Evidence for additive and synergistic action of mammalian enhancers during cell fate determination
Open accessAbstract
Enhancer activity drives cell differentiation and cell fate determination, but it remains unclear how enhancers cooperate during these processes. Here we investigate enhancer cooperation during transdifferentiation of human leukemia B-cells to macrophages. Putative enhancers are established by binding of the pioneer factor C/EBPα followed by chromatin opening and enhancer RNA (eRNA) synthesis from H3K4-monomethylated regions. Using eRNA synthesis as a proxy for enhancer activity, we find that most putative enhancers cooperate in an additive way to regulate transcription of assigned target genes. However, transcription from 136 target genes depends exponentially on the summed activity of its putative paired enhancers, indicating that these enhancers cooperate synergistically. The target genes are cell type-specific, suggesting that enhancer synergy can contribute to cell fate determination. Enhancer synergy appears to depend on cell type-specific transcription factors, and such interacting enhancers are not predicted from occupancy or accessibility data that are used to detect superenhancers.
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Synergistic effects were observed in mammalian cell fate determination systems, for example, at Fgf5 enhancers during differentiation of mouse embryonic stem cells to epiblast-like cells and at up to 20% enhancers upon transdifferentiation of human leukemia B-cells into macrophages.
“synergistic effects were observed in mammalian cell fate determination systems, for example, at Fgf5 enhancers during the differentiation of mouse embryonic stem cells to epiblast-like cells (EpiLCs) [523] and at up to 20% enhancers upon transdifferentiation of human leukemia B-cells into macrophages [524].”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [524]
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“Additive cooperation was also demonstrated for enhancers within the Myc-regulating superenhancer and for limb enhancers (Bahr et al., 2018; Osterwalder et al., 2018).”
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MethodTT-seq maps the human transient transcriptome
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“Such enhancer cooperation could be simultaneous and may rely on cooperative nuclear condensation based on liquid–liquid phase separation (Boehning et al., 2018; Boija et al., 2018; Chong et al., 2018; Hnisz et al., 2017; Murray et al., 2017; Nair et al., 2019; Sabari et al., 2018).”
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“It remains controversial whether enhancer transcription is required for enhancer priming (Calo and Wysocka, 2013; Dorighi et al., 2017; Kaikkonen et al., 2013), but our data support that in our system the chromatin modification H3K4me1 generally precedes nucleosome depletion and enhancer transcription (Bonn et al.”
BackgroundGenetic dissection of the α-globin super-enhancer in vivo
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“In contrast to our time-resolved study, previous studies investigated enhancer cooperation in steady state or at an end point, and at selected genes, rather than genome-wide (Hay et al., 2016; Osterwalder et al., 2018; Stine et al., 2011).”
BackgroundResultdbSUPER: a database of super-enhancers in mouse and human genome
Khan, A., & Zhang, X. (2015) · Nucleic Acids Research · doi:10.1093/nar/gkv1002 · Cited by 384 · cited 1× · see citing works
“Indeed, previously identified superenhancers from the dbSUPER database (Hnisz et al., 2013; Khan and Zhang, 2016) overlapped to similar extents with our additive or synergistic enhancers (Figure 5—figure supplement 4D).”
BackgroundTFBSTools: an R/bioconductor package for transcription factor binding site analysis
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MethodPhase separation of ligand-activated enhancers licenses cooperative chromosomal enhancer assembly
Nair, S. J., Lu, Y., Meluzzi, D., Oh, S., Yang, F., Friedman, M. J., Wang, S. S., Suter, T., Alshareedah, I., Gamliel, A., et al. (2019) · Nature Structural & Molecular Biology · doi:10.1038/s41594-019-0190-5 · Cited by 366 · cited 1× · see citing works
“Such enhancer cooperation could be simultaneous and may rely on cooperative nuclear condensation based on liquid–liquid phase separation (Boehning et al., 2018; Boija et al., 2018; Chong et al., 2018; Hnisz et al., 2017; Murray et al., 2017; Nair et al., 2019; Sabari et al., 2018).”
BackgroundStadhouders, R., Vidal, E., Serra, F., Stefano, B. D., Dily, F. L., Quilez, J., Gómez, A., Collombet, S., Berenguer, C., Cuartero, Y., et al. (2018) · Nature Genetics · doi:10.1038/s41588-017-0030-7 · Cited by 352 · see citing works
Self-citationWidespread transcriptional pausing and elongation control at enhancers
Henriques, T., Scruggs, B. S., Inouye, M. O., Muse, G. W., Williams, L. H., Burkholder, A. B., Lavender, C. A., Fargo, D. C., & Adelman, K. (2018) · Genes & Development · doi:10.1101/gad.309351.117 · Cited by 350 · cited 2× · see citing works
“Using eRNA production as a proxy for enhancer transactivation activity (Henriques et al., 2018; Mikhaylichenko et al., 2018), TT-seq is very well suitable to identify active enhancers, to pair enhancers with their putative target promoters, and to measure the transcription activity of enhancers and promoters genome-wi…”
BackgroundMethodA Myc enhancer cluster regulates normal and leukaemic haematopoietic stem cell hierarchies
Bahr, C., von Paleske, L., Uslu, V. V., Remeseiro, S., Takayama, N., Ng, S. W., Murison, A., Langenfeld, K., Petretich, M., Scognamiglio, R., et al. (2018) · Nature · doi:10.1038/nature25193 · Cited by 328 · cited 2× · see citing works
“Additive cooperation was also demonstrated for enhancers within the Myc-regulating superenhancer and for limb enhancers (Bahr et al., 2018; Osterwalder et al., 2018).”
BackgroundRubin, A. J., Barajas, B. C., Furlan-Magaril, M., Lopez-Pajares, V., Mumbach, M. R., Howard, I., Kim, D. S., Boxer, L. D., Cairns, J., Spivakov, M., et al. (2017) · Nature Genetics · doi:10.1038/ng.3935 · Cited by 293 · cited 2× · see citing works
“In summary, we identified putative target genes for the majority of enhancers and found that many genes can be paired with multiple enhancers, in line with previous reports (Beagrie et al., 2017; Rubin et al., 2017).”
ResultMikhaylichenko, O., Bondarenko, V., Harnett, D., Schor, I. E., Males, M., Viales, R. R., & Furlong, E. E. M. (2018) · Genes & Development · doi:10.1101/gad.308619.117 · Cited by 293 · see citing works
Static and dynamic DNA loops form AP-1 bound activation hubs during macrophage development
Phanstiel, D., Bortle, K. V., Spacek, D., Hess, G., Shamim, M., Machol, I., Love, M., Aiden, E. L., Bassik, M., & Snyder, M. (2017) · bioRxiv · doi:10.1101/142026 · Cited by 283 · cited 2×
“To gain additional support for the promoter–enhancer pairing, we tested whether the pairs were located within the same TAD obtained from Hi-C data (Stik et al., 2020; Phanstiel et al., 2017).”
MethodHierarchy within the mammary STAT5-driven Wap super-enhancer
Shin, H. Y., Willi, M., Yoo, K. H., Zeng, X., Wang, C., Metser, G., & Hennighausen, L. (2016) · Nature Genetics · doi:10.1038/ng.3606 · Cited by 282 · cited 1× · see citing works
“It has been suggested that the individual constituent enhancers of such clusters cooperate in a synergistic manner to activate target genes (Hnisz et al., 2017; Shin et al., 2016).”
