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Genome-wide mapping of autonomous promoter activity in human cells
Open accessAbstract
Previous methods to systematically characterize sequence-intrinsic activity of promoters have been limited by relatively low throughput and the length of the sequences that could be tested. Here we present 'survey of regulatory elements' (SuRE), a method that assays more than 10 8 DNA fragments, each 0.2-2 kb in size, for their ability to drive transcription autonomously. In SuRE, a plasmid library of random genomic fragments upstream of a 20-bp barcode is constructed, and decoded by paired-end sequencing. This library is used to transfect cells, and barcodes in transcribed RNA are quantified by high-throughput sequencing. When applied to the human genome, we achieve 55-fold genome coverage, allowing us to map autonomous promoter activity genome-wide in K562 cells. By computational modeling we delineate subregions within promoters that are relevant for their activity. We show that antisense promoter transcription is generally dependent on the sense core promoter sequences, and that most enhancers and several families of repetitive elements act as autonomous transcription initiation sites.
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“In contrast with MPRAs relying on re-synthesis of candidate sequences, genome-wide ‘shotgun MPRAs’108,174,183,188 nicely avoid a priori assumptions about which sequences to test.”
From Towards a comprehensive catalogue of validated and target-linked human enhancers (2020) · cites this paper as [188]
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“A breakthrough in the analysis of distal cis-regulatory elements was provided by the development of high-throughput reporter assays to assess promoters (85,86), enhancers (28) or insulator activities (87).”
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MPRAbase: A Massively Parallel Reporter Assay Database
Zhao, J.-J., Baltoumas, F. A., Konnaris, M. A., Mouratidis, I., Liu, Z., Sims, J., Agarwal, V., Pavlopoulos, G. A., Georgakopoulos-Soares, I., & Ahituv, N. (2023) · bioRxiv · doi:10.1101/2023.11.19.567742 · Cited by 8
“…et al. 2013; Patwardhan et al. 2009, 2012; Melnikov et al. 2012; Agarwal et al. 2023), input of natural sequences from whole-genome fragmentation (van Arensbergen et al. 2016, 2019; Liu et al. 2017; Kvon et al. 2014; Arnold et al. 2013), isolation of nucleosome free regions (Murtha et al. 2014),…”
BackgroundOptimisation of TP53 reporters by systematic dissection of synthetic TP53 response elements
Trauernicht, M., Rastogi, C., Manzo, S. G., Bussemaker, H., & van Steensel, B. (2023) · bioRxiv · doi:10.1093/nar/gkad718 · Cited by 8
Self-citationIdentification, Design, and Application of Noncoding Cis-Regulatory Elements
Xu, L., & Liu, Y. (2024) · Biomolecules · doi:10.3390/biom14080945 · Cited by 9
“In a related study, van Arensbergen et al. employed this approach on a genome-wide scale in K562 cells to map active gene promoters [37].”
BackgroundTSC tunes progenitor balance and upper-layer neuron generation in neocortex
Casingal, C. R., Nakagawa, N., Yabuno-Nakagawa, K., Meyer, C., Liu, S., Gkini, V., Cho, S.-J., Škarica, M., Liang, D., Simon, J. M., et al. (2025) · Nature · doi:10.1038/s41586-025-09810-5 · Cited by 8
“Trimethylation of histone H3 at lysine 27 (H3K27me3) is associated with transcriptional silencing 48,49 , whereas acetylation of histone H3 at lysine 27 (H3K27ac) in promoter regions is linked to active promoters and transcriptional activation 50 .”
Proformer: a hybrid macaron transformer model predicts expression values from promoter sequences
Kwak, I., Kim, B.-C., Lee, J., Kang, T., Garry, D. J., Zhang, J. J., & Gong, W. (2024) · BMC Bioinformatics · doi:10.1186/s12859-024-05645-5 · Cited by 10
Patel, Z. M., & Hughes, T. R. (2021) · Genome biology · doi:10.1186/s13059-021-02503-y · Cited by 7
Deciphering Transcriptional Regulation of Human Core Promoters
Weingarten-Gabbay, S., Nir, R., Lubliner, S., Sharon, E., Kalma, Y., Weinberger, A., & Segal, E. (2017) · doi:10.1101/174904 · Cited by 6
“With the growing appreciation of the importance of core promoters in determining gene expression, two recent studies measured the autonomous promoter activity of random sequences genomewide in human and Drosophila(5-7).”
