Identification of genetic elements that autonomously determine DNA methylation states

Lienert, Florian; Wirbelauer, C; Som, Indrani; Dean, Ann; Mohn, Fabio; Schübeler, Dirk

doi:10.1038/ng.946

Cited by 366 publications

(380 citation statements)

References 51 publications

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“…This finding has important implications for transcriptional regulation: First, it argues that context-dependent TF binding is determined by the cis-regulatory sequence, consistent with the sufficiency of enhancer sequences to recapitulate their endogenous chromatin state (i.e., histone modifications and DNA methylation) (e.g., Lienert et al 2011) and activity (e.g., Banerji et al 1983;Doyle et al 1989;Visel et al 2009) in different contexts. Second, in vivo binding appears to be determined by combinations of TF motifs rather than a single TF's motif, therefore substantially increasing the information content and specificity of in vivo binding.…”

Section: Discussionmentioning

confidence: 65%

Uncovering cis-regulatory sequence requirements for context-specific transcription factor binding

et al. 2012

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The regulation of gene expression is mediated at the transcriptional level by enhancer regions that are bound by sequence-specific transcription factors (TFs). Recent studies have shown that the in vivo binding sites of single TFs differ between developmental or cellular contexts. How this context-specific binding is encoded in the cis-regulatory DNA sequence has, however, remained unclear. We computationally dissect context-specific TF binding sites in Drosophila, Caenorhabditis elegans, mouse, and human and find distinct combinations of sequence motifs for partner factors, which are predictive and reveal specific motif requirements of individual binding sites. We predict that TF binding in the early Drosophila embryo depends on motifs for the early zygotic TFs Vielfaltig (also known as Zelda) and Tramtrack. We validate experimentally that the activity of Twist-bound enhancers and Twist binding itself depend on Vielfaltig motifs, suggesting that Vielfaltig is more generally important for early transcription. Our finding that the motif content can predict contextspecific binding and that the predictions work across different Drosophila species suggests that characteristic motif combinations are shared between sites, revealing context-specific motif codes (cis-regulatory signatures), which appear to be conserved during evolution. Taken together, this study establishes a novel approach to derive predictive cis-regulatory motif requirements for individual TF binding sites and enhancers. Importantly, the method is generally applicable across different cell types and organisms to elucidate cis-regulatory sequence determinants and the corresponding trans-acting factors from the increasing number of tissue-and cell-type-specific TF binding studies.

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Section: Discussionmentioning

confidence: 65%

Uncovering cis-regulatory sequence requirements for context-specific transcription factor binding

et al. 2012

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“…All nine elements were inserted separately into a previously described target site in the β-globin locus using CRE-mediated recombination (28) (Fig. 1A).…”

Section: Resultsmentioning

confidence: 99%

“…We have previously suggested that TF binding within CGIs contributes to their low DNA methylation (28), which could be relevant for the recruitment of the H3K27me3 mark because occupancy of DNA methylation and H3K27me3 in ES cells has been observed to be mutually exclusive at CGIs (33), leading to the hypothesis that DNA methylation could inhibit H3K27me3 acquisition. To explore whether increased DNA methylation could account for the absence of H3K27me3 at the two elements with modified sequence backbone, we first determined their DNA methylation state.…”

Section: Dna Methylation and H3k27me3 Recruitment Exclude Each Other Atmentioning

confidence: 99%

Short sequences can efficiently recruit histone H3 lysine 27 trimethylation in the absence of enhancer activity and DNA methylation

Jermann

Hoerner

Burger

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Significance Polycomb repressive complex 2 functions in gene repression and acts by methylating histone H3 at lysine 27 (H3K27me3). Despite its relevance, it remains elusive how this complex is recruited to its target sites in the genome. Here, we used repeated genomic targeting in embryonic stem cells to identify DNA sequence determinants that autonomously confer H3K27me3 recruitment. We show that surprisingly small CG-rich DNA sequences are sufficient to recruit H3K27me3, but only if they are devoid of DNA methylation and transcriptional activity. This study provides new insights into the mechanisms recruiting H3K27me3 and the cross-talk between diverse chromatin modifications.

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“…However, DNA methylation is conserved across extremely long evolutionary times (20). Moreover, DNA methylation patterns of specific genomic regions may be determined by sequence characteristics themselves (21).…”

Section: Majority Of Duplicate Genes Exhibit Consistent Patterns Of Dnamentioning

confidence: 99%

DNA methylation and evolution of duplicate genes

Keller

2014

Proc. Natl. Acad. Sci. U.S.A.

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The evolutionary mechanisms underlying duplicate gene maintenance and divergence remain highly debated. Epigenetic modifications, such as DNA methylation, may contribute to duplicate gene evolution by facilitating tissue-specific regulation. However, the role of epigenetic divergence on duplicate gene evolution remains little understood. Here we show, using comprehensive data across 10 diverse human tissues, that DNA methylation plays critical roles in several aspects of duplicate gene evolution. We first demonstrate that duplicate genes are initially heavily methylated, before gradually losing DNA methylation as they age. Within each pair, DNA methylation divergence between duplicate partners increases with evolutionary age. Importantly, tissuespecific DNA methylation of duplicates correlates with tissuespecific expression, implicating DNA methylation as a causative factor for functional divergence of duplicate genes. These patterns are apparent in promoters but not in gene bodies, in accord with the complex relationship between gene-body DNA methylation and transcription. Remarkably, many duplicate gene pairs exhibit consistent division of DNA methylation across multiple, divergent tissues: For the majority (73%) of duplicate gene pairs, one partner is always hypermethylated compared with the other. This is indicative of a common underlying determinant of DNA methylation. The division of DNA methylation is also consistent with their chromatin accessibility profiles. Moreover, at least two sequence motifs known to interact with the Sp1 transcription factor mark promoters of more hypomethylated duplicate partners. These results demonstrate critical roles of DNA methylation, as well as complex interaction between genome and epigenome, on duplicate gene evolution.gene duplication | tissue specificity | epigenomics | genomics G ene duplication is a main process generating genomic repertoires for subsequent functional innovation (1, 2). Elucidating the mechanisms by which newly duplicated genes are retained and evolve new functions is one of the most fundamental problems in molecular evolution. Even though significant progresses have been made (3-9), detailed molecular mechanisms of duplicate gene divergence are not satisfactorily resolved (10, 11).Here we examine a relatively new avenue of research on duplicate gene evolution: the epigenetic divergence of duplicate genes and how this divergence might relate to functional differentiation of duplicate genes. We focus on DNA methylation. It has been proposed that epigenetic mechanisms such as DNA methylation may facilitate evolution by gene duplication (12). Rodin and Riggs (12) have demonstrated by computational modeling that rates of functional diversification such as subfunctionalization and neofunctionalization increase when epigenetic silencing of duplicates is possible. This advantage of epigenetic silencing is particularly significant when effective population sizes are small, as in humans (12).Some earlier observations are consistent with epigenetic silencing...

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Identification of genetic elements that autonomously determine DNA methylation states

Cited by 366 publications

References 51 publications

Uncovering cis-regulatory sequence requirements for context-specific transcription factor binding

Uncovering cis-regulatory sequence requirements for context-specific transcription factor binding

Short sequences can efficiently recruit histone H3 lysine 27 trimethylation in the absence of enhancer activity and DNA methylation

DNA methylation and evolution of duplicate genes

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