BackgroundVSIG4, a B7 family-related protein, is a negative regulator of T cell activation
Vogt, L., Schmitz, N., Kurrer, M. O., Bauer, M., Hinton, H. I., Behnke, S., Gatto, D., Sebbel, P., Beerli, R. R., Sonderegger, I., et al. (2006) · Journal of Clinical Investigation · doi:10.1172/jci25673 · Cited by 273 · see citing works
CDK9-dependent RNA polymerase II pausing controls transcription initiation
Gressel, S., Schwalb, B., Decker, T.-M., Qin, W., Leonhardt, H., Eick, D., & Cramer, P. (2017) · eLife · doi:10.7554/elife.29736 · Cited by 239 · see citing works
Self-citationMultiple enhancers ensure precision of gap gene-expression patterns in the <i>Drosophila</i> embryo
Perry, M. W., Boettiger, A. N., & Levine, M. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1109873108 · Cited by 228 · cited 1× · see citing works
“Indeed, expression of gap genes in Drosophila are regulated by multiple enhancers, and deleting one of these enhancers has little effect on the gene expression pattern (Perry et al., 2011).”
BackgroundEnhancer hubs and loop collisions identified from single-allele topologies
Allahyar, A., Vermeulen, C., Bouwman, B. A. M., Krijger, P. H. L., Verstegen, M. J. A. M., Geeven, G., van Kranenburg, M., Pieterse, M., Straver, R., Haarhuis, J. H. I., et al. (2018) · Nature Genetics · doi:10.1038/s41588-018-0161-5 · Cited by 227 · cited 1× · see citing works
“Moreover, multiple enhancers can interact simultaneously with their target gene promoter in mouse and human cells (Allahyar et al., 2018; Oudelaar et al., 2018).”
BackgroundSingle-allele chromatin interactions identify regulatory hubs in dynamic compartmentalized domains
Oudelaar, A. M., Davies, J. O. J., Hanssen, L. L. P., Telenius, J. M., Schwessinger, R., Liu, Y., Brown, J. M., Downes, D. J., Chiariello, A. M., Bianco, S., et al. (2018) · Nature Genetics · doi:10.1038/s41588-018-0253-2 · Cited by 196 · cited 1× · see citing works
“Moreover, multiple enhancers can interact simultaneously with their target gene promoter in mouse and human cells (Allahyar et al., 2018; Oudelaar et al., 2018).”
BackgroundPedersen, T. Å., Kowenz‐Leutz, E., Leutz, A., & Nerlov, C. (2001) · Genes & Development · doi:10.1101/gad.209901 · Cited by 196 · cited 1× · see citing works
“, 2013) and with SWI/SNF chromatin remodeling complexes (Pedersen et al., 2001).”
BackgroundMoorthy, S. D., Davidson, S., Shchuka, V. M., Singh, G., Malek-Gilani, N., Langroudi, L., Martchenko, A., So, V., Macpherson, N. N., & Mitchell, J. A. (2016) · Genome Research · doi:10.1101/gr.210930.116 · Cited by 190 · see citing works
Role of Krüppel-like factors in leukocyte development, function, and disease
Cao, Z., Sun, X., Icli, B., Wara, A. K., & Feinberg, M. W. (2010) · Blood · doi:10.1182/blood-2010-05-285353 · Cited by 186 · cited 1× · see citing works
“Members of the KLF family, such as KLF1-4 and KLF6, are important for monocyte and macrophage activation (Cao et al., 2010; Date et al., 2014).”
Backgroundc-Myb Is Critical for B Cell Development and Maintenance of Follicular B Cells
Thomas, M., Kremer, C. S., Ravichandran, K. S., Rajewsky, K., & Bender, T. P. (2005) · Immunity · doi:10.1016/j.immuni.2005.08.005 · Cited by 185 · cited 1× · see citing works
“B cell-specific genes controlled by synergistic enhancers include MYB, BLNK, VPREB1, and IGLL5 (Cobaleda et al., 2007; Thomas et al., 2005).”
BackgroundSawado, T., Halow, J., Bender, M., & Groudine, M. (2003) · Genes & Development · doi:10.1101/gad.1072303 · Cited by 183 · cited 1× · see citing works
“Additionally or alternatively, enhancer synergy may also stem from sequential cooperation if different enhancers target different steps of transcription such as initiation and elongation (Beagrie and Pombo, 2016; Haberle and Stark, 2018; Henriques et al., 2018; Kim et al., 1998; Sawado et al., 2003; Spicuglia et al.,…”
BackgroundRobertson, A. G., Bilenky, M., Tam, A., Zhao, Y., Zeng, T., Thiessen, N., Cezard, T., Fejes, A. P., Wederell, E. D., Cullum, R., et al. (2008) · Genome Research · doi:10.1101/gr.078519.108 · Cited by 182 · cited 1× · see citing works
“Putative enhancers can be detected by mapping of chromatin signatures (Creyghton et al., 2010; Heintzman et al., 2007; Robertson et al., 2008).”
BackgroundKruppel-like Transcription Factor 6 Regulates Inflammatory Macrophage Polarization
Date, D. A., Das, R., Narla, G., Simon, D. I., Jain, M. K., & Mahabeleshwar, G. H. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.526749 · Cited by 182 · cited 1× · see citing works
“Members of the KLF family, such as KLF1-4 and KLF6, are important for monocyte and macrophage activation (Cao et al., 2010; Date et al., 2014).”
BackgroundHaddad, R. (2004) · Blood · doi:10.1182/blood-2004-05-1845 · Cited by 151 · see citing works
Takaku, M., Grimm, S. A., Shimbo, T., Perera, L., Menafra, R., Stunnenberg, H. G., Archer, T. K., Machida, S., Kurumizaka, H., & Wade, P. A. (2016) · Genome Biology · doi:10.1186/s13059-016-0897-0 · Cited by 151 · see citing works
Rapino, F. A., Robles, E. F., Richter, J. Á., Kallin, E. M., Martinez-Climent, J. A., & Graf, T. (2013) · Cell Reports · doi:10.1016/j.celrep.2013.03.003 · Cited by 144 · cited 6× · see citing works
“Transdifferentiation involves dramatic changes in gene expression, including silencing and activation of cell type-specific genes (Rapino et al., 2013).”
BackgroundMethodInfluentialSelf-citationStik, G., Vidal, E., Barrero, M., Cuartero, S., Vila-Casadesús, M., Mendieta-Esteban, J., Tian, T. V., Choi, J., Berenguer, C., Abad, A., et al. (2020) · Nature Genetics · doi:10.1038/s41588-020-0643-0 · Cited by 139 · see citing works
Self-citationKeshav, S., Chung, P., Milon, G., & Gordon, S. (1991) · Journal of Experimental Medicine · doi:10.1084/jem.174.5.1049 · Cited by 121 · cited 1× · see citing works
“These genes showed an exponential change in mRNA synthesis over time relative to the sum of eRNA synthesis from paired enhancers (Figure 5B), and included macrophage-related genes such as CITED2, LYZ (Keshav et al., 1991; Kranc et al., 2009), and B cell-related genes such as BCL7A, LEF1, and TLE1 (Haddad et al.”
