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HomeNatureIn vivo mapping of mutagenesis sensitivity of human enhancers

In vivo mapping of mutagenesis sensitivity of human enhancers

  • Long, H. K., Prescott, S. L. & Wysocka, J. Ever-changing landscapes: transcriptional enhancers in development and evolution. Cell 167, 1170–1187 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kvon, E. Z. et al. Comprehensive in vivo interrogation reveals phenotypic impact of human enhancer variants. Cell 180, 1262–1271 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lambert, S. A. et al. The human transcription factors. Cell 172, 650–665 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Fickett, J. W. Quantitative discrimination of MEF2 sites. Mol. Cell. Biol. 16, 437–441 (1996).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Gotea, V. et al. Homotypic clusters of transcription factor binding sites are a key component of human promoters and enhancers. Genome Res. 20, 565–577 (2010).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Johnson, D. S., Mortazavi, A., Myers, R. M. & Wold, B. Genome-wide mapping of in vivo protein-DNA interactions. Science 316, 1497–1502 (2007).

    Article 
    ADS 
    CAS 
    PubMed 

    Google Scholar
     

  • Dickel, D. E. et al. Ultraconserved enhancers are required for normal development. Cell 172, 491–499 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hong, J.-W., Hendrix, D. A. & Levine, M. S. Shadow enhancers as a source of evolutionary novelty. Science 321, 1314 (2008).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Osterwalder, M. et al. Characterization of mammalian in vivo enhancers using mouse transgenesis and CRISPR genome editing. Methods Mol. Biol. 2403, 147–186 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Snetkova, V. et al. Ultraconserved enhancer function does not require perfect sequence conservation. Nat. Genet. 53, 521–528 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Attanasio, C. et al. Fine tuning of craniofacial morphology by distant-acting enhancers. Science 342, 1241006 (2013).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Inoue, F. & Ahituv, N. Decoding enhancers using massively parallel reporter assays. Genomics 106, 159–164 (2015).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Visel, A. et al. ChIP-seq accurately predicts tissue-specific activity of enhancers. Nature 457, 854–858 (2009).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Visel, A. et al. A high-resolution enhancer atlas of the developing telencephalon. Cell 152, 895–908 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Visel, A., Minovitsky, S., Dubchak, I. & Pennacchio, L. A. VISTA Enhancer Browser—a database of tissue-specific human enhancers. Nucleic Acids Res. 35, D88–D92 (2007).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Spurrell, C. H. et al. Genome-wide fetalization of enhancer architecture in heart disease. Cell Rep. 40, 111400 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • May, D. et al. Large-scale discovery of enhancers from human heart tissue. Nat. Genet. 44, 89–93 (2011).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Dickel, D. E. et al. Genome-wide compendium and functional assessment of in vivo heart enhancers. Nat. Commun. 7, 12923 (2016).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Pampari, A. et al. ChromBPNet: bias factorized, base-resolution deep learning models of chromatin accessibility reveal cis-regulatory sequence syntax, transcription factor footprints and regulatory variants. Preprint at bioRxiv https://doi.org/10.1101/2024.12.25.630221 (2025).

  • Shrikumar, A., Greenside, P. & Kundaje, A. Learning important features through propagating activation differences. In Proc. 34th International Conference on Machine Learning (eds Precup, D. & Teh, Y. W.) Vol. 70, 3145–3153 (PMLR, 2017).

  • Firulli, B. A., Redick, B. A., Conway, S. J. & Firulli, A. B. Mutations within helix I of Twist1 result in distinct limb defects and variation of DNA binding affinities. J. Biol. Chem. 282, 27536–27546 (2007).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Selleri, L. & Rijli, F. M. Shaping faces: genetic and epigenetic control of craniofacial morphogenesis. Nat. Rev. Genet. 24, 610–626 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Prescott, S. L. et al. Enhancer divergence and cis-regulatory evolution in the human and chimp neural crest. Cell 163, 68–83 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kim, S. et al. DNA-guided transcription factor cooperativity shapes face and limb mesenchyme. Cell 187, 692–711 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Olson, E. N. Gene regulatory networks in the evolution and development of the heart. Science 313, 1922–1927 (2006).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Smith, R. P. et al. Massively parallel decoding of mammalian regulatory sequences supports a flexible organizational model. Nat. Genet. 45, 1021–1028 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lettice, L. A. et al. Opposing functions of the ETS factor family define Shh spatial expression in limb buds and underlie polydactyly. Dev. Cell 22, 459–467 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lettice, L. A., Devenney, P., De Angelis, C. & Hill, R. E. The conserved Sonic Hedgehog limb enhancer consists of discrete functional elements that regulate precise spatial expression. Cell Rep. 20, 1396–1408 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Spitz, F. & Furlong, E. E. M. Transcription factors: from enhancer binding to developmental control. Nat. Rev. Genet. 13, 613–626 (2012).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Gorkin, D. U. et al. An atlas of dynamic chromatin landscapes in mouse fetal development. Nature 583, 744–751 (2020).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • ENCODE Project Consortium et al. Expanded encyclopaedias of DNA elements in the human and mouse genomes. Nature 583, 699–710 (2020).

