblast cells found both the germ-line and somatic lineages in the developing embryo. These epiblast cells carry epigenetic information from both parents that is required for development and cell function in the fetus and during post-natal life. However, germ cells must establish an epigenetic program that supports totipotency and the configuration of parent-specific epigenetic states in the gametes. To achieve this, the epigenetic information inherited by the primordial germ cells at specification is erased and new epigenetic states are established during development of the male and female germ-lines. Errors in this process can lead to transmission of epimutations through the germ-line, which have the potential to affect development and disease in the parent's progeny. This review discusses epigenetic reprogramming in the germ-line and the transmission of epigenetic information to the following generation. PMID 23633622
Extensive epigenetic reprogramming in human somatic tissues between fetus and adult
Epigenetics Chromatin. 2011 May 5;4:7.
Yuen RK, Neumann SM, Fok AK, Peñaherrera MS, McFadden DE, Robinson WP, Kobor MS. Source Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada. firstname.lastname@example.org.
BACKGROUND: Development of human tissue is influenced by a combination of intrinsic biological signals and extrinsic environmental stimuli, both of which are mediated by epigenetic regulation, including DNA methylation. However, little is currently known of the normal acquisition or loss of epigenetic markers during fetal and postnatal development.
RESULTS: The DNA methylation status of over 1000 CpGs located in the regulatory regions of nearly 800 genes was evaluated in five somatic tissues (brain, kidney, lung, muscle and skin) from eight normal second-trimester fetuses. Tissue-specific differentially methylated regions (tDMRs) were identified in 195 such loci. However, comparison with corresponding data from trisomic fetuses (five trisomy 21 and four trisomy 18) revealed relatively few DNA methylation differences associated with trisomy, despite such conditions having a profound effect on development. Of interest, only 17% of the identified fetal tDMRs were found to maintain this same tissue-specific DNA methylation in adult tissues. Furthermore, 10% of the sites analyzed, including sites associated with imprinted genes, had a DNA methylation difference of >40% between fetus and adult. This plasticity of DNA methylation over development was further confirmed by comparison with similar data from embryonic stem cells, with the most altered methylation levels being linked to domains with bivalent histone modifications.
CONCLUSIONS: Most fetal tDMRs seem to reflect transient DNA methylation changes during development rather than permanent epigenetic signatures. The extensive tissue-specific and developmental-stage specific nature of DNA methylation will need to be elucidated to identify abnormal patterns of DNA methylation associated with abnormal development or disease.
Maternal genome-wide DNA methylation patterns and congenital heart defects
PLoS One. 2011 Jan 24;6(1):e16506.
Chowdhury S, Erickson SW, Macleod SL, Cleves MA, Hu P, Karim MA, Hobbs CA. Department of Pediatrics, College of Medicine, University of Arkansas for Medical Sciences, Arkansas Children's Hospital Research Institute, Little Rock, Arkansas, United States of America.
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 conducted a population based, case-control study of genome-wide maternal DNA methylation to determine if alterations in gene-specific methylation were associated with CHDs. Using the Illumina Infinium Human Methylation27 BeadChip, we assessed maternal gene-specific methylation in over 27,000 CpG sites from DNA isolated from peripheral blood lymphocytes. Our study sample included 180 mothers with non-syndromic CHD-affected pregnancies (cases) and 187 mothers with unaffected pregnancies (controls). Using a multi-factorial statistical model, we observed differential methylation between cases and controls at multiple CpG sites, although no CpG site reached the most stringent level of genome-wide statistical significance. The majority of differentially methylated CpG sites were hypermethylated in cases and located within CpG islands. Gene Set Enrichment Analysis (GSEA) revealed that the genes of interest were enriched in multiple biological processes involved in fetal development. Associations with canonical pathways previously shown to be involved in fetal organogenesis were also observed. 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.
Stage-specific histone modification profiles reveal global transitions in the Xenopus embryonic epigenome
PLoS One. 2011;6(7):e22548. Epub 2011 Jul 22.
