Systematic interrogation of human promoters
Open accessPublished version of a preprint
Abstract
Despite much research, our understanding of the architecture and cis -regulatory elements of human promoters is still lacking. Here, we devised a high-throughput assay to quantify the activity of approximately 15,000 fully designed sequences that we integrated and expressed from a fixed location within the human genome. We used this method to investigate thousands of native promoters and preinitiation complex (PIC) binding regions followed by in-depth characterization of the sequence motifs underlying promoter activity, including core promoter elements and TF binding sites. We find that core promoters drive transcription mostly unidirectionally and that sequences originating from promoters exhibit stronger activity than those originating from enhancers. By testing multiple synthetic configurations of core promoter elements, we dissect the motifs that positively and negatively regulate transcription as well as the effect of their combinations and distances, including a 10-bp periodicity in the optimal distance between the TATA and the initiator. By comprehensively screening 133 TF binding sites, we find that in contrast to core promoters, TF binding sites maintain similar activity levels in both orientations, supporting a model by which divergent transcription is driven by two distinct unidirectional core promoters sharing bidirectional TF binding sites. Finally, we find a striking agreement between the effect of binding site multiplicity of individual TFs in our assay and their tendency to appear in homotypic clusters throughout the genome. Overall, our study systematically assays the elements that drive expression in core and proximal promoter regions and sheds light on organization principles of regulatory regions in the human genome.
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Hennighausen, L., & Fleckenstein, B. (1986) · EMBO Journal · doi:10.1002/j.1460-2075.1986.tb04368.x · Cited by 116 · cited 1×
“…Hansen and Sharp 1983; Adachi et al. 1986; Hennighausen and Fleckenstein 1986; Adra et al. 1987; Eisenstein and Munro 1990; Moriyama et al. 1994; Nenoi et al. 1996; Lay et al. 2000; Wang et…”
van Beveren, C., Rands, E., Chattopadhyay, S. K., Lowy, D. R., & Verma, I. M. (1982) · Journal of Virology · doi:10.1128/jvi.41.2.542-556.1982 · Cited by 115 · see citing works
Probing the effect of promoters on noise in gene expression using thousands of designed sequencesPreprint
Sharon, E., van Dijk, D., Kalma, Y., Keren, L., Manor, O., Zohar Yakhini, B., & Segal, E. (2014) · Genome Research · doi:10.1101/gr.168773.113 · Cited by 107 · cited 2× · see citing works
“However, in contrast to yeast, in which the noise levels of promoters with similar mean expression can vary more than one order of magnitude (Sharon et al. 2014), here we do not find large differences in noise for the same mean expression, with most of the variability explained by the mean…”
Self-citationEmami, K. H., Jain, A., & Smale, S. T. (1997) · Genes & Development · doi:10.1101/gad.11.22.3007 · Cited by 103 · cited 1× · see citing works
“Moreover, previous studies demonstrated that their coordinated effect on transcription depends on the distance between the elements (O ’ Shea-Greenfield and Smale 1992; Emami et al. 1997).”
Conflict between Noise and Plasticity in Yeast
Lehner, B. (2010) · PLoS Genetics · doi:10.1371/journal.pgen.1001185 · Cited by 100 · cited 1× · see citing works
“In addition to regulating mean expression, core promoter elements such as the TATA-box were also shown to have an effect on cell-to-cell variability(expressionnoise)inyeast (TiroshandBarkai 2008; Lehner 2010).”
Caudal, a key developmental regulator, is a DPE-specific transcriptional factor.Preprint
Juven-Gershon, T., Hsu, J.-Y., & Kadonaga, J. T. (2008) · Genes & Development · doi:10.1101/gad.1698108 · Cited by 100 · cited 2× · see citing works
“For example, the BRE motifs have been reported to act both as an activator and a repressor of transcription (Evans et al. 2001; Chen and Manley 2003; Deng and Roberts 2005; Juven-Gershon et al. 2008; Kadonaga 2012).”
Papatsenko, D. A., Makeev, V., Lifanov, A., Régnier, M., Nazina, A., & Desplan, C. (2002) · Genome Research · doi:10.1101/gr.212502 · Cited by 94 · cited 1× · see citing works
“This architecture may have several mechanistic advantages such as cooperativity binding (Hertel et al. 1997), lateral diffusion between adjacent binding sites (Kim et al. 1987; Khoury et al. 1990), and functional redundancy (Somma et al. 1991; Papatsenko et al. 2002).”
The grammar of transcriptional regulation
Weingarten-Gabbay, S., & Segal, E. (2014) · Human Genetics · doi:10.1007/s00439-013-1413-1 · Cited by 93 · cited 3× · see citing works
“In a recent study, Core et al. (2014) investigated the landscape and architecture of TSSs across the human genome and found that divergent transcription in both promoters and enhancers is facilitated by two distinct core promoters separated by ∼ 110 bp (Weingarten-Gabbay and Segal 2014b).”
Self-citationSequences controlling in vitro transcription of SV40 promoters.
Hansen, U., & Sharp, P. A. (1983) · EMBO Journal · doi:10.1002/j.1460-2075.1983.tb01737.x · Cited by 91 · cited 1×
“…promoter activity, we designed 153-nt-longsequencestilingtheentirelengthofpreviouslycharac-terizedpromoters(SupplementalTableS1;VanBeverenetal.1982; Hansen and Sharp 1983; Adachi et al. 1986; Hennighausen and Fleckenstein 1986; Adra et al. 1987; Eisenstein and Munro 1990; Moriyama et al. 1994;…”
Genome-wide assessment of sequence-intrinsic enhancer responsiveness at single-base-pair resolution
Arnold, C. D., Zabidi, M. M. A., Pagani, M., Rath, M., Schernhuber, K., Kazmar, T., & Stark, A. (2016) · Nature Biotechnology · doi:10.1038/nbt.3739 · Cited by 87 · see citing works
Evans, R., Fairley, J., & Roberts, S. G. E. (2001) · Genes & Development · doi:10.1101/gad.206901 · Cited by 80 · cited 2× · see citing works
“For example, the BRE motifs have been reported to act both as an activator and a repressor of transcription (Evans et al. 2001; Chen and Manley 2003; Deng and Roberts 2005; Juven-Gershon et al. 2008; Kadonaga 2012).”
