Synthetic CpG islands reveal DNA sequence determinants of chromatin structure

Wächter, Elisabeth; Quante, Timo; Merusi, Cara; Arczewska, Aleksandra; Stewart, Francis; Webb, Shaun; Bird, Adrian

doi:10.7554/elife.03397

Cited by 109 publications

(106 citation statements)

References 40 publications

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“…10a). These results identify phylo(−)DMRs as developmentally activated enhancers of high CpG density in zebrafish and mouse and low and intermediate CpG density in Xenopus , and they support previous notions that CpG density alone is not a major driver of regulatory function 34–36 .…”

Section: Resultssupporting

confidence: 88%

Active DNA demethylation at enhancers during the vertebrate phylotypic period

et al. 2016

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The vertebrate body plan and organs are shaped during a conserved embryonic phase called the phylotypic stage. However, the mechanisms that guide the epigenome through this transition and their evolutionary conservation remain elusive. Here we report widespread DNA demethylation of enhancers during the phylotypic period in zebrafish, Xenopus tropicalis and mouse. These enhancers are linked to developmental genes that display coordinated transcriptional and epigenomic changes in the diverse vertebrates during embryogenesis. Binding of Tet proteins to (hydroxy)methylated DNA and enrichment of 5-hydroxymethylcytosine in these regions implicated active DNA demethylation in this process. Furthermore, loss of function of Tet1, Tet2 and Tet3 in zebrafish reduced chromatin accessibility and increased methylation levels specifically at these enhancers, indicative of DNA methylation being an upstream regulator of phylotypic enhancer function. Overall, our study highlights a regulatory module associated with the most conserved phase of vertebrate embryogenesis and suggests an ancient developmental role for Tet dioxygenases.

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Section: Resultssupporting

confidence: 88%

Active DNA demethylation at enhancers during the vertebrate phylotypic period

et al. 2016

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“…Therefore, the propensity of a CGI to gain methylation earlier or later in oogenesis may be a consequence of the degree of K4me2/3 that it initially contains as well as the timing of K4me2/3 removal. In somatic contexts, CpG density and transcription factor binding, both of which directly or indirectly enrich for K4me2/3, have been shown to be instrumental in protecting CGIs during de novo methylation (Krebs et al 2014;Wachter et al 2014). It may be that, in the oocyte, multiple rounds of transcription and targeting are required to enrich K36me3 and deplete K4me2/3 sufficiently to overcome these protections and allow DNMT3A/3L to access and methylate CGI DNA.…”

Section: Discussionmentioning

confidence: 99%

“…Methylated CGIs in both the oocyte and somatic contexts tend to be CpG-poor ( Fig. 2A; Thomson et al 2010;Krebs et al 2014;Wachter et al 2014). We therefore put CGIs into subsets by CpG density to compare K4me2 and K4me3 enrichment in GVmeth and GVunmeth CGIs (Fig.…”

Section: H3k4 Methylation Dynamics At Cgis Destined For Dna Methylationmentioning

confidence: 99%

Dynamic changes in histone modifications precede de novo DNA methylation in oocytes

et al. 2015

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Erasure and subsequent reinstatement of DNA methylation in the germline, especially at imprinted CpG islands (CGIs), is crucial to embryogenesis in mammals. The mechanisms underlying DNA methylation establishment remain poorly understood, but a number of post-translational modifications of histones are implicated in antagonizing or recruiting the de novo DNA methylation complex. In mouse oogenesis, DNA methylation establishment occurs on a largely unmethylated genome and in nondividing cells, making it a highly informative model for examining how histone modifications can shape the DNA methylome. Using a chromatin immunoprecipitation (ChIP) and genome-wide sequencing (ChIP-seq) protocol optimized for low cell numbers and novel techniques for isolating primary and growing oocytes, profiles were generated for histone modifications implicated in promoting or inhibiting DNA methylation. CGIs destined for DNA methylation show reduced protective H3K4 dimethylation (H3K4me2) and trimethylation (H3K4me3) in both primary and growing oocytes, while permissive H3K36me3 increases specifically at these CGIs in growing oocytes. Methylome profiling of oocytes deficient in H3K4 demethylase KDM1A or KDM1B indicated that removal of H3K4 methylation is necessary for proper methylation establishment at CGIs. This work represents the first systematic study performing ChIP-seq in oocytes and shows that histone remodeling in the mammalian oocyte helps direct de novo DNA methylation events.

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“…Class 3a origins also show high CGI content that can create bivalent domains in mESCs (Wachter et al 2014). These domains (80.6% of bivalent domains are in mESC origins) are composed of an activating (H3K4me3) and a repressive mark (H3K27me3) (Bernstein et al 2006) and contain promoters of developmentally important genes that are kept poised for activation until lineage specification.…”

Section: Plasticity and Synergy Of Origin Selection By Specialized Epmentioning

confidence: 99%

The chromatin environment shapes DNA replication origin organization and defines origin classes

et al. 2015

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To unveil the still-elusive nature of metazoan replication origins, we identified them genome-wide and at unprecedented high-resolution in mouse ES cells. This allowed initiation sites (IS) and initiation zones (IZ) to be differentiated. We then characterized their genetic signatures and organization and integrated these data with 43 chromatin marks and factors. Our results reveal that replication origins can be grouped into three main classes with distinct organization, chromatin environment, and sequence motifs. Class 1 contains relatively isolated, low-efficiency origins that are poor in epigenetic marks and are enriched in an asymmetric AC repeat at the initiation site. Late origins are mainly found in this class. Class 2 origins are particularly rich in enhancer elements. Class 3 origins are the most efficient and are associated with open chromatin and polycomb protein-enriched regions. The presence of Origin G-rich Repeated elements (OGRE) potentially forming G-quadruplexes (G4) was confirmed at most origins. These coincide with nucleosome-depleted regions located upstream of the initiation sites, which are associated with a labile nucleosome containing H3K64ac. These data demonstrate that specific chromatin landscapes and combinations of specific signatures regulate origin localization. They explain the frequently observed links between DNA replication and transcription. They also emphasize the plasticity of metazoan replication origins and suggest that in multicellular eukaryotes, the combination of distinct genetic features and chromatin configurations act in synergy to define and adapt the origin profile.

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Synthetic CpG islands reveal DNA sequence determinants of chromatin structure

Cited by 109 publications

References 40 publications

Active DNA demethylation at enhancers during the vertebrate phylotypic period

Active DNA demethylation at enhancers during the vertebrate phylotypic period

Dynamic changes in histone modifications precede de novo DNA methylation in oocytes

The chromatin environment shapes DNA replication origin organization and defines origin classes

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