Transient transcription in the early embryo sets an epigenetic state that programs postnatal growth

Greenberg, Maxim V. C.; Glaser, Juliane; Borsos, Máté; Marjou, Fatima El; Walter, Marius; Teissandier, Aurélie; Bourc’his, Déborah

doi:10.1038/ng.3718

Cited by 85 publications

(123 citation statements)

References 59 publications

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“…As expected, the ATAC-Seq peak for pLiz diminished as it became repressed and DNA methylated in EpiLCs. An ATAC-Seq peak was already present at pZdbf2 in ESCs; this is correlated with our previous data indicating that pZdbf2 is bivalent and poised in ESCs (22,24).…”

Section: Two Classes Of Putative Enhancers Lie In the Liz/zdbf2 Locussupporting

confidence: 91%

“…To test this, we generated homozygous deletions of combinations of putative enhancer elements ( Figure S2D). The E3 element also serves as the promoter of the Gpr1 gene, which is lowly expressed in our system and we previously showed plays no role in Zdbf2 regulation (22). As such, deleting the element had no impact on expression or DNA methylation at the Zdbf2 locus ( Figure S2E and S2F).…”

Section: Determination Of Enhancer Function and Regulationmentioning

confidence: 49%

“…To discover functional genetic elements that regulate Zdbf2 alternative promoter usage during the de novo DNA methylation program, we performed an assay for transposase-accessible chromatin followed by sequencing (ATAC-Seq) (23) in naïve ESCs (cultured in 2i/LIF+vitC), when pLiz is active and pZdbf2 is repressed (22) ( Figure 1A). We previously showed that by differentiating ESCs into primed, highly DNA methylated epiblast-like cells (EpiLCs), we can faithfully recapitulate in vivo pLiz to pZdbf2 promoter usage dynamics (22). Therefore, we also performed ATAC-Seq in day 7 (D7) EpiLCs ( Figure 1A).…”

Section: Two Classes Of Putative Enhancers Lie In the Liz/zdbf2 Locusmentioning

confidence: 99%

“…Rather, there is a stratified relationship between the two promoters: pLiz activity is absolutely required for deposition of DNA methylation at a somatic differentially methylated region (sDMR). The sDMR DNA methylation, in turn, antagonizes polycombmediated repression, freeing pZdbf2 ( Figure S1A) (21,22). Mice that are deficient for Liz are never able to activate Zdbf2, and this leads to a substantial growth defect.…”

Section: Introductionmentioning

confidence: 99%

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Dynamic enhancer partitioning instructs activation of a growth regulator during exit from naïve pluripotency

Greenberg

Teissander

Walter

et al. 2018

Preprint

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During early mammalian development, the genome undergoes profound transitions in chromatin states, topological organization and recruitment of cis regulatory factors involved in transcriptional control. How these three layers of gene regulation interact is the matter of intense research. The Zdbf2 gene-which is involved in growth control-provides a valuable model to study this question: upon exit from naïve pluripotency and prior to tissue differentiation, it undergoes a switch in usage from a distal to a proximal promoter, along with a switch in chromatin states, from polycomb to DNA methylation occupancy. Using an embryonic stem cell (ESC) culture system to mimic this period, we show here that four enhancers contribute to the Zdbf2 promoter switch, concomitantly with dynamic changes in chromosome architecture. Indeed, CTCF plays a key role in partitioning the locus in ESCs, to facilitate enhancer contact with the distal Zdbf2 promoter only. Partition relieving enhances proximal Zdbf2 promoter activity, as observed during differentiation or with mutants that lack local CTCF-based partition. Importantly, we show that CTCF-based regulation occurs independently of the polycomb and DNA methylation pathways. Our study reveals the importance of multi-layered regulatory frameworks to ensure proper spatio-temporal activation of developmentally important genes.

