Species-specific organization of CpG island promoters at mammalian homologous genes.
Ontology highlight
ABSTRACT:
SUBMITTER: Cuadrado M
PROVIDER: S-EPMC1083945 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundMore than 50% of human genes initiate transcription from CpG dinucleotide-rich regions referred to as CpG islands. These genes show differences in their patterns of transcription initiation, and have been reported to have higher levels of some activation-associated chromatin modifications.ResultsHere we report that genes with CpG island promoters have a characteristic transcription-associated chromatin organization. This signature includes high levels of the transcription elongation-associated histone modifications H4K20me1, H2BK5me1 and H3K79me1/2/3 in the 5' end of the gene, depletion of the activation marks H2AK5ac, H3K14ac and H3K23ac immediately downstream of the transcription start site (TSS), and characteristic epigenetic asymmetries around the TSS. The chromosome organization factor CTCF may be bound upstream of RNA polymerase in most active CpG island promoters, and an unstable nucleosome at the TSS may be specifically marked by H4K20me3, the first example of such a modification. H3K36 monomethylation is only detected as enriched in the bodies of active genes that have CpG island promoters. Finally, as expression levels increase, peak modification levels of the histone methylations H3K9me1, H3K4me1, H3K4me2 and H3K27me1 shift further away from the TSS into the gene body.ConclusionsThese results suggest that active genes with CpG island promoters have a distinct step-like series of modified nucleosomes after the TSS. The identity, positioning, shape and relative ordering of transcription-associated histone modifications differ between genes with and without CpG island promoters. This supports a model where chromatin organization reflects not only transcription activity but also the type of promoter in which transcription initiates.
| S-EPMC3580500 | biostudies-literature
Project description:The longstanding dogma that telomeres, the heterochromatic extremities of linear eukaryotic chromosomes, are transcriptionally silent was overturned by the discovery that DNA-dependent RNA polymerase II (RNAPII) transcribes telomeric DNA into telomeric repeat-containing RNA (TERRA). Here, we show that CpG dinucleotide-rich DNA islands, shared among multiple human chromosome ends, promote transcription of TERRA molecules. TERRA promoters sustain cellular expression of reporter genes, are located immediately upstream of TERRA transcription start sites, and are bound by active RNAPII in vivo. Finally, the identified promoter CpG dinucleotides are methylated in vivo, and cytosine methylation negatively regulates TERRA abundance. The existence of subtelomeric promoters, driving TERRA transcription from independent chromosome ends, supports the idea that TERRA exerts fundamental functions in the context of telomere biology.
| S-EPMC2779677 | biostudies-literature
Project description:In embryonic stem (ES) cells, developmental regulators have a characteristic bivalent chromatin signature marked by simultaneous presence of both activation (H3K4me3) and repression (H3K27me3) signals and are thought to be in a 'poised' state for subsequent activation or silencing during differentiation. We collected eleven pairs (H3K4me3 and H3K27me3) of ChIP sequencing datasets in human ES cells and eight pairs in murine ES cells, and predicted high-confidence (HC) bivalent promoters. Over 85% of H3K27me3 marked promoters were bivalent in human and mouse ES cells. We found that (i) HC bivalent promoters were enriched for developmental factors and were highly likely to be differentially expressed upon transcription factor perturbation; (ii) murine HC bivalent promoters were occupied by both polycomb repressive component classes (PRC1 and PRC2) and grouped into four distinct clusters with different biological functions; (iii) HC bivalent and active promoters were CpG rich while H3K27me3-only promoters lacked CpG islands. Binding enrichment of distinct sets of regulators distinguished bivalent from active promoters. Moreover, a 'TCCCC' sequence motif was specifically enriched in bivalent promoters. Finally, this analysis will serve as a resource for future studies to further understand transcriptional regulation during embryonic development.
