Genome-wide quantification of the effects of DNA methylation on human gene regulation

Lea, Amanda J.; Vockley, Christopher M.; Johnston, Rachel A; Carpio, Christina A. Del; Barreiro, Luis B.; Reddy, Timothy E.; Tung, Jenny

doi:10.1101/146829

Cited by 40 publications

(48 citation statements)

References 30 publications

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“…Together, these patterns suggest that epigenetic modifications play a role in the phenotypic differentiation observed between continental and insular populations. Follow‐up assays to quantify genome‐wide genetic variation and methylation‐dependent expression are necessary to implicate DNA methylation in functional biological differences and control for genetic variation (Dubin et al, ; Tadut, Colomé‐Tatché, & Johannes, ; Lea et al, ), and confirm consistent epigenetic patterning over gene promoters and enhancers. While we found minimal differences between our putatively regulatory and unannotated region methylation data sets, we predict that comparative analyses of methylation between promoter and unannotated regions could be used to assess relative variation explained by phenotypically‐relevant environmental predictors and a step towards deconvoluting the evolutionary significance of certain loci (Figure ).…”

Section: Discussionmentioning

confidence: 99%

Genome‐scale sampling suggests cryptic epigenetic structuring and insular divergence in Canada lynx

2019

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Determining the molecular signatures of adaptive differentiation is a fundamental component of evolutionary biology. A key challenge is to identify such signatures in wild organisms, particularly between populations of highly mobile species that undergo substantial gene flow. The Canada lynx (Lynx canadensis) is one species where mainland populations appear largely undifferentiated at traditional genetic markers, despite inhabiting diverse environments and displaying phenotypic variation. Here, we used high‐throughput sequencing to investigate both neutral genetic structure and epigenetic differentiation across the distributional range of Canada lynx. Newfoundland lynx were identified as the most differentiated population at neutral genetic markers, with demographic modelling suggesting that divergence from the mainland occurred at the end of the last glaciation (20–33 KYA). In contrast, epigenetic structure revealed hidden levels of differentiation across the range coincident with environmental determinants including winter conditions, particularly in the peripheral Newfoundland and Alaskan populations. Several biological pathways related to morphology were differentially methylated between populations, suggesting that epigenetic modifications might explain morphological differences seen between geographically peripheral populations. Our results indicate that epigenetic modifications, specifically DNA methylation, are powerful markers to investigate population differentiation in wild and non‐model systems.

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Section: Discussionmentioning

confidence: 99%

Genome‐scale sampling suggests cryptic epigenetic structuring and insular divergence in Canada lynx

2019

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“…An additional caveat to consider is that some cell lines have lost cGAS/STING signaling and thus it would not be possible to assess this mtp53 gain-of-function in those cells. ( 40–43 )…”

