ArticleGenome research2017
Distal CpG islands can serve as alternative promoters to transcribe genes with silenced proximal promoters.
Article in Genome research, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 48 citations in OpenAlex.
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- Genome-wide methylome-based molecular pathologies associated with depression and suicide.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2025Article
- The transcribed ultraconserved regions: emerging players in colorectal cancer biology and therapy.Frontiers in cell and developmental biology · 2025Review
- Genome-wide analyses reveal the regulatory roles of DNA methylation-regulated alternative promoter transcripts in breast cancer.Human genetics · 2024Article
- Profiling the immune epigenome across global cattle breeds.Genome biology · 2023Article
- Alternative promoters in CpG depleted regions are prevalently associated with epigenetic misregulation of liver cancer transcriptomes.Nature communications · 2023Article
- Large-scale manipulation of promoter DNA methylation reveals context-specific transcriptional responses and stability.Genome biology · 2022Article
- Review
- Regulatory effect of heat shock transcription factor-1 gene on heat shock proteins and its transcriptional regulation analysis in small abalone Haliotis diversicolor.BMC molecular and cell biology · 2020Article
- Paternal deprivation impairs social behavior putatively via epigenetic modification to lateral septum vasopressin receptor.Science advances · 2020Article
- Dopamine response gene pathways in dorsal striatum MSNs from a gene expression viewpoint: cAMP-mediated gene networks.BMC neuroscience · 2020Article
- Article
- Evidence that alternative transcriptional initiation is largely nonadaptive.PLoS biology · 2019Article
- CpG traffic lights are markers of regulatory regions in human genome.BMC genomics · 2019Article
- Responses ofMolecules (Basel, Switzerland) · 2019Article
- Systematic discovery of conservation states for single-nucleotide annotation of the human genome.Communications biology · 2019Article
- Genome-Wide Comparative Analysis of HIF Binding Sites inFrontiers in genetics · 2019Article
- Zinc Finger Readers of Methylated DNA.Molecules (Basel, Switzerland) · 2018Review
- Comprehensive comparative analysis of 5'-end RNA-sequencing methods.Nature methods · 2018Article
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
DNA methylation at the promoter of a gene is presumed to render it silent, yet a sizable fraction of genes with methylated proximal promoters exhibit elevated expression. Here, we show, through extensive analysis of the methylome and transcriptome in 34 tissues, that in many such cases, transcription is initiated by a distal upstream CpG island (CGI) located several kilobases away that functions as an alternative promoter. Specifically, such genes are expressed precisely when the neighboring CGI is unmethylated but remain silenced otherwise. Based on CAGE and Pol II localization data, we found strong evidence of transcription initiation at the upstream CGI and a lack thereof at the methylated proximal promoter itself. Consistent with their alternative promoter activity, CGI-initiated transcripts are associated with signals of stable elongation and splicing that extend into the gene body, as evidenced by tissue-specific RNA-seq and other DNA-encoded splice signals. Furthermore, based on both inter- and intra-species analyses, such CGIs were found to be under greater purifying selection relative to CGIs upstream of silenced genes. Overall, our study describes a hitherto unreported conserved mechanism of transcription of genes with methylated proximal promoters in a tissue-specific fashion. Importantly, this phenomenon explains the aberrant expression patterns of some cancer driver genes, potentially due to aberrant hypomethylation of distal CGIs, despite methylation at proximal promoters.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.