BackgroundTFClass: expanding the classification of human transcription factors to their mammalian orthologs
Wingender, E., Schoeps, T., Haubrock, M., Krull, M., & Dönitz, J. (2017) · Nucleic Acids Res. · doi:10.1093/nar/gkx987 · Cited by 114 · see citing works
Kim, T. K., Kim, T. H., & Maniatis, T. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.21.12191 · Cited by 109 · cited 1× · see citing works
“Additionally or alternatively, enhancer synergy may also stem from sequential cooperation if different enhancers target different steps of transcription such as initiation and elongation (Beagrie and Pombo, 2016; Haberle and Stark, 2018; Henriques et al., 2018; Kim et al., 1998; Sawado et al., 2003; Spicuglia et al.,…”
Backgroundvan Oevelen, C. J. C., Collombet, S., Vicent, G. P., Hoogenkamp, M., Lepoivre, C., Badeaux, A. I., Bussmann, L. H., Sardina, J. L., Thieffry, D., Beato, M., et al. (2015) · Stem Cell Reports · doi:10.1016/j.stemcr.2015.06.007 · Cited by 108 · see citing works
Self-citationCited2 Is an Essential Regulator of Adult Hematopoietic Stem Cells
Kranc, K. R., Schepers, H., Rodrigues, N. P., Bamforth, S. D., Villadsen, E., Ferry, H., Bouriez‐Jones, T., Sigvardsson, M., Bhattacharya, S., Jacobsen, S. E. W., et al. (2009) · Cell stem cell · doi:10.1016/j.stem.2009.11.001 · Cited by 106 · see citing works
Spicuglia, S., Kumar, S., Yeh, J.-H., Vachez, E., Chasson, L., Gorbatch, S., Cautres, J., & Ferrier, P. (2002) · Molecular Cell · doi:10.1016/s1097-2765(02)00791-8 · Cited by 95 · see citing works
Zacher, B., Michel, M., Schwalb, B., Cramer, P., Tresch, A., & Gagneur, J. (2017) · PLOS ONE · doi:10.1371/journal.pone.0169249 · Cited by 91 · see citing works
Self-citationMaekawa, T., Imamoto, F., Merlino, G., Pastan, I., & Ishii, S. (1989) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)83571-2 · Cited by 80
Is a super-enhancer greater than the sum of its parts?
Dukler, N., Gulko, B., Huang, Y.-F., & Siepel, A. (2017) · Nature Genetics · doi:10.1038/ng.3759 · Cited by 79 · cited 1× · see citing works
“We fitted these data to three models (Dukler et al., 2017), an additive, a synergistic (or exponential), and a logistic model (Figure 5A,B and Figure 5—figure supplement 1A, respectively; Materials and methods).”
MethodTemporal dynamics of pair-rule stripes in living Drosophila embryos
Lim, B., Fukaya, T., Heist, T., & Levine, M. (2018) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.1810430115 · Cited by 60 · cited 1×
“Evidence for enhancer–enhancer interactions was also obtained in Drosophila (Lim et al., 2018).”
BackgroundYan, K., Lou, S., & Gerstein, M. (2017) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1005647 · Cited by 56 · cited 2× · see citing works
“With the 1 Mb method, enhancers were paired with all promoters within 1 Mb, which corresponds to the median width of a human topologically associating domain (TAD) (Dixon et al., 2012; Yan et al., 2017).”
MethodJubb, A. W., Boyle, S., Hume, D. A., & Bickmore, W. A. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.11.053 · Cited by 48 · cited 1× · see citing works
“Our results also explain how activation of the glucocorticoid receptor can induce chromatin decompaction in the presence of the transcription inhibitor aamanitin (Jubb et al., 2017).”
BackgroundSteroid hormone modulation of RET through two estrogen responsive enhancers in breast cancer.
Stine, Z. E., McGaughey, D. M., Bessling, S. L., Li, S., & McCallion, A. (2011) · Human Molecular Genetics · doi:10.1093/hmg/ddr291 · Cited by 46 · cited 1× · see citing works
“In contrast to our time-resolved study, previous studies investigated enhancer cooperation in steady state or at an end point, and at selected genes, rather than genome-wide (Hay et al., 2016; Osterwalder et al., 2018; Stine et al., 2011).”
ResultGene activation by metazoan enhancers: Diverse mechanisms stimulate distinct steps of transcription
Beagrie, R. A., & Pombo, A. (2016) · BioEssays · doi:10.1002/bies.201600032 · Cited by 43 · cited 2× · see citing works
“Additionally or alternatively, enhancer synergy may also stem from sequential cooperation if different enhancers target different steps of transcription such as initiation and elongation (Beagrie and Pombo, 2016; Haberle and Stark, 2018; Henriques et al., 2018; Kim et al., 1998; Sawado et al., 2003; Spicuglia et al.,…”
BackgroundLi, H., Gade, P., Nallar, S., Raha, A., Roy, S., Karra, S., Reddy, J., Reddy, S., & Kalvakolanu, D. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m800604200 · Cited by 43 · see citing works
E2f1–3 Are Critical for Myeloid Development
Trikha, P., Sharma, N., Opavský, R., Reyes, A., Pena, C., Ostrowski, M. C., Roussel, M. F., & Leone, G. W. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.182733 · Cited by 37 · see citing works
Secondary enhancers synergise with primary enhancers to guarantee fine-tuned muscle gene expression
Guerrero, L., Marco-Ferreres, R., Serrano, A. L., Arredondo, J. J., & Cervera, M. (2009) · Developmental Biology · doi:10.1016/j.ydbio.2009.10.006 · Cited by 29 · see citing works
Fulton, R., & Ness, B. V. V. (1994) · Nucleic Acids Research · doi:10.1093/nar/22.20.4216 · Cited by 27 · see citing works
Initiation of transcription by T7 RNA polymerase as its natural promoters.
Ikeda, R. A., Lin, A.-C., & Clarke, J. (1992) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)45929-7 · Cited by 25 · cited 1×
“The logistic model postulates that promoter activity reaches a limit and cannot increase any further even if the sum of the enhancer activities increases more, reflecting the known upper limit of promoter activity (Gressel et al., 2017; Ikeda et al., 1992).”
BackgroundA Transcription Factor Pulse Can Prime Chromatin for Heritable Transcriptional Memory
Badeaux, A. I., Collombet, S., Laurent, B., van Oevelen, C. J. C., Chin, K., Thieffry, D., Graf, T., & Shi, Y. (2016) · Molecular and Cellular Biology · doi:10.1128/mcb.00372-16 · Cited by 19 · cited 1× · see citing works
“These observations are consistent with the capacity of the pioneering factor C/EBPa to induce DNA opening (Iberg-Badeaux et al., 2017; van Oevelen et al., 2015), and its ability to reorganize chromatin states and genome architecture before gene expression changes (Stadhouders et al.”
BackgroundSelf-citation
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Research works printed but not linked: 2
- Dobin A Davis CA Schlesinger F Drenkow J Zaleski C Jha S Batut P Chaisson M Gingeras TR 2013 STAR: ultrafast universal RNA-seq aligner Bioinformatics 29 15 21 10.1093/bioinformatics/bts635 23104886 PMC3530905 · DOI · Paper page
- Michel M Demel C Zacher B Schwalb B Krebs S Blum H Gagneur J Cramer P 2017 TT-seq captures enhancer landscapes immediately after T-cell stimulation Molecular Systems Biology 13 920 10.15252/msb.20167507 28270558 PMC5371733 · DOI
Cited by
Sorted by citations
Adipose tissue retains an epigenetic memory of obesity after weight loss
Hinte, L. C., Castellano‐Castillo, D., Ghosh, A., Melrose, K., Gasser, E., Noé, F., Massier, L., Dong, H., Sun, W., Hoffmann, A., et al. (2024) · Nature · doi:10.1038/s41586-024-08165-7 · Cited by 300 · see citing works
“Enhancers are key drivers of cellular identity and cell fate 51,52 .”
