A promoter-level mammalian expression atlas

The FANTOM Consortium and the RIKEN PMI and CLST (DGT)

doi:10.1038/nature13182

Cited by 1,982Genomics and Chromatin DynamicsSingle-cell and spatial transcriptomicsRNA Research and Splicing

A promoter-level mammalian expression atlas

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The FANTOM Consortium and the RIKEN PMI and CLST (DGT)·2014·Nature

DOI 10.1038/nature13182PMC PMC4529748

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Abstract

Regulated transcription controls the diversity, developmental pathways and spatial organization of the hundreds of cell types that make up a mammal. Using single-molecule cDNA sequencing, we mapped transcription start sites (TSSs) and their usage in human and mouse primary cells, cell lines and tissues to produce a comprehensive overview of mammalian gene expression across the human body. We find that few genes are truly ‘housekeeping’, whereas many mammalian promoters are composite entities composed of several closely separated TSSs, with independent cell-type-specific expression profiles. TSSs specific to different cell types evolve at different rates, whereas promoters of broadly expressed genes are the most conserved. Promoter-based expression analysis reveals key transcription factors defining cell states and links them to binding-site motifs. The functions of identified novel transcripts can be predicted by coexpression and sample ontology enrichment analyses. The functional annotation of the mammalian genome 5 (FANTOM5) project provides comprehensive expression profiles and functional annotation of mammalian cell-type-specific transcriptomes with wide applications in biomedical research. A study from the FANTOM consortium using single-molecule cDNA sequencing of transcription start sites and their usage in human and mouse primary cells, cell lines and tissues reveals insights into the specificity and diversity of transcription patterns across different mammalian cell types. FANTOM5 (standing for functional annotation of the mammalian genome 5) is the fifth major stage of a major international collaboration that aims to dissect the transcriptional regulatory networks that define every human cell type. Two Articles in this issue of Nature present some of the project's latest results. The first paper uses the FANTOM5 panel of tissue and primary cell samples to define an atlas of active, in vivo bidirectionally transcribed enhancers across the human body. These authors show that bidirectional capped RNAs are a signature feature of active enhancers and identify more than 40,000 enhancer candidates from over 800 human cell and tissue samples. The enhancer atlas is used to compare regulatory programs between different cell types and identify disease-associated regulatory SNPs, and will be a resource for studies on cell-type-specific enhancers. In the second paper, single-molecule sequencing is used to map human and mouse transcription start sites and their usage in a panel of distinct human and mouse primary cells, cell lines and tissues to produce the most comprehensive mammalian gene expression atlas to date. The data provide a plethora of insights into open reading frames and promoters across different cell types in addition to valuable annotation of mammalian cell-type-specific transcriptomes.

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Human promoters are mostly CG-rich and have distinct promoter architecture and regulation compared to CG-poor promoters which are mostly tissue-specific.
“Human promoters are mostly CG-rich35,62 and have distinct promoter architecture and regulation11 compared to CG-poor promoters which are mostly tissue-specific17”
From Alternative promoters in CpG depleted regions are prevalently associated with epigenetic misregulation of liver cancer transcriptomes (2023) · cites this paper as [17]
Citation 11 is attached to the claim that CG-rich promoters have distinct architecture and regulation from CG-poor promoters. In “Features of cell-type-specific promoters” (page unavailable), the paper instead says that cell-type-specific CpG-island and non-CpG-island promoters use the same type of signals; the cited passages do not establish the claimed architectural distinction. (LLM, conf=0.82)
Checked by a reasoning model — may be wrong.
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Many genes utilize alternative promoters for specific processes such as cell fate transitions in yeast and mammalian cells, vertebrate embryogenesis, and may have important roles in cancer.
“In addition to reference promoters, many genes utilize alternative promoters for specific processes, such as cell fate transitions in yeast16 and mammalian cells17, in vertebrate embryogenesis12,18, and may have important roles in cancer19.”
From Alternative promoters in CpG depleted regions are prevalently associated with epigenetic misregulation of liver cancer transcriptomes (2023) · cites this paper as [17]
The Abstract reports that most mammalian genes have more than one transcription start site and that promoters have cell-type-specific expression profiles. The Conclusion connects promoter-based analysis to identifying drivers of reprogramming between cell lineages. These passages support a link between promoter usage and mammalian cell states, but do not show that alternative promoters are utilized during cell-fate transitions. (LLM, conf=0.78)
Experimental — accuracy not yet measured
Enformer substantially outperformed Basenji2 for predicting RNA expression as measured by CAGE at the TSS of human protein-coding genes, with mean correlation increasing from 0.81 to 0.85.
“Enformer substantially outperformed the previous best model, Basenji2, for predicting RNA expression as measured by Cap Analysis Gene Expression10 (CAGE) at the TSS of human protein-coding genes, with the mean correlation increasing from 0.81 to 0.85 (Fig. 1b, left).”
From Effective gene expression prediction from sequence by integrating long-range interactions (2021) · cites this paper as [10]
A majority of TCs (90%) were supported by FANTOM5 CAGE peaks and/or open chromatin regions from ENCODE and TCGA.
“A majority of TCs (90%) were supported by FANTOM5 CAGE peaks17 and/or open chromatin regions from ENCODE22 and TCGA7”
From Alternative promoters in CpG depleted regions are prevalently associated with epigenetic misregulation of liver cancer transcriptomes (2023) · cites this paper as [17]
We filtered CAGE TCs overlapping small RNAs, drosha processing site of pre-miRNAs, and 5′ ends capping of snoRNAs.
“We filtered CAGE TCs overlapping small RNAs, drosha processing site of pre-miRNAs23, and 5′ ends capping of snoRNAs17”
From Alternative promoters in CpG depleted regions are prevalently associated with epigenetic misregulation of liver cancer transcriptomes (2023) · cites this paper as [17]
The ‘CAGE peak identification and thresholding’ section describes clustering CAGE tags and applying evidence thresholds to enrich for transcription start sites. It does not say that CAGE tag clusters were filtered for overlap with small RNAs, Drosha processing sites of pre-miRNAs, or capped 5′ ends of snoRNAs; searches for those terms found no supporting passage in our copy. (LLM, conf=0.72)
Experimental — accuracy not yet measured