| S-EPMC4652170 | biostudies-other
Project description:Despite the fact that 45% of all human gene promoters do not contain CpG islands, the role of DNA methylation in control of non-CpG island promoters is controversial and its relevance in normal and pathological processes is poorly understood. Among the few studies which investigate the correlation between DNA methylation and expression of genes with non-CpG island promoters, the majority do not support the view that DNA methylation directly leads to transcription silencing of these genes. Our reporter assays and gene reactivation by 5-aza-2'-deoxycytidine, a DNA demethylating agent, show that DNA methylation occurring at CpG poor LAMB3 promoter and RUNX3 promoter 1(RUNX3 P1) can directly lead to transcriptional silencing in cells competent to express these genes in vitro. Using Nucleosome Occupancy Methylome- Sequencing, NOMe-Seq, a single-molecule, high-resolution nucleosome positioning assay, we demonstrate that active, but not inactive, non-CpG island promoters display a nucleosome-depleted region (NDR) immediately upstream of the transcription start site (TSS). Furthermore, using NOMe-Seq and clonal analysis, we show that in RUNX3 expressing 623 melanoma cells, RUNX3 P1 has two distinct chromatin configurations: one is unmethylated with an NDR upstream of the TSS; another is methylated and nucleosome occupied, indicating that RUNX3 P1 is monoallelically methylated. Together, these results demonstrate that the epigenetic signatures comprising DNA methylation, histone marks and nucleosome occupancy of non-CpG island promoters are almost identical to CpG island promoters, suggesting that aberrant methylation patterns of non-CpG island promoters may also contribute to tumorigenesis and should therefore be included in analyses of cancer epigenetics.
| S-EPMC3196883 | biostudies-other
Project description:R-loops are DNA-RNA hybrids enriched at CpG islands (CGIs) that can regulate chromatin states1-8. How R-loops are recognized and interpreted by specific epigenetic readers is unknown. Here we show that GADD45A (growth arrest and DNA damage protein 45A) binds directly to R-loops and mediates local DNA demethylation by recruiting TET1 (ten-eleven translocation 1). Studying the tumor suppressor TCF21 (ref. 9), we find that antisense long noncoding (lncRNA) TARID (TCF21 antisense RNA inducing promoter demethylation) forms an R-loop at the TCF21 promoter. Binding of GADD45A to the R-loop triggers local DNA demethylation and TCF21 expression. TARID transcription, R-loop formation, DNA demethylation, and TCF21 expression proceed sequentially during the cell cycle. Oxidized DNA demethylation intermediates are enriched at genomic R-loops and their levels increase upon RNase H1 depletion. Genomic profiling in embryonic stem cells identifies thousands of R-loop-dependent TET1 binding sites at CGIs. We propose that GADD45A is an epigenetic R-loop reader that recruits the demethylation machinery to promoter CGIs.
| S-EPMC6420098 | biostudies-literature
Project description:Proteins that bind to DNA depending on its methylation status play an important role in methylation-mediated regulation of gene expression. Using a variety of genomics and proteomics approaches, we identify zinc finger and BTB domain-containing protein 2 (ZBTB2) as a reader of unmethylated DNA in mouse embryonic stem cells. ZBTB2 preferentially binds to CpG island promoters, where it acts as a transcriptional activator. The binding of ZBTB2 to its targets is direct and independent of two other zinc finger proteins, ZBTB25 and ZNF639, which we show to interact with ZBTB2. Our data suggest an anticorrelation between ZBTB2 DNA binding and DNA methylation, indicating that ZBTB2-binding dynamics in vivo are sensitive to differential DNA methylation. ZBTB2 is intricately interwoven with DNA methylation, as we find not only that its binding to DNA is methylation sensitive, but also that ZBTB2 regulates the turnover of methylated DNA In ZBTB2 knockout cells, several pluripotency factors are upregulated, inducing a delay in differentiation. We propose that ZBTB2 is a novel DNA methylation-sensitive transcription factor that regulates cellular differentiation.