Systematic Dissection of the Sequence Determinants of Gene 3’ End Mediated Expression Control
Shalem, O., Sharon, E., Lubliner, S., Regev, I., Lotan-Pompan, M., Yakhini, Z., & Segal, E. (2015) · PLoS Genetics · doi:10.1371/journal.pgen.1005147 · Cited by 69 · cited 2× · see citing works
“A growing number of studies employ MPRAs to decipher gene expression regulation at the levels of transcription, translation, and mRNA stability (Zhao et al. 2014; Shalem et al. 2015; Ernst et al. 2016; Tewhey et al. 2016; Ulirsch et al. 2016; Weingarten-Gabbay et al. 2016).”
Self-citationHuman gene promoters are intrinsically bidirectional
Andersson, R., Chen, Y., Core, L., Lis, J., Sandelin, A., & Jensen, T. (2015) · Molecules and Cells · doi:10.1016/j.molcel.2015.10.015 · Cited by 64 · cited 1× · see citing works
“The discovery of bidirectional transcription by genome-wide measurements of nested transcripts led to on-going discussion on the existence and mechanisms underlying bidirectional promoters (Andersson et al. 2015; Duttke et al. 2015).”
Maricque, B., Dougherty, J., & Cohen, B. (2016) · Nucleic Acids Research · doi:10.1093/nar/gkw942 · Cited by 56 · see citing works
GA-binding Protein-dependent Transcription Initiator Elements
Yu, M.-Y., Yang, X., Schmidt, T., Chinenov, Y., Wang, R., & Martin, M. E. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.46.29060 · Cited by 56 · cited 1× · see citing works
“…which matches the DNA double-helix geometry, implies that the stereospecific alignment between the TATA and the TSS is important for expression, as was previously described for transcription factors (Takahashi et al. 1986; Yu et al. 1997; Sharon et al. 2012; Weingarten-Gabbay and Segal 2014a).”
Promoter-Dependent EGFP Expression during Embryonic Stem Cell Propagation and Differentiation
Wang, R., Liang, J., Jiang, H., Qin, L., & Yang, H. (2008) · Stem Cells and Development · doi:10.1089/scd.2007.0084 · Cited by 53 · see citing works
CG dinucleotides enhance promoter activity independent of DNA methylationPreprint
Hartl, D., Krebs, A., Grand, R. S., Baubec, T., Isbel, L., Wirbelauer, C., Burger, L., & Schübeler, D. (2019) · Genome Research · doi:10.1101/gr.241653.118 · Cited by 53 · see citing works
Levo, M., Avnit-Sagi, T., Lotan-Pompan, M., Kalma, Y., Weinberger, A., Yakhini, Z., & Segal, E. (2017) · Molecules and Cells · doi:10.1016/j.molcel.2017.01.007 · Cited by 49 · cited 1× · see citing works
“5G; Raveh-Sadka et al. 2012; Levo et al. 2017).”
Self-citationTranslational regulation of ferritin synthesis by iron.
Eisenstein, R., & Munro, H. (1990) · Enzyme · doi:10.1159/000468746 · Cited by 49 · cited 1× · see citing works
“…Hansen and Sharp 1983; Adachi et al. 1986; Hennighausen and Fleckenstein 1986; Adra et al. 1987; Eisenstein and Munro 1990; Moriyama et al. 1994; Nenoi et al. 1996; Lay et al. 2000; Wang et al. 2008) with a 103-bp overlap between oligos and…”
Chen, Z., & Manley, J. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.20.7350-7362.2003 · Cited by 36 · cited 2× · see citing works
“For example, the BRE motifs have been reported to act both as an activator and a repressor of transcription (Evans et al. 2001; Chen and Manley 2003; Deng and Roberts 2005; Juven-Gershon et al. 2008; Kadonaga 2012).”
Somma, M. P., Pisano, C., & Lavia, P. (1991) · Nucleic Acids Research · doi:10.1093/nar/19.11.2817 · Cited by 33 · cited 1× · see citing works
“This architecture may have several mechanistic advantages such as cooperativity binding (Hertel et al. 1997), lateral diffusion between adjacent binding sites (Kim et al. 1987; Khoury et al. 1990), and functional redundancy (Somma et al. 1991; Papatsenko et al. 2002).”
Heterogeneous structure of the polyubiquitin gene UbC of HeLa S3 cells
Nenoi, M., Mita, K., Ichimura, S., Cartwright, I. L., Takahashi, E.-I., Yamauchi, M., & Tsuji, H. (1996) · Gene · doi:10.1016/0378-1119(96)00145-x · Cited by 32 · cited 1× · see citing works
“…Hansen and Sharp 1983; Adachi et al. 1986; Hennighausen and Fleckenstein 1986; Adra et al. 1987; Eisenstein and Munro 1990; Moriyama et al. 1994; Nenoi et al. 1996; Lay et al. 2000; Wang et al. 2008) with a 103-bp overlap between oligos and measured their activity in the pooled assay.”