Deciphering the multi-scale, quantitative cis-regulatory code
Kim, S., & Wysocka, J. (2023) · Molecular Cell · doi:10.1016/j.molcel.2022.12.032 · Cited by 282 · see citing works
Uyehara, C. M., & Apostolou, E. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.112068 · Cited by 143 · see citing works
Cell fate decisions, transcription factors and signaling during early retinal development
Diacou, R., Nandigrami, P., Fiser, A., Liu, W., Ashery‐Padan, R., & Cvekl, A. (2022) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2022.101093 · Cited by 103 · see citing works
“Recent studies of cell fate determination point to both additive and synergistic actions of multiple enhancers activated by lineage-specific transcription factors that can be predicted from eRNA data coupled with active H3K4me1 chromatin domains (Choi et al., 2021).”
BackgroundOber-Reynolds, B., Wang, C., Ko, J. M., Rios, E. J., Aasi, S. Z., Davis, M. M., Oro, A. E., & Greenleaf, W. J. (2023) · Nature Genetics · doi:10.1038/s41588-023-01445-4 · Cited by 83 · see citing works
“These findings support an additive, modular model of enhancer activity—a model substantiated by genetic perturbation studies of individual enhancers for alpha-globin 37 and Myc 38 , studies of enhancers involved in limb development 39 and genomic-scale measures of enhancer activity 40,41 .”
Transcriptional enhancers and their communication with gene promoters
Ray-Jones, H., & Spivakov, M. (2021) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-021-03903-w · Cited by 81 · see citing works
“In turn, synergistic effects were observed in mammalian cell fate determination systems, for example, at Fgf5 enhancers during the differentiation of mouse embryonic stem cells to epiblast-like cells (EpiLCs) [523] and at up to 20% enhancers upon transdifferentiation of human leukemia B-cells into macrophages [524].”
BackgroundThe chromatin signatures of enhancers and their dynamic regulation
Barral, A., & Déjardin, J. (2023) · Nucleus · doi:10.1080/19491034.2022.2160551 · Cited by 71 · see citing works
Estrogen/ER in anti-tumor immunity regulation to tumor cell and tumor microenvironment
Wang, T., Jin, J., Qian, C., Lou, J., Lin, J., Xu, A., Xia, K., Jin, L., Liu, B., Tao, H., et al. (2021) · Cancer Cell International · doi:10.1186/s12935-021-02003-w · Cited by 42 · see citing works
“On the other hand, the ER enhancer is able to connect with RNA polymerase II and promotes a series of noncoding enhancer RNAs transcription, called enhancer RNA (eRNA) [21].”
BackgroundTranscriptional Regulation and Implications for Controlling Hox Gene Expression
Afzal, Z., & Krumlauf, R. K. (2022) · Journal of Developmental Biology · doi:10.3390/jdb10010004 · Cited by 46 · see citing works
“Similarly, clusters of weak enhancers can synergize to serve as super enhancers to robustly regulate gene expression [68].”
BackgroundCabaj, 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
An activity-specificity trade-off encoded in human transcription factors
Naderi, J., Magalhães, A. P., Kibar, G., Stik, G., Zhang, Y., Mackowiak, S. D., Wieler, H. M., Rossi, F., Buschow, R., Christou‐Kent, M., et al. (2024) · Nature Cell Biology · doi:10.1038/s41556-024-01411-0 · Cited by 34 · see citing works
“3c and 5a).”
Self-citationZhou, T., Zhu, X., Ye, Z., Wang, Y., Yao, C., Xu, N., Zhou, M., Ma, J., Qin, Y., Shen, Y., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-29514-y · Cited by 36 · see citing works
Cao, Y., Xia, Y., Balowski, J., Ou, J.-H., Song, L.-Y., Safi, A., Curtis, T., Crawford, G. E., Poss, K., & Cao, J. (2021) · bioRxiv · doi:10.1101/2021.08.23.457406 · Cited by 31
Transcription factor condensates and signaling driven transcription
Mann, R., & Notani, D. (2023) · Nucleus · doi:10.1080/19491034.2023.2205758 · Cited by 32 · see citing works
“Two general enhancer action mechanisms have been proposed: (1) The Enhanceosome model, where TFs bind in a highly synergistic manner that leads to a profound effect on Transcription than either factor binding alone [123,124].”
BackgroundCTCF depletion decouples enhancer-mediated gene activation from chromatin hub formation
Karpińska, M. A., Zhu, Y., Ghazvini, Z. F., Ramasamy, S., Barbieri, M., Cao, T. B. N., Varahram, N., Aljahani, A., Lidschreiber, M., Papantonis, A., et al. (2025) · Nature Structural & Molecular Biology · doi:10.1038/s41594-025-01555-z · Cited by 34 · see citing works
“…high-throughput sequencing (ATAC–seq) 46 ; the distribution of histone H3 lysine 27 (H3K27) acetylation (H3K27ac), H3K27 trimethylation (H3K27me3) and CTCF by chromatin immunoprecipitation followed by sequencing (ChIP–seq) 47 ; and genome organization by Hi-C 47 during BLaER1 trans-differentiation.”
Interpreting Cis-Regulatory Interactions from Large-Scale Deep Neural Networks
Toneyan, S., & Koo, P. K. (2024) · Nature Genetics · doi:10.1038/s41588-024-01923-3 · Cited by 27 · see citing works
“In anticipation of complex CRE interactions 27,55 , we searched for necessary tile sets via an iterative greedy search, where, in each round, a new, necessary tile is identified (via a shuffle perturbation) that yields the largest effect size.”
Oct4 differentially regulates chromatin opening and enhancer transcription in pluripotent stem cells
Xiong, L., Tolen, E. A., Choi, J., Velychko, S., Caizzi, L., Velychko, T., Adachi, K., MacCarthy, C. M., Lidschreiber, M., Cramer, P., et al. (2022) · eLife · doi:10.7554/elife.71533 · Cited by 38 · see citing works
“TT-seq can quantify changes in enhancer transcription and is ideal to monitor immediate transcriptome changes after perturbation ( Choi et al., 2021 ; Gressel et al., 2019 ; Michel et al., 2017 ).”
Self-citationMiyasaka, Y., & Yamamoto, N. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.699583 · Cited by 26 · see citing works
“is assumed to be summation of the baseline promoter activity (Po) and activity-dependent promoter activity after stimulation (P) (Choi et al., 2021), L can be represented as N × (Po + P) given that a cell is transfected with N plasmids.”
BackgroundWang, J., Zhang, S., Lu, H., & Xu, H. (2022) · Nature Communications · doi:10.1038/s41467-022-30315-6 · Cited by 25 · see citing works
Super-Enhancers and Their Parts: From Prediction Efforts to Pathognomonic Status
Vasileva, A. V., Gladkova, M. G., Ashniev, G. A., Osintseva, E. D., Орлов, А. В., Kravchuk, E. V., Boldyreva, A., Burenin, A. G., Nikitin, P. I., & Orlova, N. N. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25063103 · Cited by 23 · see citing works
CEBPA phase separation links transcriptional activity and 3D chromatin hubs.
