Advances in epigenetics link genetics to the environment and disease

Cavalli, Giacomo; Heard, Edith

doi:10.1038/s41586-019-1411-0

Cited by 1,075 publications

(798 citation statements)

References 195 publications

(173 reference statements)

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“…This was also observed at MEs on the Illumina array, confirming our previous observations 18,22 . Enrichment of ERVs at SoC-CpGs is notable since most environment-sensitive mouse MEs are associated with IAPs (which are rodent-specific ERVs) 27 , and Krab zinc-finger protein (KZFP)-mediated repression of transposable elements (TEs) including ERVs has been proposed as a driver of the rapid evolution of gene regulation 38 . The KZFP ZFP57 is particularly interesting in this respect since its binding to DNA is linked both to repression of TEs and to the maintenance of genomic imprints in the pre-implantation embryo 20,39 .…”

Section: Discussionmentioning

confidence: 99%

Environmentally sensitive hotspots in the methylome of the early human embryo

Silver

Saffari

Kessler

et al. 2019

Preprint

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In humans, DNA methylation marks inherited from sperm and egg are largely erased immediately following conception, prior to construction of the embryonic methylome. Exploiting a natural experiment of cyclical seasonal variation including changes in diet and nutritional status in rural Gambia, we replicated 134 loci with a common season-ofconception methylation signature in two independent child cohorts. These robust candidates for sensitivity to early environment were highly enriched for metastable epialleles, parent-of-origin specific methylation and regions hypomethylated in sperm. They tended to co-locate with endogenous retroviral (ERV1, ERVK) elements. Identified loci were influenced but not determined by measured genetic variation, notably through geneenvironment interactions. To the extent that early methylation changes impact gene expression, environmental sensitivity during genomic remethylation in the very early embryo could thus constitute a sense-record-adapt mechanism linking early environment to later phenotype. RESULTS Association of DNA methylation with Gambian season of conception

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Section: Discussionmentioning

confidence: 99%

Environmentally sensitive hotspots in the methylome of the early human embryo

Silver

Saffari

Kessler

et al. 2019

Preprint

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“…Recent studies have begun to reveal potential molecular mechanisms of how environmental perturbations during pregnancy can impact the fetus . Interestingly, these molecular mechanisms of environment–embryo communication involve epigenetic layers of gene regulation known to impact directly the expression of TEs, such as DNA methylation . It will be important to further explore the sensitivity of mammalian embryos to environmental stressors in vivo, including how these may affect the regulation and activity of TEs.…”

Section: Stress Tes and Evolvabilitymentioning

confidence: 99%

What Doesn't Kill You Makes You Stronger: Transposons as Dual Players in Chromatin Regulation and Genomic Variation

2020

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Transposable elements (TEs) are sequences currently or historically mobile, and are present across all eukaryotic genomes. A growing interest in understanding the regulation and function of TEs has revealed seemingly dichotomous roles for these elements in evolution, development, and disease. On the one hand, many gene regulatory networks owe their organization to the spread of cis‐elements and DNA binding sites through TE mobilization during evolution. On the other hand, the uncontrolled activity of transposons can generate mutations and contribute to disease, including cancer, while their increased expression may also trigger immune pathways that result in inflammation or senescence. Interestingly, TEs have recently been found to have novel essential functions during mammalian development. Here, the function and regulation of TEs are discussed, with a focus on LINE1 in mammals. It is proposed that LINE1 is a beneficial endogenous dual regulator of gene expression and genomic diversity during mammalian development, and that both of these functions may be detrimental if deregulated in disease contexts.

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“…In conclusion, we identify H3K79 methylation by DOT1L as an activating epigenetic mark critical for CD8 + T cell differentiation and maintenance of epigenetic identity. Further investigation into the central role of the druggable epigenetic writer DOT1L in lymphocytes is likely to provide novel strategies for immune modulations and disease intervention [92][93][94][95] .…”

Section: Derepression Of Some Of the Targets Of Prc2 Is Just One Of Tmentioning

confidence: 99%

The histone methyltransferase DOT1L prevents antigen-independent differentiation and safeguards epigenetic identity of CD8⁺T cells

Kwesi-Maliepaard

Aslam

Alemdehy

et al. 2019

Preprint

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Cytotoxic T-cell differentiation is guided by epigenome adaptations but how epigenetic mechanisms control lymphocyte development has not been well defined. Here we show that the histone methyltransferase DOT1L, which marks the nucleosome core on active genes, safeguards normal differentiation of CD8 + T cells. T-cell specific ablation of Dot1L resulted in loss of naïve CD8 + T cells and premature differentiation towards a memory-like state, independent of antigen exposure and in a cellintrinsic manner. Without DOT1L, the memory-like CD8 + cells fail to acquire full effector functions in vitro and in vivo. Mechanistically, DOT1L controlled T-cell differentiation and function by ensuring normal T-cell receptor density and signaling, and by maintaining epigenetic identity, in part by indirectly supporting the repression of developmentally-regulated genes. Through our study DOT1L is emerging as a central player in physiology of CD8 + T cells, acting as a barrier to prevent premature differentiation and supporting the licensing of the full effector potential of cytotoxic T cells.

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Advances in epigenetics link genetics to the environment and disease

Cited by 1,075 publications

References 195 publications

Environmentally sensitive hotspots in the methylome of the early human embryo

Environmentally sensitive hotspots in the methylome of the early human embryo

What Doesn't Kill You Makes You Stronger: Transposons as Dual Players in Chromatin Regulation and Genomic Variation

The histone methyltransferase DOT1L prevents antigen-independent differentiation and safeguards epigenetic identity of CD8⁺T cells

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Advances in epigenetics link genetics to the environment and disease

Cited by 1,075 publications

References 195 publications

Environmentally sensitive hotspots in the methylome of the early human embryo

Environmentally sensitive hotspots in the methylome of the early human embryo

What Doesn't Kill You Makes You Stronger: Transposons as Dual Players in Chromatin Regulation and Genomic Variation

The histone methyltransferase DOT1L prevents antigen-independent differentiation and safeguards epigenetic identity of CD8+T cells

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Resources

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The histone methyltransferase DOT1L prevents antigen-independent differentiation and safeguards epigenetic identity of CD8⁺T cells