    Article 
    ADS 

    Google Scholar
     

  • Roadmap Epigenomics Consortium et al. Integrative analysis of 111 reference human epigenomes. Nature 518, 317–330 (2015).

    Article 
    PubMed Central 

    Google Scholar
     

  • Rebboah, E. et al. The ENCODE mouse postnatal developmental time course identifies regulatory programs of cell types and cell states. Preprint at bioRxiv https://doi.org/10.1101/2024.06.12.598567 (2024).

  • Ameen, M. et al. Integrative single-cell analysis of cardiogenesis identifies developmental trajectories and non-coding mutations in congenital heart disease. Cell 185, 4937–4953 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Taskiran, I. I. et al. Cell-type-directed design of synthetic enhancers. Nature 626, 212–220 (2024).

    Article 
    ADS 
    CAS 
    PubMed 

    Google Scholar
     

  • de Almeida, B. P., Reiter, F., Pagani, M. & Stark, A. DeepSTARR predicts enhancer activity from DNA sequence and enables the de novo design of synthetic enhancers. Nat. Genet. 54, 613–624 (2022).

    Article 
    PubMed 

    Google Scholar
     

  • Rafi, A. M. et al. A community effort to optimize sequence-based deep learning models of gene regulation. Nat. Biotechnol. https://doi.org/10.1038/s41587-024-02414-w (2024).

  • Karbalayghareh, A., Sahin, M. & Leslie, C. S. Chromatin interaction-aware gene regulatory modeling with graph attention networks. Genome Res. 32, 930–944 (2022).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Tan, J. et al. Cell-type-specific prediction of 3D chromatin organization enables high-throughput in silico genetic screening. Nat. Biotechnol. 41, 1140–1150 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Farley, E. K., Olson, K. M., Zhang, W., Rokhsar, D. S. & Levine, M. S. Syntax compensates for poor binding sites to encode tissue specificity of developmental enhancers. Proc. Natl Acad. Sci. USA 113, 6508–6513 (2016).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Farley, E. K. et al. Suboptimization of developmental enhancers. Science 350, 325–328 (2015).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Jindal, G. A. et al. Single-nucleotide variants within heart enhancers increase binding affinity and disrupt heart development. Dev. Cell 58, 2206–2216 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Crocker, J. et al. Low affinity binding site clusters confer hox specificity and regulatory robustness. Cell 160, 191–203 (2015).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Boisclair Lachance, J.-F., Webber, J. L., Hong, L., Dinner, A. R. & Rebay, I. Cooperative recruitment of Yan via a high-affinity ETS supersite organizes repression to confer specificity and robustness to cardiac cell fate specification. Genes Dev. 32, 389–401 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Borok, M. J., Tran, D. A., Ho, M. C. W. & Drewell, R. A. Dissecting the regulatory switches of development: lessons from enhancer evolution in Drosophila. Development 137, 5–13 (2010).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Galupa, R. et al. Enhancer architecture and chromatin accessibility constrain phenotypic space during Drosophila development. Dev. Cell 58, 51–62 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Fuqua, T. et al. Dense and pleiotropic regulatory information in a developmental enhancer. Nature 587, 235–239 (2020).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Le Poul, Y. et al. Regulatory encoding of quantitative variation in spatial activity of a enhancer. Sci. Adv. 6, eabe2955 (2020).

    Article 
    ADS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Museridze, M. et al. Entangled and non-modular enhancer sequences producing independent spatial activities. Sci. Adv. 10, eadr9856 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Swanson, C. I., Schwimmer, D. B. & Barolo, S. Rapid evolutionary rewiring of a structurally constrained eye enhancer. Curr. Biol. 21, 1186–1196 (2011).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Trevino, A. E. et al. Chromatin and gene-regulatory dynamics of the developing human cerebral cortex at single-cell resolution. Cell 184, 5053–5069 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Feng, J., Liu, T., Qin, B., Zhang, Y. & Liu, X. S. Identifying ChIP-seq enrichment using MACS. Nat. Protoc. 7, 1728–1740 (2012).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Lundberg, S. & Lee, S.-I. A unified approach to interpreting model predictions. Preprint at https://doi.org/10.48550/arXiv.1705.07874 (2017).

  • Gupta, S., Stamatoyannopoulos, J. A., Bailey, T. L. & Noble, W. S. Quantifying similarity between motifs. Genome Biol. 8, R24 (2007).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kosicki, M. et al. Massively parallel reporter assays and mouse transgenic assays provide correlated and complementary information about neuronal enhancer activity. Nat. Commun. 16, 4786 (2025).

  • Ma, X. R. et al. Molecular convergence of risk variants for congenital heart defects leveraging a regulatory map of the human fetal heart. Preprint at medRxiv https://doi.org/10.1101/2024.11.20.24317557 (2024).

  • Tenney, A. P. et al. Noncoding variants alter GATA2 expression in rhombomere 4 motor neurons and cause dominant hereditary congenital facial paresis. Nat. Genet. 55, 1149–1163 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lee, A. S. et al. A cell type-aware framework for nominating non-coding variants in Mendelian regulatory disorders. Nat. Commun. 15, 8268 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

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