BackgroundInfluentialGuzman, C., Duttke, S. H. C., Zhu, Y., Saldanha, C. D. A., Downes, N. L., Benner, C. W., & Heinz, S. (2023) · Nucleic Acids Research · doi:10.1093/nar/gkad562 · Cited by 7
Compatibility logic of human enhancer and promoter sequencesPreprint
Bergman, D. T., Jones, T., Liu, V., Siraj, L., Kang, H., Nasser, J., Kane, M., Nguyen, T. H., Grossman, S. R., Fulco, C. P., et al. (2021) · bioRxiv · doi:10.1101/2021.10.23.462170 · Cited by 5
Functional genomics and epigenomics of atrial fibrillation
Victorino, J., Álvarez, A., & Manzanares, M. (2021) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2021.04.003 · Cited by 6
Baumgartner, E. A., Compton, Z. J., Evans, S. T., Topczewski, J., & LeClair, E. E. (2019) · Gene Expression Patterns · doi:10.1016/j.gep.2019.03.001 · Cited by 5
Dual promoter–enhancer activities reflect a unified regulatory logic
Paramo, M. I., Leung, A. K.-Y., Shah, S. R., Zhang, J., Tippens, N. D., Liang, J. H., Yao, L., Jin, Y., Pan, X., Ozer, A., et al. (2026) · Nature Communications · doi:10.1038/s41467-026-68780-y · Cited by 7
Single-cell methylation analysis of brain tissue prioritizes mutations that alter transcription
Flint, J., Heffel, M. G., Chen, Z., Mefford, J., Marcus, E., Chen, P. B., Ernst, J., & Luo, C. (2023) · Cell Genomics · doi:10.1016/j.xgen.2023.100454 · Cited by 5
Defining the fine structure of promoter activity on a genome-wide scale with CISSECTOR
FitzPatrick, V., Leemans, C., van Arensbergen, J., van Steensel, B., & Bussemaker, H. J. (2023) · Nucleic Acids Research · doi:10.1093/nar/gkad232 · Cited by 4
“Howe v er, SuRE can also be used to study enhancers, because most enhancers dri v e low-le v el e xpression, and this acti vity correlates with other measures of enhancer activity ( 4 ).”
InfluentialSelf-citationLarge‐scale analysis of Drosophila core promoter function using synthetic promoters
Qi, Z., Jung, C., Bandilla, P., Ludwig, C., Heron, M., Kiesel, A., Museridze, M., Philippou‐Massier, J., Nikolov, M., Renna, A., et al. (2022) · Molecular Systems Biology · doi:10.15252/msb.20209816 · Cited by 31
A functional SNP of the core promoter region within goat CDC25A gene affects litter size
Zhang, T., Wang, J., Bai, Y., Wang, Q., Wang, K., Zhu, H.-J., Qu, L., Guo, Z.-G., Pan, C., & Lan, X.-Y. (2025) · Frontiers in Veterinary Science · doi:10.3389/fvets.2024.1471123 · Cited by 3
“Generally, the promoter region ranges from 2,000 bp upstream to 500 bp downstream of the transcription start site (TSS) in animals (15).”
A mathematical model clarifies the ABC Score formula used in enhancer-gene predictionPreprint
Nasser, J., Nam, K.-M., & Gunawardena, J. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.11.29.626072
“It is well known that the promoter sequences at some eukaryotic genes are sufficient to drive transcription even in the absence of distal enhancers [36, 37].”
A catalog of transcription start sites across 115 human tissue and cell typesPreprint
Moore, J. E., Zhang, X.-O., Elhajjajy, S. I., Fan, K.-L., Reese, F., Mortazavi, A., & Weng, Z. (2021) · bioRxiv · doi:10.1101/2021.05.12.443890 · Cited by 3
Efficient chromatin accessibility mapping in situ by nucleosome-tethered tagmentationPreprint
Henikoff, S., Henikoff, J. G., Kaya-Okur, H. S., & Ahmad, K. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.04.15.043083 · Cited by 2
“These functional inferences are supported by an ATACseq track, which shows that both sites are accessible to Tn5 and by SuRE (Survey of Regulatory Elements), a massively parallel reporter survey for autonomous active regulatory elements in K562 cells (van Arensbergen et al., 2017) .”
MethodA functional overlap between actively transcribed genes and chromatin insulator elements
Cornell, L., Harrold, C. L., Holliman, S., Tsang, F. H., Gosden, M. E., Hanssen, L. E., Stolper, R. J., Downes, D. J., Biggs, D., Preece, C., et al. (2026) · The EMBO Journal · doi:10.1038/s44318-026-00730-2 · Cited by 3
A systematic delineation of 3′UTR regulatory elements and their contextual associations
Liang, N., Li, J., Ding, Y., Wang, Y., Champer, J., Ren, L., & Gao, G. (2026) · Cell Systems · doi:10.1101/2025.06.09.658412 · Cited by 1
Uniform processing and analysis of IGVF massively parallel reporter assay data with MPRAsnakeflow
Rosen, J. D., Vasanthakumari, A. D., Salomon, K., de Lange, N., Dash, P., Keukeleire, P., Hassan, A., Barrera, A., Kircher, M., Love, M. I., et al. (2025) · bioRxiv · doi:10.1101/2025.09.25.678548 · Cited by 2
“A related method, Self-Transcribing Active Regulatory Region sequencing (STARR-seq), can be used simultaneously to study both cCREs and variants (Arnold et al. 2013; van Arensbergen et al. 2017).”