High-throughput interrogation of programmed ribosomal frameshifting in human cells
Mikl, M., Pilpel, Y., & Segal, E. (2020) · Nature Communications · doi:10.1038/s41467-020-16961-8 · Cited by 31 · see citing works
Self-citationDissecting splicing decisions and cell-to-cell variability with designed sequence libraries
Mikl, M., Hamburg, A., Pilpel, Y., & Segal, E. (2019) · Nature Communications · doi:10.1038/s41467-019-12642-3 · Cited by 31 · see citing works
Self-citationLac repressor-operator interaction: DNA length dependence.
Khoury, A. M., Lee, H. J., Lillis, M. T., & Lu, P. (1990) · Biochimica et Biophysica Acta · doi:10.1016/0167-4781(90)90120-q · Cited by 29 · cited 1× · see citing works
“This architecture may have several mechanistic advantages such as cooperativity binding (Hertel et al. 1997), lateral diffusion between adjacent binding sites (Kim et al. 1987; Khoury et al. 1990), and functional redundancy (Somma et al. 1991; Papatsenko et al. 2002).”
A shared architecture for promoters and enhancers
Weingarten-Gabbay, S., & Segal, E. (2014) · Nature Genetics · doi:10.1038/ng.3152 · Cited by 21 · cited 3×
“In a recent study, Core et al. (2014) investigated the landscape and architecture of TSSs across the human genome and found that divergent transcription in both promoters and enhancers is facilitated by two distinct core promoters separated by ∼ 110 bp (Weingarten-Gabbay and Segal 2014b).”
Self-citationErtl, G. (2013) · Nature · doi:10.1038/502s53a · Cited by 19 · see citing works
Core promoters across the genome
Cvetesic, N., & Lenhard, B. (2017) · Nature Biotechnology · doi:10.1038/nbt.3788 · Cited by 12 · see citing works
Universality of core promoter elements?
Siebert, M., & Söding, J. (2014) · Nature · doi:10.1038/nature13587 · Cited by 10 · cited 1×
“The main concerns raised were about the analyses of the core promoter elements downstream from the data acquisition (Siebert and Söding 2014), and in the retraction letter the investigators claim that to the best of their knowledge, the raw and processed ChIP-exo data are valid.”
Retraction: Genomic organization of human transcription initiation complexes
Venters, B. J., & Pugh, B. (2014) · Nature · doi:10.1038/nature13588 · Cited by 5 · cited 1×
“While working on this manuscript, the original paper that identified the PIC binding sequences in the human genome has been retracted (Venters and Pugh 2014).”
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Determinants of enhancer and promoter activities of regulatory elements
Andersson, R., & Sandelin, A. (2020) · Nature Reviews Genetics · doi:10.1038/s41576-019-0173-8 · Cited by 713 · see citing works
Base-resolution models of transcription-factor binding reveal soft motif syntax
Avsec, Ž., Weilert, M., Shrikumar, A., Krueger, S., Alexandari, A., Dalal, K., Fropf, R., McAnany, C., Gagneur, J., Kundaje, A., et al. (2021) · Nature Genetics · doi:10.1038/s41588-021-00782-6 · Cited by 610 · see citing works
Towards a comprehensive catalogue of validated and target-linked human enhancers
Gasperini, M., Tome, J. M., & Shendure, J. (2020) · Nature Reviews Genetics · doi:10.1038/s41576-019-0209-0 · Cited by 396 · see citing works
Molecular and evolutionary processes generating variation in gene expression
Hill, M. S., Zande, P. V., & Wittkopp, P. J. (2020) · Nature Reviews Genetics · doi:10.1038/s41576-020-00304-w · Cited by 262 · see citing works
A systematic evaluation of the design and context dependencies of massively parallel reporter assays
Klein, J. C., Agarwal, V., Inoue, F., Keith, A., Martin, B., Kircher, M., Ahituv, N., & Shendure, J. (2020) · Nature Methods · doi:10.1038/s41592-020-0965-y · Cited by 226 · see citing works
“Previously, a subset of preinitiation-complex-bound enhancers were shown to have strong orientation-dependent activity, highlighting that these trends may be influenced by the choice of elements tested 38 .”
BackgroundWhat Is a Transcriptional Burst?
Tunnacliffe, E., & Chubb, J. R. (2020) · Trends in Genetics · doi:10.1016/j.tig.2020.01.003 · Cited by 223 · see citing works
Synthetic promoter designs enabled by a comprehensive analysis of plant core promoters
Jores, T., Tonnies, J., Wrightsman, T., Buckler, E., Cuperus, J., Fields, S., & Queitsch, C. (2021) · Nature Plants · doi:10.1038/s41477-021-00932-y · Cited by 200 · see citing works
“…high-throughput studies have been performed in yeast, Drosophila melanogaster and human cells (Patwardhan et al., 2009; Sharon et al., 2012; Lubliner et al., 2015; Arnold et al., 2017; van Arensbergen et al., 2017; Weingarten-Gabbay et al., 2019; de Boer et al., 2020; Kotopka and Smolke, 2020).”
BackgroundSequence determinants of human gene regulatory elements
Sahu, B., Hartonen, T., Pihlajamaa, P., Wei, B., Dave, K., Zhu, F., Kaasinen, E., Lidschreiber, K., Lidschreiber, M., Daub, C. O., et al. (2022) · Nature Genetics · doi:10.1038/s41588-021-01009-4 · Cited by 198 · see citing works
Synthetic promoter design in Escherichia coli based on a deep generative network
Wang, Y., Wang, H., Wei, L., Li, S., Liu, L., & Wang, X. (2020) · Nucleic Acids Research · doi:10.1093/nar/gkaa325 · Cited by 218 · see citing works
“In addition, sequence combination strategies, such as integrating TF binding sites with promoter backgrounds (14,15), combining known short functional components (10,11) and random sequence assembly methods (16–18), have generated some novel promoters for regulating target genes.”