Christou-Kent, M., Cuartero, S., Garcia-Cabau, C., Ruehle, J., Naderi, J., Erber, J., Neguembor, M. V., Plana-Carmona, M., Alcoverro-Bertran, M., de Andrés-Aguayo, L., et al. (2023) · Cell Reports · doi:10.2139/ssrn.4156154 · Cited by 22
Self-citationEnhancer RNAs (eRNAs) in Cancer: The Jacks of All Trades
Napoli, S., Munz, N., Guidetti, F., & Bertoni, F. (2022) · Cancers · doi:10.3390/cancers14081978 · Cited by 22 · see citing works
“Most enhancers drive the expression of a common target gene acting in an additive manner, but some enhancers can cooperate synergistically at specific loci to drive target gene transcription [25].”
BackgroundInfluentialThree‐dimensional genome structure and function
Liu, H., Tsai, H., Yang, M., Li, G., Bian, Q., Ding, G., Wu, D., & Dai, J. (2023) · MedComm · doi:10.1002/mco2.326 · Cited by 18 · see citing works
Characterization of a functional endothelial super-enhancer that regulates ADAMTS18 and angiogenesis
Mushimiyimana, I., Niskanen, H., Beter, M., Laakkonen, J. P., Kaikkonen, M. U., Ylä‐Herttuala, S., & Laham-Karam, N. (2021) · Nucleic Acids Research · doi:10.1093/nar/gkab633 · Cited by 22 · see citing works
“This begs the question, why the discrepancy in enhancer activities in different assays? Of course synergistic effects of enhancer constituents within a SE may explain the difference, such that when analysed in isolation, SE12313 b may not be sufficient to increase gene expression, but when removed from the cluster of…”
BackgroundShared Gene Targets of the ATF4 and p53 Transcriptional Networks
Baniulyte, G., Durham, S. A., Merchant, L. E., & Sammons, M. A. (2023) · Molecular and Cellular Biology · doi:10.1080/10985549.2023.2229225 · Cited by 19 · see citing works
“…in the basal and stress-dependent regulation of ATF3, consistent with models whereby multiple transcription factors work in a context-dependent and combinatorial manner to drive transcription (Smith et al., 2013; Chaudhari and Cohen, 2018; Zeitlinger, 2020; Choi et al., 2021; Kim et al., 2021).”
Kneppers, J., Severson, T., Siefert, J. C., Schol, P. J., Joosten, S. E. P., Yu, I. P. L., Huang, C.-C. F., Morova, T., Altıntaş, U. B., Giambartolomei, C., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-35135-2 · Cited by 22 · see citing works
Lysakovskaia, K., Devadas, A., Schwalb, B., Lidschreiber, M., & Cramer, P. (2025) · Nature Structural & Molecular Biology · doi:10.1038/s41594-025-01486-9 · Cited by 22 · see citing works
“To determine unambiguous promoter-proximal pause positions of Pol II, we created an annotation containing only the major transcribed isoform of each protein-coding gene using RNA-seq data, resulting in a total of 8,765 genes (Methods and Fig.”
InfluentialSelf-citationModulating immune cell fate and inflammation through CRISPR-mediated DNA methylation editingPreprint
Valcárcel, G., Lazarenkov, A., López-Rubio, A. V., Berenguer, C., Calafell-Segura, J., Rodríguez-Ubreva, J., Ballestar, E., & Sardina, J. (2024) · bioRxiv · doi:10.1101/2024.07.10.599183 · Cited by 17 · see citing works
Loubière, V., de Almeida, B. P., Pagani, M., & Stark, A. (2024) · Nature Communications · doi:10.1038/s41467-024-52921-2 · Cited by 19 · see citing works
“In mammals, super-additive enhancers were found to be over-represented at cell-type-speci fi c loci 12 , and their function was proposed to rely on the formationofCOFcondensates 6 .”
InfluentialDecoding the epigenetics and chromatin loop dynamics of androgen receptor-mediated transcription
Altıntaş, U. B., Seo, J.-H., Giambartolomei, C., Özturan, D., Fortunato, B. J., Nelson, G. M., Goldman, S. R., Adelman, K., Hach, F., Freedman, M. L., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-53758-5 · Cited by 23 · see citing works
“The contribution of individual CREs has been controversial, with some studies suggesting that CREs work additively to increase gene expression 31 – 33 , while others propose that many enhancers are redundant and only contribute at speci fi c developmental stages 34 – 37 .”
Beyond modular enhancers: new questions in cis-regulatory evolution
McDonald, J. M. C., & Reed, R. D. (2024) · Trends in Ecology & Evolution · doi:10.1016/j.tree.2024.07.005 · Cited by 15 · see citing works
Miao, B., Xing, X., Bazylianska, V., Madden, P. A. F., Moszczyńska, A., & Zhang, B. (2023) · Communications Biology · doi:10.1038/s42003-023-05355-3 · Cited by 16 · see citing works
Zhao, J.-R., Zhou, Y., Tzelepis, I., Burget, N., Shi, J.-W., & Faryabi, R. (2024) · Science Advances · doi:10.1126/sciadv.adl4043 · Cited by 14 · see citing works
“This observation is in line with a recent study reporting that gene expression levels correlate with the sum of the activities of multiple interacting enhancers rather than individual enhancers ( 54 ).”
ResultDistinct transcription kinetics of pluripotent cell states
Shao, R., Kumar, B., Lidschreiber, K., Lidschreiber, M., Cramer, P., & Elsässer, S. (2022) · Molecular Systems Biology · doi:10.15252/msb.202110407 · Cited by 13 · see citing works
Self-citationDecoding the Epigenetics and Chromatin Loop Dynamics of Androgen Receptor-Mediated TranscriptionPreprint
Lack, N. A., Altıntaş, U. B., Seo, J.-H., Giambartolomei, C., Özturan, D., Fortunato, B. J., Nelson, G. M., Goldman, S. R., Adelman, K., Hach, F., et al. (2024) · Research Square · doi:10.21203/rs.3.rs-3854707/v1 · Cited by 1 · see citing works
“The contribution of individual CREs has been controversial with some studies suggesting that CREs work additively to increase gene expression 31–33 , while others propose that many enhancers are redundant and only contribute at speci�c developmental stages 34–37 .”
BackgroundIchiyama-Kobayashi, S., Hata, K., Wakamori, K., Takahata, Y., Murakami, T., Yamanaka, H., Takano, H., Yao, R., Uzawa, N., & Nishimura, R. (2024) · JCI Insight · doi:10.1172/jci.insight.175486 · Cited by 12 · see citing works
“Because cooperative transcriptional regulation by multiple enhancers has been reported (32), we also generated a construct that combined both E160 and E308 and examined if both enhancers led to synergistic gene activation.”
Makrodimitris, S., Pronk, B., Abdelaal, T., & Reinders, M. J. T. (2023) · Briefings in Bioinformatics · doi:10.1093/bib/bbad416 · Cited by 11 · see citing works
“This is motivated by the fact that neural networks can identify non-linear patterns in the data which are expected to be present in -omics data (e.g. synthetic lethality [14] or enhancer synergy [15]).”