Schneider TD, Arteaga-Salas JM, Mentele E, David R, Nicetto D, Imhof A, Rupp RA. Source Department of Molecular Biology, Adolf-Butenandt Institut, Ludwig-Maximilians-Universität München, Munich, Germany.
Vertebrate embryos are derived from a transitory pool of pluripotent cells. By the process of embryonic induction, these precursor cells are assigned to specific fates and differentiation programs. Histone post-translational modifications are thought to play a key role in the establishment and maintenance of stable gene expression patterns underlying these processes. While on gene level histone modifications are known to change during differentiation, very little is known about the quantitative fluctuations in bulk histone modifications during development. To investigate this issue we analysed histones isolated from four different developmental stages of Xenopus laevis by mass spectrometry. In toto, we quantified 59 modification states on core histones H3 and H4 from blastula to tadpole stages. During this developmental period, we observed in general an increase in the unmodified states, and a shift from histone modifications associated with transcriptional activity to transcriptionally repressive histone marks. We also compared these naturally occurring patterns with the histone modifications of murine ES cells, detecting large differences in the methylation patterns of histone H3 lysines 27 and 36 between pluripotent ES cells and pluripotent cells from Xenopus blastulae. By combining all detected modification transitions we could cluster their patterns according to their embryonic origin, defining specific histone modification profiles (HMPs) for each developmental stage. To our knowledge, this data set represents the first compendium of covalent histone modifications and their quantitative flux during normogenesis in a vertebrate model organism. The HMPs indicate a stepwise maturation of the embryonic epigenome, which may be causal to the progressing restriction of cellular potency during development.
The paternal epigenome and embryogenesis: poising mechanisms for development
Asian J Androl. 2010 Oct 25. Jenkins TG, Carrell DT.
Andrology and IVF Laboratories, Department of Surgery, University of Utah, Salt Lake City, UT, USA. Abstract The scope of paternal contributions during early embryonic development has long been considered limited. Dramatic changes in chromatin structure throughout spermatogenesis have been thought to leave the sperm void of complex layers of epigenetic regulation over the DNA blueprint, thus leaving the balance of that regulation to the oocyte. However, recent work in the fields of epigenetics and male factor infertility has placed this long-held, and now controversial dogma, in a new light. Elegant studies investigating chromatin and epigenetic modifications in the developing sperm cell have provided new insights that may establish a more critical role for the paternal epigenome in the developing embryo. DNA methylation, histone tail modifications, targeted histone retention and protamine incorporation into the chromatin have great influence in the developing sperm cell. Perturbations in the establishment and/or maintenance of any of these epigenetic marks have been demonstrated to affect fertility status, ranging in severity from mild to catastrophic. Sperm require this myriad of chromatin structural changes not only to serve a protective role to DNA throughout spermatogenesis and future delivery to the egg, but also, it appears, to contribute to the developmental program of the future embryo. This review will focus on our current understanding of the epigenetics of sperm. We will discuss sperm-specific chromatin modifications that result in genes essential to development being poised for activation early in embryonic development, the disruption of which may result in reduced fecundity.Asian Journal of Andrology advance online publication, 25 October 2010; doi:10.1038/aja.2010.61.
MLL2 is required in oocytes for bulk histone 3 lysine 4 trimethylation and transcriptional silencing
PLoS Biol. 2010 Aug 17;8(8). pii: e1000453.
Andreu-Vieyra CV, Chen R, Agno JE, Glaser S, Anastassiadis K, Stewart AF, Matzuk MM.
Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas, United States of America.