BackgroundThe sound of silence: Transgene silencing in mammalian cell engineering
Cabrera, A., Edelstein, H. I., Glykofrydis, F., Love, K. S., Palacios, S., Tycko, J., Zhang, M., Lensch, S., Shields, C. E., Livingston, M., et al. (2022) · Cell Systems · doi:10.1016/j.cels.2022.11.005 · Cited by 201 · see citing works
“moters at AAVS1 safe-harbor locus in K562 cells found that core promoters drive unidirectional transcription.(228) Screening more broadly across loci, promoter activity scales across regions of integration suggesting that integration context provides a factor over the promoter-intrinsic properties.”
BackgroundDurrant, M. G., Fanton, A., Tycko, J., Hinks, M. M., Chandrasekaran, S. S., Perry, N. T., Schaepe, J. M., Du, P. P., Lotfy, P., Bassik, M. C., et al. (2022) · Nature Biotechnology · doi:10.1038/s41587-022-01494-w · Cited by 212 · see citing works
“3c) 47 .”
Massively parallel characterization of transcriptional regulatory elements
Agarwal, V., Inoue, F., Schubach, M., Penzar, D., Martin, B. K., Dash, P. M., Keukeleire, P., Zhang, Z., Sohota, A., Zhao, J., et al. (2025) · Nature · doi:10.1038/s41586-024-08430-9 · Cited by 146 · see citing works
“In addition to observing promoter activity strand-orientation bias in line with previous studies 27,28 , we extensively characterized the sequence-based information needed to generate these on/off switches.”
Karollus, A., Mauermeier, T., & Gagneur, J. (2023) · Genome Biology · doi:10.1186/s13059-023-02899-9 · Cited by 128 · see citing works
“[25] manuscript and the construct sequences were kindly provided by the first author.”
BackgroundGenerating specificity in genome regulation through transcription factor sensitivity to chromatin
Isbel, L., Grand, R. S., & Schübeler, D. (2022) · Nature Reviews Genetics · doi:10.1038/s41576-022-00512-6 · Cited by 149 · see citing works
Georgakopoulos-Soares, I., Deng, C., Agarwal, V., Chan, C. S. Y., Zhao, J., Inoue, F., & Ahituv, N. (2023) · Nature Communications · doi:10.1038/s41467-023-37960-5 · Cited by 82 · see citing works
“Previous work has examined the effect of genomic element orientation on expression in both single locus experimental studies 7,32 and via high-throughput assays 9,13,18,33 .”
Deep flanking sequence engineering for efficient promoter design using DeepSEED
Zhang, P., Wang, H., Xu, H., Wei, L., Liu, L., Hu, Z., & Wang, X. (2023) · Nature Communications · doi:10.1038/s41467-023-41899-y · Cited by 91 · see citing works
Pimmett, V. L., Dejean, M., Fernandez, C., Trullo, A., Bertrand, E., Radulescu, O., & Lagha, M. (2021) · Nature Communications · doi:10.1038/s41467-021-24461-6 · Cited by 88 · see citing works
The dynamic, combinatorial cis-regulatory lexicon of epidermal differentiation
Kim, D. S., Risca, V. I., Reynolds, D. L., Chappell, J., Rubin, A. J., Jung, N., Donohue, L. K. H., Lopez-Pajares, V., Kathiria, A. S., Shi, M., et al. (2021) · Nature Genetics · doi:10.1038/s41588-021-00947-3 · Cited by 74 · see citing works
Dense and pleiotropic regulatory information in a developmental enhancer
Fuqua, T., Jordan, J., van Breugel, M. E., Halavatyi, A. A., Tischer, C., Polidoro, P., Abe, N., Tsai, A., Mann, R. S., Stern, D. L., et al. (2020) · Nature · doi:10.1038/s41586-020-2816-5 · Cited by 95 · see citing works
Sequence basis of transcription initiation in the human genome
Dudnyk, K., Cai, D., Shi, C., Xu, J., & Zhou, J. (2024) · Science · doi:10.1126/science.adj0116 · Cited by 103 · see citing works
“( 6 ) using a plasmid kindly provided by the authors.”
BackgroundMethodYu, T. C., Liu, W. L., Brinck, M. S., Davis, J. E., Shek, J., Bower, G., Einav, T., Insigne, K. D., Phillips, R., Kosuri, S., et al. (2021) · Nature Communications · doi:10.1038/s41467-020-20094-3 · Cited by 59 · see citing works
What do Transcription Factors Interact With?
Chen, H., & Pugh, B. F. (2021) · Journal of Molecular Biology · doi:10.1016/j.jmb.2021.166883 · Cited by 57 · see citing works
CG dinucleotides enhance promoter activity independent of DNA methylationPreprint
Hartl, D., Krebs, A., Grand, R. S., Baubec, T., Isbel, L., Wirbelauer, C., Burger, L., & Schübeler, D. (2019) · Genome Research · doi:10.1101/gr.241653.118 · Cited by 53 · see citing works
“Combined with two other approaches to measure in parallel at the same genomic site which were reported following submission of our work (Maricque et al. 2018; Weingarten-Gabbay et al. 2019) this largely extends the toolset to study cis-acting sequences.”