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An atlas of active enhancers across human cell types and tissues
The FANTOM Consortium, Andersson, R., Gebhard, C., Miguel-Escalada, I., Hoof, I., Bornholdt, J., Boyd, M., Chen, Y., Zhao, X., Schmidl, C., et al. (2014) · Nature · doi:10.1038/nature12787 · Cited by 2,550 · see citing works
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Genome-wide analysis of mammalian promoter architecture and evolution
Carninci, P., Sandelin, A., Lenhard, B., Katayama, S., Shimokawa, K., Ponjavic, J., Semple, C. A. M., Taylor, M. S., Engström, P. G., Frith, M. C., et al. (2006) · Nature Genetics · doi:10.1038/ng1789 · Cited by 1,350 · see citing works
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Method
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Authors: The FANTOM Consortium and the RIKEN PMI and CLST (DGT)
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2014-03
Volume: 507
Issue: 7493
Pages: 462-470
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature13182
PMC: PMC4529748
OpenAlex: W1986223165
Cited by: 1,982
References: 5
Citations by year: 2026: 85 · 2025: 106 · 2024: 126 · 2023: 124 · 2022: 172 · 2021: 202 · 2020: 197 · 2019: 184 · 2018: 178 · 2017: 179 · 2016: 184 · 2015: 157 · 2014: 78 · 2013: 3 · 2012: 1
FWCI: 82.06
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: public-domain
www.springer.com/tdm (tdm)
Locations: Nature (publishedVersion, public-domain)
PubMed (publishedVersion)
Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Rice Research Repository (Rice University) (acceptedVersion)
QUT ePrints (Queensland University of Technology) (submittedVersion, public-domain)
SDL (submittedVersion)
UWA Profiles and Research Repository (UWA) (submittedVersion)
Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (submittedVersion)
Data Archiving and Networked Services (DANS) (submittedVersion)
Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
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Leiden Repository (Leiden University) (submittedVersion)
ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (submittedVersion)
ePrints Soton (University of Southampton) (submittedVersion)
University of Regensburg Publication Server (University of Regensburg) (submittedVersion)
Repository@Nottingham (University of Nottingham) (submittedVersion, cc-by)
Lund University Publications (Lund University) (submittedVersion)
The Mouseion at the JAXlibrary (Jackson Laboratory) (submittedVersion)
Repository@Nottingham (University of Nottingham) (submittedVersion)
Pure Amsterdam UMC (submittedVersion)
Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
KNAW research portal (Royal Academy of Art and Sciences (KNAW)) (submittedVersion)
King Abdullah University of Science and Technology Repository (King Abdullah University of Science and Technology) (submittedVersion)
Bristol Research (University of Bristol) (submittedVersion)
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Rice Research Repository (Rice University) (submittedVersion)
Funders: Wellcome Trust (103258/Z/13/Z)
Ministry of Education, Culture, Sports, Science and Technology
Lundbeckfonden (R82-2010-6779)
Novo Nordisk Fonden (NNF12OC1016371)
Biotechnology and Biological Sciences Research Council (BBS/E/D/20251969, BBS/E/D/20231759, BBS/E/D/20211552, BB/G022771/1, BB/I025018/1, BB/F003722/1, BBS/E/D/20211550, BBS/E/D/20211551, BB/I001107/1, BB/I024801/1)
Japan Society for the Promotion of Science (23790791, 23689044, 25330333, 22228005, 26713029, 22118001)
RIKEN
National Institute of General Medical Sciences (R01GM084875)
National Institute of Dental and Craniofacial Research (R01DE022969)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
Keywords: transcription start sites, promoter usage, cell type-specific gene expression, FANTOM5, cell type-specific transcriptome, transcription factor binding sites, regulatory SNPs
MeSH terms: Animals, Atlases as Topic, Cell Line, Cells, Cultured, Gene Expression Regulation, Humans, Organ Specificity, Promoter Regions, Genetic, RNA, Messenger, Transcription Factors, Transcription, Genetic, Cluster Analysis, Open Reading Frames, Genome, Conserved Sequence, Genes, Essential, Transcription Initiation Site, Mice, Gene Regulatory Networks, Molecular Sequence Annotation, Transcriptome

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