BackgroundCisinteractions in theIrf8locus regulate stage-dependent enhancer activationPreprint
Liu, T., Ou, F., Belk, J. A., Bagadia, P., Anderson, D. A., Durai, V., Yao, W., Satpathy, A. T., Murphy, T. L., & MURPHY, K. M. M. (2023) · Genes & Development · doi:10.1101/gad.350339.122 · Cited by 14 · see citing works
“Enhancer–enhancer interactions may be additive or synergistic and may occur concurrently or in a stage- or timedependent manner (Blobel et al. 2021; Choi et al. 2021).”
BackgroundMaking connections: enhancers in cellular differentiation
Herrmann, J. C., Beagrie, R. A., & Hughes, J. R. (2021) · Trends in Genetics · doi:10.1016/j.tig.2021.10.008 · Cited by 13 · see citing works
Zhu, X., Zhang, Y., Yin, Z., Ye, Z., Qin, Y., Cheng, Z., Shen, Y., Yin, Z., Ma, J., Tang, Y., et al. (2023) · Arthritis & Rheumatology · doi:10.1002/art.42703 · Cited by 10 · see citing works
“The data from GSE131620 16 were used to analyze the chromatin accessibility induced by C/EBP α expression.”
MethodCis-Regulatory Control of Mammalian Sex Determination
Ridnik, M., Schoenfelder, S., & Gonen, N. (2021) · Sexual Development · doi:10.1159/000519244 · Cited by 10 · see citing works
“A single gene (as is often the case for developmental genes) can be regulated by multiple enhancers, which can act in a redundant, additive, or synergistic manner [Choi et al., 2021; Kvon et al., 2021].”
BackgroundThe application of irreversible genomic states to define and trace ancient cell type homologies
Simakov, O., & Wagner, G. P. (2025) · EvoDevo · doi:10.1186/s13227-025-00242-w · Cited by 6 · see citing works
“…function and development should also be tested in this context and it should be expected that the regulatory entanglement facilitated the emergence of a more complex regulatory logic, e.g., by creating additive sub-functionalized enhancers or entangled super-enhancers within that region [50, 51].”
Wilderman, A. S., D’haene, E., Baetens, M., Yankee, T. N., Winchester, E. W., Glidden, N. C., Roets, E., Dorpe, J. V., Janssens, S., Miller, D. E., et al. (2024) · Nature Communications · doi:10.1038/s41467-023-44506-2 · Cited by 21 · see citing works
“The behavior of individualenhancerelementsvarieswithinsuperenhancers,withsome studies suggesting they cooperate in an additive, redundant, or even synergistic manner 4,11,13 – 15 .”
Glucocorticoid receptor collaborates with pioneer factors and AP-1 to execute genome-wide regulationPreprint
Wissink, E. M., Martinez, D. M., Ehmsen, K. T., Yamamoto, K. R., & Lis, J. T. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.06.01.444518 · Cited by 6 · see citing works
“Recent work shows that during macrophage differentiation, enhancers can act additively or synergistically (Choi et al. 2021), in alignment with our data.”
BackgroundSynthetic genomic dissection of enhancer context sensitivity and synergyPreprint
Ordóñez, R., Ribeiro-dos-Santos, A. M., Mcloughlin, C., Ellis, G., Ashe, H. J., Berastegui, N., Brosh, R., Majewski, M., Barriball, K., Camellato, B. R., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.08.13.669251 · Cited by 3 · see citing works
“…sequences within these clusters can interact in multiple ways: redundantly, additively or synergistically, when their combined activity exceed the sum of their individual effects (Bothma 2015; Thomas 2021; Choi 2021; Martinez-Ara 2022; Lin 2022; Brosh 2023; Blayney 2023; Zhou 2025; Koeppel 2025).”
An Emerging Role for Enhancer RNAs in Brain Disorders
Patel, A., & Dharap, A. A. (2024) · NeuroMolecular Medicine · doi:10.1007/s12017-024-08776-3 · Cited by 8 · see citing works
“Enhancers are known to play a central role in these events (Choi et al., 2021; de la Torre-Ubieta et al., 2018; Frank et al., 2015; Nord et al., 2013).”
Ac/Ds transposition for CRISPR/dCas9-SID4x epigenome modulation in zebrafish
Chong-Morrison, V., Mayes, S., Simões, F. C., Senanayake, U., Carroll, D. S., Riley, P. R., Wilson, S. W., & Sauka‐Spengler, T. (2023) · Biology Open · doi:10.1242/bio.059995 · Cited by 8 · see citing works
“This was consistent with the additive action of multiple enhancers in regulating gene expression of their target genes (Choi et al., 2021; Fulco et al., 2016).”
BackgroundAfzal, Z., Lange, J. J., Nolte, C., McKinney, S. A., Wood, C., Paulson, A., de Kumar, B., Unruh, J., Slaughter, B. D., & Krumlauf, R. (2022) · bioRxiv · doi:10.1101/2022.08.30.505933 · Cited by 8 · see citing works
“…et al., 1994; Studer et al., 1994; Tümpel et al., 2002; Berlivet et al., 2013; Delpretti et al., 2013; Paris et al., 2013; Crocker et al., 2015; Heinz et al., 2015; Parker and Krumlauf, 2017; Henriques et al., 2018; Nolte et al., 2019; Parker et al., 2019; Choi et al., 2021; Kreibich et al., 2022).”
Enhancing Gonadotrope Gene Expression Through Regulatory lncRNAs
Refael, T., & Melamed, P. (2021) · Endocrinology · doi:10.1210/endocr/bqab116 · Cited by 6 · see citing works
Long-range massively parallel reporter assay reveals rules of distal enhancer-promoter interactionsPreprint
Wu, Y., Li, J., Bartley-Dier, E. L., Pitts, C., & Cohen, B. A. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.04.21.649048 · Cited by 5 · see citing works
Three-dimensional regulatory hubs support oncogenic programs in glioblastoma
Breves, S. L., Giammartino, D. C. D., Nicholson, J., Cirigliano, S. M., Mahmood, S. R., Lee, U. J., Martinez‐Fundichely, A., Jungverdorben, J., Singhania, R., Rajkumar, S., et al. (2024) · Molecular Cell · doi:10.1016/j.molcel.2025.03.007 · Cited by 15 · see citing works
Long, T., Bhattacharyya, T., Repele, A., Naylor, M., Nooti, S. K., Krueger, S., & Manu (2023) · G3 Genes Genomes Genetics · doi:10.1093/g3journal/jkad269 · Cited by 6 · see citing works
Enhancer cooperativity in the folded genome
Friman, E. T., & Bickmore, W. A. (2025) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2025.102416 · Cited by 7 · see citing works
From Genotype to Phenotype: How Enhancers Control Gene Expression and Cell Identity in Hematopoiesis
Mulet-Lazaro, R., & Delwel, R. (2023) · HemaSphere · doi:10.1097/hs9.0000000000000969 · Cited by 6 · see citing works
Wilderman, A., D'Haene, E., Baetens, M., Yankee, T. N., Winchester, E. W., Glidden, N., Roets, E., Dorpe, J. V., Vergult, S., Cox, T., et al. (2022) · bioRxiv · doi:10.1101/2022.03.10.483852 · Cited by 6
“Studies suggest that individual enhancer elements within superenhancers cooperate in an additive, redundant or synergistic manner (Hay et al., 2016; Osterwalder et al., 2018; Moorthy et al., 2017; Guerrero et al., 2010; Choi et al., 2021).”
BackgroundThe Making of a cDC1 : Precision Programming of Progenitor Potential
Murphy, T. L., & MURPHY, K. M. M. (2025) · Immunological Reviews · doi:10.1111/imr.70081 · Cited by 7 · see citing works
“Their combined effect might be simply additive or a more complex synergistic one, and these interactions can happen all at once or in a specific sequence over time [135, 136].”