BackgroundAgarwal, V., Inoue, F., Schubach, M., Martin, B., Dash, P., Zhang, Z.-C., Sohota, A., Noble, W. S., Yardımcı, G., Kircher, M., et al. (2023) · bioRxiv · doi:10.1101/2023.03.05.531189 · Cited by 42 · see citing works
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Genome-wide mRNA profiling identifies X-box-binding protein 1 (XBP1) as an IRE1 and PUMA repressor
Gebert, M., Sobolewska, A., Bartoszewska, S., Cabaj, A., Crossman, D., Króliczewski, J., Madanecki, P., Dąbrowski, M., Collawn, J., & Bartoszewski, R. (2021) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-021-03952-1 · Cited by 39 · see citing works
Designing Eukaryotic Gene Expression Regulation Using Machine Learning
de Jongh, R. P. H., van Dijk, A. D. J., Julsing, M. K., Schaap, P. J., & de Ridder, D. (2019) · Trends in biotechnology · doi:10.1016/j.tibtech.2019.07.007 · Cited by 46 · see citing works
Identification of the Human DPR Promoter Element by using Machine Learning
Ngoc, L. V., Huang, C., Cassidy, C. J., Medrano, C., & Kadonaga, J. T. (2020) · Nature · doi:10.1038/s41586-020-2689-7 · Cited by 37
Cabaj, A., Moszyńska, A., Charzyńska, A., Bartoszewski, R., & Dąbrowski, M. (2022) · Cellular Signalling · doi:10.1016/j.cellsig.2021.110209 · Cited by 37 · see citing works
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“Quantification summary can be found in Supplementary Data 5.”
InfluentialDeep learning at base-resolution reveals motif syntax of the cis-regulatory codePreprint
Avsec, Ž., Weilert, M., Shrikumar, A., Alexandari, A. M., Krueger, S., Dalal, K., Fropf, R., McAnany, C. E., Gagneur, J., Kundaje, A., et al. (2019) · bioRxiv · doi:10.1101/737981 · Cited by 36 · see citing works
High-throughput interrogation of programmed ribosomal frameshifting in human cells
Mikl, M., Pilpel, Y., & Segal, E. (2020) · Nature Communications · doi:10.1038/s41467-020-16961-8 · Cited by 31 · see citing works
Self-citationDissecting splicing decisions and cell-to-cell variability with designed sequence libraries
Mikl, M., Hamburg, A., Pilpel, Y., & Segal, E. (2019) · Nature Communications · doi:10.1038/s41467-019-12642-3 · Cited by 31 · see citing works
Self-citationDissecting the cis-regulatory syntax of transcription initiation with deep learningPreprint
Cochran, K., Yin, M., Mantripragada, A., Schreiber, J. M., Marinov, G. K., Shah, S. R., Yu, H., Lis, J. T., & Kundaje, A. B. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.05.28.596138 · Cited by 32 · see citing works
“…effects of individual base mutations 49,50 , while massively parallel reporter assays measuring promoter activity remove the promoter from its endogenous chromatin and distal enhancer context 51,52 ; neither approach typically incorporates measurement of nascent transcription specifically.”
Grapotte, M., Saraswat, M., Bessière, C., Menichelli, C., Ramilowski, J. A., Severin, J., Hayashizaki, Y., Itoh, M., Tagami, M., Murata, M., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-23143-7 · Cited by 29 · see citing works
“As a consequence, ( T ) n can increase transcription of reporter genes in similar levels to TF-binding sites 53 .”
BackgroundDavis, J. E., Insigne, K. D., Jones, E. M., Hastings, Q. B., Boldridge, W. C., & Kosuri, S. (2020) · Cell Systems · doi:10.1016/j.cels.2020.05.011 · Cited by 34 · see citing works
Ding, N., Yuan, Z., Ma, Z., Wu, Y., & Yin, L. (2024) · Molecules · doi:10.3390/molecules29153512 · Cited by 27 · see citing works
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“The cloning was performed essentially as described in (37).”
Self-citationCurrent Practice in Bicistronic IRES Reporter Use: A Systematic Review
van den Akker, G. G. H., Zacchini, F., Housmans, B., van der Vloet, L., Caron, M., Montanaro, L., & Welting, T. J. M. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22105193 · Cited by 24 · see citing works
Rewriting regulatory DNA to dissect and reprogram gene expression
Martyn, G. E., Montgomery, M. T., Jones, H., Guo, K., Doughty, B. R., Linder, J., Bisht, D., Xia, F., Cai, X. S., Chen, Z., et al. (2023) · Cell · doi:10.1016/j.cell.2025.03.034 · Cited by 52 · see citing works
“56 To comply with the design of this initial 8-bp sequence insertion pilot screen, we designed insertions for specific TFs using the center 8-bp consensus sequence from the binding profiles.”
Resurrecting essential amino acid biosynthesis in mammalian cells
Trolle, J., McBee, R. M., Kaufman, A., Pinglay, S., Berger, H., German, S., Liu, L., Shen, M. J., Guo, X., Martin, J. A., et al. (2021) · bioRxiv · doi:10.1101/2021.08.03.454854 · Cited by 20 · see citing works
Modeling and designing enhancers by introducing and harnessing transcription factor binding units
Li, J., Zhang, P., Xi, X., Liu, L., Wei, L., & Wang, X. (2025) · Nature Communications · doi:10.1038/s41467-025-56749-2 · Cited by 16 · see citing works
Fan, K., Moore, J. E., Zhang, X.-O., & Weng, Z. (2021) · Nucleic Acids Research · doi:10.1093/nar/gkab345 · Cited by 22 · see citing works
“Plus strand signal Peak Minus strand signal GM12878 RAMPAGE [0-127] [0-831] [0-127]”
BackgroundMethodInfluentialOrthogonal control of mean and variability of endogenous genes in a human cell line
Bonny, A. R., Fonseca, J. P., Park, J. E., & El-Samad, H. (2020) · Nature Communications · doi:10.1038/s41467-020-20467-8 · Cited by 16 · see citing works
Bakoulis, S., Krautz, R., Alcaraz, N., Salvatore, M., & Andersson, R. (2022) · Nucleic Acids Research · doi:10.1093/nar/gkac088 · Cited by 21 · see citing works
“The activity of a regulatory element is controlled by the specificity of transcription factors (TFs) to bind the element and the density of their binding sites, both of which are in turn dependent on its DNA sequence (Nguyen et al. 2016; Weingarten-Gabbay et al. 2019; Smith et al. 2013; Grossman et al. 2017).”