| S-EPMC5891434 | biostudies-literature
Project description:CpG islands (CGIs) are associated with over half of human gene promoters and are characterized by a unique chromatin environment and high levels of bidirectional transcriptional activity relative to surrounding genomic regions, suggesting that RNA polymerase (Pol II) progression past the CGI boundaries is restricted. Here we describe a novel transcriptional regulatory step wherein Pol II encounters an additional barrier to elongation distinct from the promoter-proximal pause and occurring at the downstream boundary of the CGI domain. For most CGI-associated promoters, Pol II exhibits a dominant pause at either the promoter-proximal or this distal site that correlates, both in position and in intensity, with local regions of high GC skew, a sequence feature known to form unique secondary structures. Upon signal-induced gene activation, long-range enhancer contacts at the dominant pause site are selectively enhanced, suggesting a new role for enhancers at the downstream pause. These data point to an additional level of control over transcriptional output at a subset of CGI-associated genes that is linked to DNA sequence and the integrity of the CGI domain.
| S-EPMC4617957 | biostudies-literature
Project description:CpG islands (CGIs) are vertebrate genomic landmarks that encompass the promoters of most genes and often lack DNA methylation. Querying their apparent importance, the number of CGIs is reported to vary widely in different species and many do not co-localise with annotated promoters. We set out to quantify the number of CGIs in mouse and human genomes using CXXC Affinity Purification plus deep sequencing (CAP-seq). We also asked whether CGIs not associated with annotated transcripts share properties with those at known promoters. We found that, contrary to previous estimates, CGI abundance in humans and mice is very similar and many are at conserved locations relative to genes. In each species CpG density correlates positively with the degree of H3K4 trimethylation, supporting the hypothesis that these two properties are mechanistically interdependent. Approximately half of mammalian CGIs (>10,000) are "orphans" that are not associated with annotated promoters. Many orphan CGIs show evidence of transcriptional initiation and dynamic expression during development. Unlike CGIs at known promoters, orphan CGIs are frequently subject to DNA methylation during development, and this is accompanied by loss of their active promoter features. In colorectal tumors, however, orphan CGIs are not preferentially methylated, suggesting that cancer does not recapitulate a developmental program. Human and mouse genomes have similar numbers of CGIs, over half of which are remote from known promoters. Orphan CGIs nevertheless have the characteristics of functional promoters, though they are much more likely than promoter CGIs to become methylated during development and hence lose these properties. The data indicate that orphan CGIs correspond to previously undetected promoters whose transcriptional activity may play a functional role during development.
| S-EPMC2944787 | biostudies-literature
Project description:GC skew is a measure of the strand asymmetry in the distribution of guanines and cytosines. GC skew favors R-loops, a type of three stranded nucleic acid structures that form upon annealing of an RNA strand to one strand of DNA, creating a persistent RNA:DNA hybrid. Previous studies show that GC skew is prevalent at thousands of human CpG island (CGI) promoters and transcription termination regions, which correspond to hotspots of R-loop formation. Here, we investigated the conservation of GC skew patterns in 60 sequenced chordates genomes. We report that GC skew is a conserved sequence characteristic of the CGI promoter class in vertebrates. Furthermore, we reveal that promoter GC skew peaks at the exon 1/ intron1 junction and that it is highly correlated with gene age and CGI promoter strength. Our data also show that GC skew is predictive of unmethylated CGI promoters in a range of vertebrate species and that it imparts significant DNA hypomethylation for promoters with intermediate CpG densities. Finally, we observed that terminal GC skew is conserved for a subset of vertebrate genes that tend to be located significantly closer to their downstream neighbors, consistent with a role for R-loop formation in transcription termination.
| S-EPMC4787789 | biostudies-literature
Project description:CpG islands (CGIs) function as promoters for approximately 60% of human genes. Most of these elements remain protected from CpG methylation, a prevalent epigenetic modification associated with transcriptional silencing. Here, we report that methylation-resistant CGI promoters are characterized by significant strand asymmetry in the distribution of guanines and cytosines (GC skew) immediately downstream from their transcription start sites. Using innovative genomics methodologies, we show that transcription through regions of GC skew leads to the formation of long R loop structures. Furthermore, we show that GC skew and R loop formation potential is correlated with and predictive of the unmethylated state of CGIs. Finally, we provide evidence that R loop formation protects from DNMT3B1, the primary de novo DNA methyltransferase in early development. Altogether, these results suggest that protection from DNA methylation is a built-in characteristic of the DNA sequence of CGI promoters that is revealed by the cotranscriptional formation of R loop structures.
| S-EPMC3319272 | biostudies-literature