Interpretable prediction of mRNA abundance from promoter sequence using contextual regression models
Wang, S., & Wang, W. (2024) · NAR Genomics and Bioinformatics · doi:10.1093/nargab/lqae055 · Cited by 3
“For example, the ETS:IRF composite element (EICE) prefers two nucleotide-long spacers and ETS:IRF response element (EIRE) prefers three nucleotide-long spacers ( 25 ).”
Letiagina, A. E., Omelina, E. S., Ivankin, A. V., & Pindyurin, A. V. (2021) · Frontiers in Genetics · doi:10.3389/fgene.2021.618189 · Cited by 2
Redondo‐Antón, J., Fontela, M. G., Notario, L., Torres-Ruiz, R., Rodríguez, S., Lorente, E., & Lauzurica, P. (2020) · Frontiers in Genetics · doi:10.3389/fgene.2020.552949 · Cited by 3
Zhang, Y. P., Fan, Y., Wu, H., & Zhang, X.-O. (2026) · Nature Communications · doi:10.1038/s41467-026-68934-y · Cited by 2
“1C) and exhibit signi fi cantly higher intrinsic transcriptional activity in SuRE assays 26 than other TE-overlapping TSSs (Fig.”
TRANCERs: Engineering enhancers into autonomous tissue-specific expression cassettesPreprint
Molina, E. K. B., Smith, A., López‐Cuevas, P., Nicholls, M., Sharma, S., White, R. M., Milne, T. A., & Hughes, J. R. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.10.27.684763 · Cited by 2
“In contrast, there are estimated to be millions of cell type-specific enhancers in the human genome controlling development, differentiation and cellular responses to extrinsic signals 15 .”
Using Synthetic DNA Libraries to Investigate Chromatin and Gene Regulation
Kleinschmidt, H., Xu, C., & Bai, L. (2023) · Chromosoma · doi:10.1007/s00412-023-00796-5 · Cited by 2
Taking a STAP at Core Promoter-Transcriptional Cofactor Specificity.
Siegenfeld, A. P., Lee, C., & Liau, B. B. (2019) · Biochemistry · doi:10.1021/acs.biochem.9b00537 · Cited by 1
BARe-seq enables high-throughput dissection of cis-regulatory control of transcriptional bursting
Lorbeer, F. K., Alvarez, R. E. R., Bergauer, K., Grün, D., & Stark, A. (2026) · bioRxiv · doi:10.64898/2026.08.19.745405
“…massively parallel reporter assays (MPRAs) offer the scalability to assess thousands of sequences, including perturbed and designed synthetic sequences (Arnold et al., 2013; Kwasnieski et al., 2014; Arnold et al., 2017; van Arensbergen et al., 2017; Bergman et al., 2022; de Almeida et al., 2022).”
Metadata
- Authors
- van Arensbergen, J., FitzPatrick, V. D., de Haas, M., Pagie, L., Sluimer, J., Bussemaker, H. J., & van Steensel, B.
- Affiliations
- The Netherlands Cancer Institute (NL)
- Columbia University Irving Medical Center (US)
- Corresponding author
- van Arensbergen, Joris
- Bussemaker, Harmen J
- van Steensel, Bas
- Venue
- Nature Biotechnology
- Published
- 2016-12-26
- Volume
- 35
- Issue
- 2
- Pages
- 145-153
- ISSN
- 0733-222X (ISSN-L)
- 1087-0156
- 1546-1696
- PMC
- PMC5498152
- OpenAlex
- W2566958422
- Cited by
- 140
- References
- 54
- Citations by year
- 2026: 9 · 2025: 18 · 2024: 18 · 2023: 21 · 2022: 15 · 2021: 11 · 2020: 18 · 2019: 15 · 2018: 10 · 2017: 5
- FWCI
- 5.20
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Biotechnology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (1s10od021764-01)
- National Human Genome Research Institute (R01HG003008)
- National Institute of General Medical Sciences (T32GM008281, T32GM008798)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Chromosomal and Genetic Variations
- Keywords
- transcription initiation, SURE, barcode sequencing, K562 cells, core promoter, enhancers, repetitive elements, genome-wide mapping
- MeSH terms
- Chromosome Mapping, DNA, Humans, Promoter Regions, Genetic, Transcriptional Activation, Gene Library, Genome, Human, Sequence Analysis, DNA, K562 Cells, Transcription Initiation, Genetic
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