BackgroundDiscovery of diverse and high-quality mRNA capping enzymes through a language model–enabled platform
Wang, T., Qin, B.-W., Li, S.-H., Wang, Z., Li, X., Jiang, Y.-Y., Qin, C., Ouyang, Q., Lou, C., & Qian, L. (2025) · Science Advances · doi:10.1126/sciadv.adt0402 · Cited by 14 · see citing works
“…features, as well as machine learning–assisted synbio-part design, has revealed an expanded set of CRISPR-associated nucleases ( 8 ), diverse surface ligands ( 9 ), tunable transcriptional regulators ( 5 , 6 ), and potential synbio-parts for gene delivery and biochemical catalysis ( 10 , 11 ).”
Multiplex profiling of developmental enhancers with quantitative, single-cell expression reportersPreprint
Lalanne, J.-B., Regalado, S. G., Domcke, S., Calderon, D., Martin, B., Li, T., Suiter, C. C., Lee, C., Trapnell, C., & Shendure, J. (2022) · bioRxiv · doi:10.1101/2022.12.10.519236 · Cited by 14 · see citing works
Yang, Y., Shao, Y.-H., Chaffin, T. A., Lee, J. H., Poindexter, M. R., Ahkami, A. H., Blumwald, E., & Stewart, C. (2022) · Frontiers in Plant Science · doi:10.3389/fpls.2022.1011939 · Cited by 14
“Several DNA sequence studies have used high throughput techniques to study core promoter sequences from yeast, Drosophila melanogaster, and human cells (Lubliner et al., 2015; Arnold et al., 2017; van Arensbergen et al., 2017; Weingarten-Gabbay et al., 2019; de Boer et al., 2020; Kotopka and Smolke, 2020).”
BackgroundSynthetic Promoter Design in Escherichia coli based on Generative Adversarial Network
Wang, Y., Wang, H.-C., Liu, L., & Wang, X.-W. (2019) · bioRxiv · doi:10.1101/563775 · Cited by 14
Short tandem repeats are important contributors to silencer elements in T cells
Hussain, S., Sadouni, N., van Essen, D., Dao, L. T. M., Ferré, Q., Charbonnier, G., Torres, M., Gallardo, F., Lecellier, C., Sexton, T., et al. (2023) · Nucleic Acids Research · doi:10.1093/nar/gkad187 · Cited by 16 · see citing works
“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).”
BackgroundWidespread perturbation of ETS factor binding sites in cancer
Pro, S. C., Hook, H., Bray, D., Berenzy, D., Moyer, D. C., Yin, M., Labadorf, A., Tewhey, R., Siggers, T., & Bass, J. F. F. (2022) · bioRxiv · doi:10.1038/s41467-023-36535-8 · Cited by 10 · see citing works
Molecular and experimental tools to design synthetic enhancers.
Vaknin, I., & Amit, R. (2022) · Current Opinion in Biotechnology · doi:10.1016/j.copbio.2022.102728 · Cited by 9 · see citing works
ReFeaFi: Genome-wide prediction of regulatory elements driving transcription initiation
Umarov, R., Li, Y., Arakawa, T., Takizawa, S., Gao, X., & Arner, E. (2021) · bioRxiv · doi:10.1371/journal.pcbi.1009376 · Cited by 9 · see citing works
“devised a high-throughput assay to quantify the activity of fully designed sequences that were integrated and expressed from a fixed location within the human genome [32], using the method to investigate binding regions of core promoters.”
BackgroundMethodFish-Ing for Enhancers in the Heart
Parisi, C., Vashisht, S., & Winata, C. L. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22083914 · Cited by 10 · see citing works
“They include promoters [4], silencer [5], insulator [6], and cis- and trans-regulatory elements [7,8].”
BackgroundDesign and deep learning of synthetic B-cell-specific promoters
Fu, Z.-H., He, S.-D., Wu, Y., & Zhao, G.-R. (2023) · Nucleic Acids Research · doi:10.1093/nar/gkad930 · Cited by 8 · see citing works
“The GC content of the promoter sequence is one factor that influences the promoters’ strength ( 43 ,44 ).”
BackgroundStrand asymmetries across genomic processes
Moeckel, C. M., Zaravinos, A., & Georgakopoulos‐Soares, I. (2023) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2023.03.007 · Cited by 9 · see citing works
“the orientation and correct positioning of promoter-related motifs, including the initiation element, the TATA-box, and the upstream and downstream promoter elements, among others [74,75].”
BackgroundYin, X., Chen, H.-X., Chen, Z., Yang, Q., Han, J., & He, G.-W. (2022) · Journal of Gene Medicine · doi:10.1002/jgm.3450 · Cited by 8
“The promoter region of a gene may interrupt transcriptional regulation, which alters the gene expression, leading to disease.(22,23) In our previous study, novel variants in the ISL1 gene promoter region have been identified in ventricular septal defect.”
BackgroundDeePromClass: Delineator for Eukaryotic Core Promoters Employing Deep Neural Networks
Kari, H., Bandi, S. M. S., Kumar, A., & Yella, V. R. (2022) · IEEE/ACM Transactions on Computational Biology & Bioinformatics · doi:10.1109/tcbb.2022.3163418 · Cited by 8 · see citing works
“The -100 to þ 50 region indicates the highest core promoter activity with the majority of the promoter sequence signals are located within -40 to þ 40 [27], [28].”