During gametogenesis and pre-implantation development, the mammalian epigenome is reprogrammed to establish pluripotency in the epiblast. Here we show that the histone 3 lysine 4 (H3K4) methyltransferase, MLL2, controls most of the promoter-specific chromatin modification, H3K4me3, during oogenesis and early development. Using conditional knockout mutagenesis and a hypomorph model, we show that Mll2 deficiency in oocytes results in anovulation and oocyte death, with increased transcription of p53, apoptotic factors, and Iap elements. MLL2 is required for (1) bulk H3K4me3 but not H3K4me1, indicating that MLL2 controls most promoters but monomethylation is regulated by a different H3K4 methyltransferase; (2) the global transcriptional silencing that preceeds resumption of meiosis but not for the concomitant nuclear reorganization into the surrounded nucleolus (SN) chromatin configuration; (3) oocyte survival; and (4) normal zygotic genome activation. These results reveal that MLL2 is autonomously required in oocytes for fertility and imply that MLL2 contributes to the epigenetic reprogramming that takes place before fertilization. We propose that once this task has been accomplished, MLL2 is not required until gastrulation and that other methyltransferases are responsible for bulk H3K4me3, thereby revealing an unexpected epigenetic control switch amongst the H3K4 methyltransferases during development.
A comparative analysis of extra-embryonic endoderm cell lines
PLoS One. 2010 Aug 6;5(8):e12016.
Brown K, Legros S, Artus J, Doss MX, Khanin R, Hadjantonakis AK, Foley A.
Greenberg Division of Cardiology, Weill Cornell Medical College, New York, New York, United States of America. Abstract Prior to gastrulation in the mouse, all endodermal cells arise from the primitive endoderm of the blastocyst stage embryo. Primitive endoderm and its derivatives are generally referred to as extra-embryonic endoderm (ExEn) because the majority of these cells contribute to extra-embryonic lineages encompassing the visceral endoderm (VE) and the parietal endoderm (PE). During gastrulation, the definitive endoderm (DE) forms by ingression of cells from the epiblast. The DE comprises most of the cells of the gut and its accessory organs. Despite their different origins and fates, there is a surprising amount of overlap in marker expression between the ExEn and DE, making it difficult to distinguish between these cell types by marker analysis. This is significant for two main reasons. First, because endodermal organs, such as the liver and pancreas, play important physiological roles in adult animals, much experimental effort has been directed in recent years toward the establishment of protocols for the efficient derivation of endodermal cell types in vitro. Conversely, factors secreted by the VE play pivotal roles that cannot be attributed to the DE in early axis formation, heart formation and the patterning of the anterior nervous system. Thus, efforts in both of these areas have been hampered by a lack of markers that clearly distinguish between ExEn and DE. To further understand the ExEn we have undertaken a comparative analysis of three ExEn-like cell lines (END2, PYS2 and XEN). PYS2 cells are derived from embryonal carcinomas (EC) of 129 strain mice and have been characterized as parietal endoderm-like , END2 cells are derived from P19 ECs and described as visceral endoderm-like, while XEN cells are derived from blastocyst stage embryos and are described as primitive endoderm-like. Our analysis suggests that none of these cell lines represent a bona fide single in vivo lineage. Both PYS2 and XEN cells represent mixed populations expressing markers for several ExEn lineages. Conversely END2 cells, which were previously characterized as VE-like, fail to express many markers that are widely expressed in the VE, but instead express markers for only a subset of the VE, the anterior visceral endoderm. In addition END2 cells also express markers for the PE. We extended these observations with microarray analysis which was used to probe and refine previously published data sets of genes proposed to distinguish between DE and VE. Finally, genome-wide pathway analysis revealed that SMAD-independent TGFbeta signaling through a TAK1/p38/JNK or TAK1/NLK pathway may represent one mode of intracellular signaling shared by all three of these lines, and suggests that factors downstream of these pathways may mediate some functions of the ExEn. These studies represent the first step in the development of XEN cells as a powerful molecular genetic tool to study the endodermal signals that mediate the important developmental functions of the extra-embryonic endoderm. Our data refine our current knowledge of markers that distinguish various subtypes of endoderm. In addition, pathway analysis suggests that the ExEn may mediate some of its functions through a non-classical MAP Kinase signaling pathway downstream of TAK1.