Wu, C., & Huang, J. (2024) · BMC Genomics · doi:10.1186/s12864-024-10408-w · Cited by 8 · see citing works
“…and synergistic patterns have been described at the level of SEs and exert a greater impact on controlling cell identity during development and tumorigenesis [7–9], such as SEs controlling α-globin and MYC genes, where gene activity increases linearly with the number of enhancers [10, 11].”
BackgroundIdriss, S., Hallal, M., Kurdi, A., Zalzali, H., El-Rassi, I., Ehli, E. A., Davis, C. M., Chung, P. E. D., Gendoo, D. M. A., Zacksenhaus, E., et al. (2023) · Genome Research · doi:10.1101/gr.277037.122 · Cited by 3 · see citing works
“Also, synergistic and additive actions of mammalian enhancers (Choi et al. 2021), distance to target gene, epigenetic effects,”
BackgroundExtensive enhancer crosstalk controls PPARG2 activation during adipogenesis
Cetnarowska, A., Hyldahl, M., Nygård, M., Dashti, H., Hansen, B. M., Holm, L. K., Madsen, K., Madsen, M. S., Shukla, V., Mitchell, E. D., et al. (2026) · Nature Communications · doi:10.1038/s41467-026-70401-7 · Cited by 4 · see citing works
Borsari, B., Frank, M., Wattenberg, E. S., Xu, K., Liu, S. X., Yu, X.-Z., & Gerstein, M. (2025) · Nature Communications · doi:10.1038/s41467-025-61921-9 · Cited by 4 · see citing works
“This knowledge can be applied to develop temporal models that predict gene expression at future time points, accounting for the additive effect of multiple cCREs associated with a given gene 44 .”
Hattori, N., Takamatsu, H., Iida, N., Asano, N., Yamashita, S., Oba, G. M., Kimura, K., Yoshida, A., Kobayashi, E., Nakayama, R., et al. (2025) · Frontiers in Oncology · doi:10.3389/fonc.2025.1419877 · Cited by 3 · see citing works
Identification of ZNF384 as a regulator of epigenome in leukemia.
Vargas, L. C. Z., Ortiz-Ortiz, J., Martínez, Y. A., Viguri, G. E. C., Rojas, F. I. T., & Ávila-López, P. (2025) · Leukemia research : a Forum for Studies on Leukemia and Normal Hemopoiesis · doi:10.1016/j.leukres.2025.107691 · Cited by 3 · see citing works
Combinatorial perturbation analysis of CD4+ T cell regulatory networks based on bifurcation theory
Lu, X., Hu, Q., Xue, Z., & Wang, R. (2025) · Advances in Continuous and Discrete Models · doi:10.1186/s13662-025-03887-y · Cited by 4 · see citing works
“Multiple exogenous cytokines can interact to synergistically regulate gene expression and determine cell fate transitions (Yan et al. [50], Choi et al. [7]).”
Yan, J., Luo, R.-H., Rosen, B. P., Liu, D., Wong, W., Leslie, C. S., & Huangfu, D. (2024) · bioRxiv · doi:10.1016/j.stemcr.2025.102511 · Cited by 3 · see citing works
Ling, Z., Li, J., Jiang, T., Zhang, Z., Zhu, Y., Zhou, Z., Yang, J., Tong, X., Yang, B. J., & Huang, L. (2024) · Communications Biology · doi:10.1038/s42003-024-06050-7 · Cited by 4 · see citing works
“Besides, 52,53 .”
Borsari, B., Frank, M., Wattenberg, E. S., Xu, K., Liu, S., Yu, X.-Z., & Gerstein, M. (2023) · bioRxiv · doi:10.1101/2023.12.13.571513 · Cited by 3
“To achieve this goal, we compiled a catalog of cCRE-gene pairs, by linking each cCRE to its nearest protein-coding gene based on linear distance 28,29 .”
MethodResultInterpreting Cis-Regulatory Interactions from Large-Scale Deep Neural Networks for GenomicsPreprint
Toneyan, S., & Koo, P. K. (2023) · bioRxiv · doi:10.1101/2023.07.03.547592 · Cited by 3 · see citing works
The BAFfling story of MN1-induced leukemogenesis
Stonestrom, A., & Levine, R. (2021) · Molecules and Cells · doi:10.1016/j.molcel.2021.05.001 · Cited by 3
Guo, C., Hua, D., Gan, S., Zhang, Y.-D., Liu, H., Ding, M., Cao, M., Wen, Q., Chen, Y., Lu, J., et al. (2026) · Molecular Biology and Evolution · doi:10.1093/molbev/msag190 · Cited by 3 · see citing works
Remodeling of XIST regulatory landscape during primate evolution
Cazottes, E., Alfeghaly, C., Rognard, C., Necşulea, A., Loda, A., Castel, G., Villacorta, L., Dong, M. X., Heard, É., Aksoy, I., et al. (2026) · Science Advances · doi:10.1126/sciadv.adw5839 · Cited by 4 · see citing works
“The impact of Enh5 deletion on XIST expression in rhESCs is quite mild, which suggests that additional molecular players, including JPX , might have additive or synergistic effects on XIST regulation as described at other loci ( 62 , 63 ).”
Enhancer Trajectories in Lineage Commitment: Regulatory Logic of States and Cooperation
Oh, M., Jeong, S., Kang, K., & Kim, S.-K. (2026) · Biomolecules · doi:10.3390/biom16010087 · Cited by 2 · see citing works
“…stochastic and environmental noise and maintain expression thresholds; (3) influence the timing and probability of fate-switch activation; and (4) selectively enhance distinct enhancer modules so that the same locus operates under different subsets in different cellular contexts (Figure 2) [97].”
Thorvaldsen, J. L., Juan, A. M., Lan, Y., Krapp, C. J., & Bartolomei, M. S. (2025) · PLoS Genetics · doi:10.1371/journal.pgen.1011834 · Cited by 3 · see citing works
Xu, X., Chen, Q., Huang, Q., Cox, T. C., Zhu, H., Hu, J., Han, X., Meng, Z., Wang, B., Liao, Z., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-59735-w · Cited by 1 · see citing works
“45 of the PRS locus 28 , the Fgf5 locus 51 , and regulating gap gene-expression patterns in Drosophila embryos 52 and coordinating cell fate determination 53 .”
LucFlow: A method to measure Luciferase reporter expression in single cells
Nooti, S. K., Naylor, M., Long, T., Groll, B., & Manu (2023) · PLoS ONE · doi:10.1371/journal.pone.0292317 · Cited by 2 · see citing works
Klonizakis, A., Nikolaou, C., & Graf, T. (2022) · Bioinform. · doi:10.1093/bioinformatics/btac742 · Cited by 2 · see citing works
“…originally termed ‘transcription factories’ has been extended by the more recent discovery of transcriptional condensates within the eukaryotic nucleus that contain transcription factors and co-factors, such as MED1 and BRD4, as well as PolII and are associated with chromatin (Cramer, 2019).”
BackgroundSelf-citationBoolean logic links chromatin accessibility states to gene expression variability across cell types
Malekpour, S. A., Jafari, M., & Sadeghi, M. (2026) · Nucleic Acids Research · doi:10.1093/nar/gkag230 · Cited by 1 · see citing works
“Supporting this, these genes show enrichment for nonredundant, combinatorial regulation at cell-type-specific loci [ 70 ].”