BackgroundLeveraging genomic deep learning models for the prediction of noncoding variant effects.
Kathail, P., Bajwa, A., & Ioannidis, N. (2024) · Nature Genetics · doi:10.1038/s41588-026-02769-7 · Cited by 7
A synthetic synthesis to explore animal evolution and development
Perkins, M. L., Gándara, L., & Crocker, J. (2022) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2020.0517 · Cited by 9 · see citing works
Large-scale discovery of recombinases for integrating DNA into the human genome
Durrant, M., Fanton, A., Tycko, J., Hinks, M. M., Chandrasekaran, S. S., Perry, N. T., Schaepe, J. M., Du, P. P., Lotfy, P., Bassik, M., et al. (2021) · doi:10.1101/2021.11.05.467528 · Cited by 7
“3C) (Weingarten-Gabbay et al. 2019).”
Multiplexed dissection of a model human transcription factor binding site architecturePreprint
Davis, J. E., Insigne, K. D., Jones, E. M., Hastings, Q. B., & Kosuri, S. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/625434 · Cited by 5 · see citing works
“In contrast, a recently published MPRA in human cell lines found increasing number of CREB binding sites did not increase expression, although these sites were assayed in the absence of forskolin (Weingarten-Gabbay et al., 2019).”
BackgroundInfluentialProformer: 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 · see citing works
Dense encoding of developmental regulatory information may constrain evolvabilityPreprint
Fuqua, T., Jordan, J., van Breugel, M. V., Halavatyi, A., Tischer, C., Polidoro, P., Abe, N., Tsai, A., Mann, R., Stern, D., et al. (2020) · bioRxiv · doi:10.1101/2020.04.17.046052 · Cited by 6 · see citing works
Guzman, 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 8 · see citing works
The origin of genetic and metabolic systems: Evolutionary structuralinsights
Deng, S. (2023) · Heliyon · doi:10.1016/j.heliyon.2023.e14466 · Cited by 7 · see citing works
Cloning of DNA oligo pools for in vitro expression
Uzonyi, A., Nir, R., & Schwartz, S. (2022) · STAR Protocols · doi:10.1016/j.xpro.2021.101103 · Cited by 5
Self-citationCompatibility 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 · see citing works
Artificial design of the genome: from sequences to the 3D structure of chromosomes
Wang, J., Xie, Z., Cui, Y., Li, B., & Yuan, Y. (2024) · Trends in biotechnology · doi:10.1016/j.tibtech.2024.08.012 · Cited by 4 · see citing works
Pan-viral ORFs discovery using Massively Parallel Ribosome Profiling
Weingarten-Gabbay, S., Bauer, M., Stanton, A. C., Klaeger, S., Verzani, E. K., López, D., Clauser, K., Carr, S. A., Abelin, J. G., Rice, C. M., et al. (2023) · bioRxiv · doi:10.1101/2023.09.26.559641 · Cited by 4
Self-citationProformer: a hybrid macaron transformer model predicts expression values from promoter sequences
Kwak, I.-Y., Kim, B.-C., Lee, J., Garry, D., Zhang, J., & Gong, W. (2023) · bioRxiv · doi:10.1101/2023.03.10.532129 · Cited by 4
“(c) Systematic 294 evaluation of global average pooling and MEH with mask filing on different model 295 specifications such as dimension heads (2, 4, and 8), macaron blocks (1, 2, 4, and 8), 296 and number of expression heads (1, 8, 16, 32, 64) was performed.”
MethodBioinformatic Design of Dendritic Cell-Specific Synthetic Promoters
Johnson, A. O., Fowler, S., Webster, C., Brown, A. J., & James, D. C. (2022) · ACS Synthetic Biology · doi:10.1021/acssynbio.2c00027 · Cited by 4
Gummadi, A. S. C., & Yella, V. R. (2025) · Biochemical Genetics · doi:10.1007/s10528-025-11231-y · Cited by 3 · see citing works
“The variability observed in perplexity profiles across taxa indicate the evolutionary pressures shaping regulatory DNA and highlights the adaptability of transcriptional grammar to meet species-specific functional demands (Vanaja and Yella 2022; Weingarten-Gabbay et al. 2019).”
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].”
Bose, M. L., Tovar, A., Kyono, Y., Varshney, A., Kitzman, J., & Parker, S. C. J. (2025) · bioRxiv · doi:10.1101/2025.10.13.659964 · Cited by 2 · see citing works
“…in a single position relative to their promoter element and sequence orientation (Figure 1B), which likewise may not reflect the full spectrum of the function of these sequences in their native context, especially in the case of testing strongly unidirectional elements such as promoters (19, 20).”
Siegel, D. A., Tonquèze, O. L., Biton, A., Erle, D. J., & Zaitlen, N. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.02.12.945113 · Cited by 1 · see citing works
“Myint et al [10] classified MPRAs into three broad categories: characterization studies[17, 18, 19], which examine and classify the sequence features of regulatory elements; saturation mutagenesis studies[4, 20, 21, 22], which look at the impact of all possible mutations to a functional element; and…”
BackgroundEvidence of transcription at polyT short tandem repeatsPreprint
Bessière, C., Saraswat, M., Grapotte, M., Menichelli, C., Ramilowski, J. A., Severin, J., Hayashizaki, Y., Itoh, M., Hasegawa, A., Suzuki, H., et al. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/634261 · Cited by 4 · see citing works
“transcription of reporter genes in similar levels to TF binding sites [65].”