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Section: Two Classes Of Putative Enhancers Lie In the Liz/zdbf2 Locussupporting

confidence: 91%

Section: Determination Of Enhancer Function and Regulationmentioning

confidence: 49%

Section: Two Classes Of Putative Enhancers Lie In the Liz/zdbf2 Locusmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Dynamic enhancer partitioning instructs activation of a growth regulator during exit from naïve pluripotency

Greenberg

Teissander

Walter

et al. 2018

Preprint

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“…Our findings also caution against overinterpreting the functional significance of the epigenome and 3D genome organisation -at least in ESCs. It will now be interesting to establish how DNA methylation and polycomb become increasingly functionally important for gene regulation as development progresses (Greenberg et al, 2017).…”

Section: The Epigenome and 3d Genome Do Not Affect The Naive Pluripotmentioning

confidence: 99%

DNA methylation directs polycomb-dependent 3D genome re- organisation in naive pluripotency

McLaughlin

Flyamer

Thomson

et al. 2019

Preprint

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The DNA hypomethylation that occurs when embryonic stem cells (ESCs) are directed to the ground state of naïve pluripotency by culturing in 2i conditions results in redistribution of polycomb (H3K27me3) away from its target loci. Here we demonstrate that 3D genome organisation is also altered in 2i. We found chromatin decompaction at polycomb target loci as well as loss of long-range polycomb interactions. By preventing DNA hypomethylation during the transition to the ground-state, we are able to restore the H3K27me3 distribution, and polycomb-mediated 3D genome organisation that is characteristic of primed ESCs grown in serum, to ESCs in 2i. However, these cells retain the functional characteristics of 2i ground state ESCs. Our findings demonstrate the central role of DNA methylation in shaping major aspects of 3D genome organisation but caution against assuming causal roles for the epigenome and 3D genome in gene regulation and function in ESCs.

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Genomic Imprinting at the Transcriptional Level

Brandão

Rocha

2018

Encyclopedia of Life Sciences

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Genomic imprinting is an epigenetic mechanism of gene regulation causing genes to be expressed from only one of the two parentally inherited chromosomes in mammals. Imprinted genes often cluster in large chromosomal domains and their expression is regulated by cis ‐acting imprinting control regions. These regions carry an epigenetic imprint, mostly in the form of deoxyribonucleic acid methylation, laid down during gametogenesis, when the two genomes are separated. Regulation of imprinting in these clusters is thought to be explained by competition of promoters of different genes to common enhancers or cis ‐regulation induced by long noncoding RNAs. Aberrant expression of imprinted genes leads to human pathologies characterised by mental, developmental and metabolic abnormalities. Imprinting errors are also often seen in stem cells, including induced pluripotent stem cells and affect their physiology and pluripotent potential. For these reasons, genomic imprinting remains a crucial model for understanding the epigenetic influence on transcriptional activity and repression. Key Concepts A subset of genes in the mammalian genome (<1%) known as imprinted genes are expressed exclusively from one of the two parental alleles. Imprinted genes are involved in foetal growth and placental development in the uterus, as well as brain function and metabolism in adults. Most imprinted genes are physically linked in chromosomal regions known as imprinted clusters and are coordinatively regulated. Genomic imprinting at clusters is regulated by imprinting control regions (ICRs) that acquired an imprint distinguishing the two parental alleles during gametogenesis. DNA methylation is the bona fide imprint mark at ICRs, but chromatin modifications, such as H3K27me3, also serve as an imprint mark at transient and/or placental‐specific ICRs. Methylation imprints are established in the parental germ line, resist the wave of DNA demethylation after fertilisation and are erased before resetting in the germ line according to the sex. Insulation of common enhancers by the methylated sensitive protein Ctcf explains the imprinting regulation at the Igf2/H19 region. Silencing of genes in cis by long noncoding RNAs (lncRNAs) explains the imprinting regulation of, at least, three clusters through transcription interference and recruitment of chromatin modifiers. Deregulation of genomic imprinting can cause imprinted disorders in humans, which exhibit parent of origin effects in their pattern of inheritance. Imprinting defects occur in stem cells and during somatic reprogramming into induced pluripotent stem cells (iPSCs) affecting their pluripotency and harness their potential clinical applications.

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Transient transcription in the early embryo sets an epigenetic state that programs postnatal growth

Cited by 85 publications

References 59 publications

Dynamic enhancer partitioning instructs activation of a growth regulator during exit from naïve pluripotency

Dynamic enhancer partitioning instructs activation of a growth regulator during exit from naïve pluripotency

DNA methylation directs polycomb-dependent 3D genome re- organisation in naive pluripotency

Genomic Imprinting at the Transcriptional Level

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