An epigenome atlas of mouse adipocytes
Hinte, L. C., Ghosh, A., Castellano‐Castillo, D., Wolfrum, C., & von Meyenn, F. (2025) · Molecular Metabolism · doi:10.1016/j.molmet.2025.102197 · Cited by 4 · see citing works
“S3) suggesting that enhancers, which are crucial for de fi ning cellular identity and fate and represent cell lineages [27,28], distinguish adipocytes derived from BAT and WAT, rather than promoter usage or repressed chromatin regions.”
3D Epigenome Evolution Underlies Divergent Gene Regulatory Programs in Primate Neural DevelopmentPreprint
Vangelisti, S., Chong, F., Dietl, T., Zywitza, V., Diecke, S., Enard, W., & Bonev, B. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.03.11.642620 · Cited by 1 · see citing works
“Such enhancer synergy has been shown to confer robust gene expression in developmental contexts 67,68 and our findings extend this concept to the evolution of the primate epigenome.”
Klonizakis, A., Alcoverro-Bertran, M., Massó, P., Thomas, J., de Andrés-Aguayo, L., Wei, X., Varamogianni‐Mamatsi, V., Nikolaou, C., & Graf, T. (2025) · The EMBO Journal · doi:10.1038/s44318-025-00380-w · Cited by 1 · see citing works
“ATAC-seq, RNA-seq, CTCF ChIP-seq, and Hi-C datasets are derived from (Stik et al., 2020), while CEBPA ChIP-seq datasets are from (Choi et al., 2021).”
Self-citationRomero, A., Heidenreich, A. C., Román, C. L., Algañarás, M., Názer, E., Gagliardino, J. J., Maiztegui, B., Flores, L. E., & Rodríguez‐Seguí, S. A. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1226615 · Cited by 1 · see citing works
“Increased expression of already active genes can be achieved by cooperative recruitment of enhancers (47).”
BackgroundPons, T., Serra, F., Fütterer, A., van Wely, K. V., Pazos, F., Pacios, C., Cayuela-Lopez, A., Sorzano, C. O. S., Valencia, A., & Martínez-A, C. (2021) · bioRxiv · doi:10.1101/2021.09.27.462041 · Cited by 1 · see citing works
Integration by parts: The multi-layered mechanisms of cis-regulatory control
Cornwall-Scoones, J., Briscoe, J., & Delàs, M. J. (2026) · Molecular Cell · doi:10.1016/j.molcel.2026.09.016
Regulation of lineage reprogramming by dynamic chromatin SUMOylation
Valima, E., Manjur, A. B. M. K., Savinainen, E., Varis, V., Launonen, K.-M., Graf, T., Varjosalo, M., Niskanen, E., & Palvimo, J. (2026) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-026-06255-5
“Here, we utilized a well-established BLaER1 cell system [ 17, 38] to study the impact of SUMOylation during human B-cell-to-macrophage transdifferentiation.”
Self-citationRepele, A., Handzlik, J. E., Samarawickrama, N., Long, T., Nooti, S. K., Potluri, V., Loh, Y. L., & Manu (2026) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1014276
TET2-driven activation of AGO2 links epigenetic remodeling to myeloid commitment and leukemia
Lazarenkov, A., Valcárcel, G., Martínez, A., Berenguer, C., López-Rubio, A. V., Obiols, M., Fontanet, C., Barba, A., Rodríguez-Sevilla, J. J., Stik, G., et al. (2026) · bioRxiv · doi:10.64898/2026.04.23.719229
Self-citationCharacterization of a cis-regulatory element upstream of matrix metalloproteinase-9
Rangaraj, A., Kaur, H., Mejia, L., Hansen, J., Biswas, A., & Tuteja, G. (2025) · Scientific Reports · doi:10.1038/s41598-025-31297-3
“This result would indicate enhancer synergy, in which multiple elements coordinate to drive total enhancer activity 69–71 .”
Adversarial attack of sequence-free enhancer prediction identifies chromatin architecture
Gafur, J., Lang, O. W., & Lai, W. (2025) · Bioinformatics · doi:10.1093/bioinformatics/btaf371
“The complex combinatorial interactions be-tween enhancers and their target genes are believed to be responsible in part for how complex multicellular organisms achieve distinct cell types even with identical DNA content in all cells of a single organism (Heinz et al. 2015, Choi et al. 2021).”
Kimura, Y., Ono, Y., Katayama, K., & Imoto, S. (2024) · Bioinformatics Advances · doi:10.1093/bioadv/vbae118
“Thus, exponential and logistic function models have been proposed (Dukler et al. 2016, Choi et al. 2021).”
BackgroundLong, T., Bhattacharyya, T., Repele, A., Naylor, M., Nooti, S., Krueger, S., & Manu (2023) · bioRxiv · doi:10.1101/2023.02.22.529579
The winding road towards transcriptional repression
Zhang, Q., & Brand, M. (2023) · Molecules and Cells · doi:10.1016/j.molcel.2023.02.005
Phase separation as higher-order catalystPreprint
Huang, K., Quan, X., & Qin, S. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.10.27.514140
Ober-Reynolds, B., Wang, C., Ko, J., Rios, E. J., Aasi, S., Davis, M. M., Oro, A., & Greenleaf, W. (2022) · bioRxiv · doi:10.1101/2022.09.28.509620
Zhou, T., Zhu, X., Ye, Z., Wang, Y., Yao, C., Xu, N., Zhou, M., Ma, J., Qin, Y., Shen, Y., et al. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.06.11.448156
- Authors
- Choi, J., Lysakovskaia, K., Stik, G., Demel, C., Söding, J., Tian, T. V., Graf, T., & Cramer, P.
- Affiliations
- Max Planck Institute for Biophysical Chemistry (DE)
- Gene Regulation, Stem Cells and Cancer Program, Centre for Genomic Regulation (CRG), Barcelona, Spain
- Max Planck Society (DE)
- Centre for Genomic Regulation (ES)
- Corresponding author
- Cramer, Patrick
- ORCID
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2021-03-26
- Volume
- 10
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC8004103
- OpenAlex
- W3136167697
- Cited by
- 117
- References
- 110
- Citations by year
- 2026: 11 · 2025: 23 · 2024: 25 · 2023: 25 · 2022: 18 · 2021: 15
- FWCI
- 6.59
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- GoeScholar The Publication Server of the Georg-August-Universität Göttingen (Georg-August-Universität Göttingen) (submittedVersion, cc-by)
- Repositori digital de la UPF (Universitat Pompeu Fabra) (submittedVersion, cc-by)
- Funders
- Max-Planck-Gesellschaft (Open-access funding)
- Deutsche Forschungsgemeinschaft (SFB860, SPP1935, SPP2191)
- European Research Council (693023)
- Volkswagen Foundation
- 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 › Epigenetics and DNA Methylation
- Keywords
- enhancer RNA, C/EBPα, pioneer factors, chromatin accessibility, H3K4 methylation, macrophage differentiation, leukemia, cell fate determination, transcriptional regulation, cell type-specific transcription factors
- MeSH terms
- THP-1 Cells, Cell Differentiation, Chromatin, Enhancer Elements, Genetic, Histones, Humans, Promoter Regions, Genetic, RNA, Transcription, Genetic, CCAAT-Enhancer-Binding Proteins
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