BackgroundZhang, J., Ma, Y.-N., & Song, S. (2026) · Animals · doi:10.3390/ani16030481 · Cited by 1 · see citing works
Pan-viral ORFs discovery using Massively Parallel Ribosome Profiling
Weingarten-Gabbay, S., Bauer, M., Stanton, A. C., Yu, Y.-P., Freije, C., Welch, N., Boehm, C., Klaeger, S., Verzani, E. K., López, D., et al. (2025) · Science · doi:10.1126/science.ado6670 · Cited by 1 · see citing works
Self-citationXu, S., Peng, C., Ren, R., Lu, H., Zhao, H., Xia, S., Shen, Y., Xu, B., Zhang, H., Cheng, X., et al. (2025) · Cell Reports · doi:10.1016/j.celrep.2025.115476 · Cited by 1 · see citing works
A universal system for boosting gene expression in eukaryotic cell-lines
Vaknin, I., Willinger, O., Mandl, J., Heuberger, H., Ben-Ami, D., Zeng, Y., Goldberg, S., Orenstein, Y., & Amit, R. (2024) · Nature Communications · doi:10.1038/s41467-024-46573-5 · Cited by 1 · see citing works
“…the second approach, a multitude of synthetic cis-regulatory regions (e.g., synthetic enhancers) composed of a small number of TFBSs arranged in various con fi gurations were encoded in an oligo library (OL) and characterized using massively parallel reporter assays (MPRA) such as SORT-seq 8,12,13 .”
Evaluating single-cell variability in proteasomal decay.Preprint
Das, S., Singh, A., & Shah, P. (2023) · bioRxiv · doi:10.1101/2023.08.22.554358 · Cited by 1 · see citing works
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 1 · see citing works
“These elements are among the most well-characterized regulatory sequence classes, in part due to their predictable location relative to the gene TSS.”
BackgroundInfluentialDeep flanking sequence engineering for efficient promoter design
Zhang, P.-C., Wang, H.-C., Xu, H., Wei, L., Hu, Z., & Wang, X.-W. (2023) · bioRxiv · doi:10.1101/2023.04.14.536502 · Cited by 1
Mikl, M., Alon, A., Mordret, E., Pilpel, Y., & Segal, E. (2018) · bioRxiv · doi:10.1101/469692 · Cited by 1
Self-citationPoolParty: streamlined design of DNA sequence libraries in Python
Liu, Z., Cordero, A., & Kinney, J. B. (2026) · BMC Bioinformatics · doi:10.1186/s12859-026-06696-6
Qiu, Y., Hebraud, E., Pouyet, F., & Palazzo, A. F. (2026) · PLoS Biology · doi:10.1371/journal.pbio.3004063
“High GC-content in the promoter region enhances transcription [5,6], while high GC-content at the 5'end of mRNAs that have few introns promotes their efficient export from the nucleus [7–12].”
PoolParty: streamlined design of DNA sequence libraries in PythonPreprint
Liu, Z., Cordero, A., & Kinney, J. B. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.04.06.716802
Jin, C., Liu, C., Liu, Z., & Xiao, X. (2026) · 2026 International Conference on Communication Networks and Machine Learning (CNML) · doi:10.1109/cnml68938.2026.11453063
“In 2018, Zhao et al. introduced IRESfinder[14], a logistic-regression model for eukaryotic IRES prediction based on the Weingarten-Gabbay dataset[15].”
PccGEO: prior constraints conditioned genetic elements optimizationPreprint
Xu, H., Zhang, P., Wang, H., Wei, L., Hu, Z., & Wang, X. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.11.08.467823
Renganaath, K., Cheung, R., Day, L., Kosuri, S., Kruglyak, L., & Albert, F. (2020) · bioRxiv · doi:10.1101/2020.08.31.276337
“…2013; Mogno et al., 2013; Sharon et al., 2012; Smith et al., 2013) in promoters (Kotopka and Smolke, 2020; Lubliner et al., 2015; Sharon et al., 2012; Weingarten-Gabbay et al., 2019), UTRs (Cuperus et al., 2017; Dvir et al., 2013; Rabani et al., 2017; Shalem et al., 2015) and enhancers (Arnold et…”
BackgroundKreimer, A., & Yosef, N. (2020) · Cell Systems · doi:10.1016/j.cels.2020.07.001
- Authors
- Weingarten-Gabbay, S., Nir, R., Lubliner, S., Sharon, E., Kalma, Y., Weinberger, A., & Segal, E.
- Affiliations
- Weizmann Institute of Science (IL)
- Venue
- Genome Research
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2019-01-08
- Volume
- 29
- Issue
- 2
- Pages
- 171-183
- ISSN
- 1088-9051 (ISSN-L)
- 1549-5469
- PMC
- PMC6360817
- OpenAlex
- W2910487490
- Cited by
- 110
- References
- 94
- Citations by year
- 2026: 8 · 2025: 10 · 2024: 8 · 2023: 16 · 2022: 23 · 2021: 18 · 2020: 18 · 2019: 9
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genome Research (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- European Research Council (ERC 786344)
- MRG-Grammar FET project (EU project 664918)
- Israel Science Foundation (ISF 161/16)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene Regulatory Network Analysis
- Keywords
- human promoters, core promoter elements, transcription factor binding sites, promoter activity, TATA box, initiator element, divergent transcription, bidirectional promoter, enhancers, transcriptional regulation
- MeSH terms
- Binding Sites, Enhancer Elements, Genetic, Gene Expression Regulation, Humans, Nucleosomes, Promoter Regions, Genetic, Transcription Factors, Transcription, Genetic, Genome, Human, TATA Box, Sequence Analysis, DNA, High-Throughput Nucleotide Sequencing
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