Section: Discussionmentioning

confidence: 99%

Mutant p53 suppresses innate immune signaling to promote tumorigenesis

Ghosh

Saha

Bettke

et al. 2020

Preprint

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29Mutations in the p53 tumor suppressor occur very frequently in human cancer. 30Often, such mutations lead to the constitutive overproduction of mutant p53 31 (mtp53) proteins, which can exert a cancer-promoting gain-of-function (GOF). We 32 have identified a novel mechanism by which mtp53 controls both cell-autonomous 33 and non-cell autonomous signaling to promote cancer cell survival and suppress 34 tumor immune surveillance. Mtp53 interferes with the function of the cytoplasmic 35 DNA sensing machinery, cGAS-STING-TBK1-IRF3, that controls the activation of 36 the innate immune response. We find that mtp53, but not wildtype p53, binds to 37 TANK binding protein kinase (TBK1) and inhibits both its basal and agonist-38 induced activity. The association of mtp53 with TBK1 prevents the formation of a 39 trimeric complex between TBK1-STING-IRF3, which is required for activation, 40 nuclear translocation and transcriptional activity of IRF3. Mtp53 knockdown 41 restores TBK1 activity, resulting in the transcriptional induction of IRF3 target 42 genes and IRF3-dependent apoptosis. Furthermore, inactivation of innate immune 43 signaling by mtp53 alters cytokine production resulting in immune evasion. 44 Restored TBK1 signaling was sufficient to bypass mtp53 and reactivate cell-45 autonomous and non-cell autonomous tumor control. Thus, overriding mtp53's 46 inhibition of this cytosolic DNA sensing pathway may ultimately lead to restored 47 an oncogenic mtp53 protein that exhibits gain-of function activities.(5) Recently, it has been 62 reported that 91% of cancers that have a mtp53 allele have lost their second allele through 63 mutation or chromosomal loss.(6) Furthermore, the presence of mtp53 correlates with increased 64 chromosomal instability leading to loss of tumor suppressor genes and amplification of 65 oncogenes.(6, 7) 66 Aneuploidy is considered one of the hallmarks of cancer and is thought to play an 67 important role in driving tumor cell evolution.(8) Aneuploidy has been shown to provoke cell 68 cycle arrest, senescence, increased pro-inflammatory cytokine production and upregulation of 69 Natural Killer (NK) cell ligands in tumor cells, resulting in their subsequent killing by NK 70 cells.(9) In an in vivo setting, the increased production of pro-inflammatory cytokines coupled 71 with increased NK cell ligand expression permits the recruitment of immune cells and clearance 72 of abnormal cells.(10) Thus, in addition to the cell-autonomous mechanisms that suppress 73 genetic instability, cells also utilize non-cell autonomous mechanisms to signal their own 74 destruction.(9) However, chromosomal instability can give rise to micronuclei, which are prone 75 to rupturing and releasing the DNA into the cytoplasm.(11) DNA leaked into the cytoplasm is 76 recognized by the DNA binding protein, cyclic GMP-AMP synthase (cGAS), which in turn triggers 77 innate immune signaling that results in the production of type I interferons.(12) Mechanistically, 78 DNA promotes cGAS homodimerization and production of the secon...

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“…Epigenetic modifications, such as DNA methylation, contribute to complex traits and diseases 27; 28 . Methylation of cytosine residues within CpG dinucleotides is an important mechanism of variation and regulation in the genome 29–32 . Cytosine methylation, particularly in the promoter region of genes, is often associated with a decrease in transcription 33 , and DNA methylation in the first intron and gene expression is correlated and conserved across tissues and vertebrate species 34 .…”

Section: Introductionmentioning

confidence: 99%

Genome-wide DNA methylation analysis of heavy cannabis exposure in a New Zealand longitudinal cohort

Osborne¹,

Pearson

Noble³

et al. 2019

Preprint

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ABSTRACTCannabis use is of increasing public health interest globally. Here we examined the effect of cannabis use, with and without tobacco, on genome-wide DNA methylation in a longitudinal birth cohort (Christchurch Health and Development Study). We found the most differentially methylated sites in cannabis with tobacco users were in the AHRR and F2RL3 genes, replicating previous studies on the effects of tobacco. Cannabis-only users had no evidence of differential methylation in these genes, or at any other loci at the epigenomewide significance level (P<10−7). However, there were 521 sites differentially methylated at P<0.001 which were enriched for genes involved in cardiomyopathy and neuronal signalling. Further, the most differentially methylated loci were associated with genes with reported roles in brain function (e.g. TMEM190, MUC3L, CDC20 and SP9). We conclude that the effects of cannabis use on the mature human blood methylome differ from, and are less pronounced than, the effects of tobacco use, and that larger sample sizes are required to investigate this further.

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Genome-wide quantification of the effects of DNA methylation on human gene regulation

Abstract: . CC-BY-NC-ND 4.0 International license It is made available under a was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.

Cited by 40 publications

References 30 publications

Genome‐scale sampling suggests cryptic epigenetic structuring and insular divergence in Canada lynx

Genome‐scale sampling suggests cryptic epigenetic structuring and insular divergence in Canada lynx

Mutant p53 suppresses innate immune signaling to promote tumorigenesis

Genome-wide DNA methylation analysis of heavy cannabis exposure in a New Zealand longitudinal cohort

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