3D Enhancer-promoter networks provide predictive features for gene expression and coregulation in early embryonic lineages.
Journal
Nature structural & molecular biology
ISSN: 1545-9985
Titre abrégé: Nat Struct Mol Biol
Pays: United States
ID NLM: 101186374
Informations de publication
Date de publication:
05 Dec 2023
05 Dec 2023
Historique:
received:
24
10
2022
accepted:
18
09
2023
medline:
6
12
2023
pubmed:
6
12
2023
entrez:
5
12
2023
Statut:
aheadofprint
Résumé
Mammalian embryogenesis commences with two pivotal and binary cell fate decisions that give rise to three essential lineages: the trophectoderm, the epiblast and the primitive endoderm. Although key signaling pathways and transcription factors that control these early embryonic decisions have been identified, the non-coding regulatory elements through which transcriptional regulators enact these fates remain understudied. Here, we characterize, at a genome-wide scale, enhancer activity and 3D connectivity in embryo-derived stem cell lines that represent each of the early developmental fates. We observe extensive enhancer remodeling and fine-scale 3D chromatin rewiring among the three lineages, which strongly associate with transcriptional changes, although distinct groups of genes are irresponsive to topological changes. In each lineage, a high degree of connectivity, or 'hubness', positively correlates with levels of gene expression and enriches for cell-type specific and essential genes. Genes within 3D hubs also show a significantly stronger probability of coregulation across lineages compared to genes in linear proximity or within the same contact domains. By incorporating 3D chromatin features, we build a predictive model for transcriptional regulation (3D-HiChAT) that outperforms models using only 1D promoter or proximal variables to predict levels and cell-type specificity of gene expression. Using 3D-HiChAT, we identify, in silico, candidate functional enhancers and hubs in each cell lineage, and with CRISPRi experiments, we validate several enhancers that control gene expression in their respective lineages. Our study identifies 3D regulatory hubs associated with the earliest mammalian lineages and describes their relationship to gene expression and cell identity, providing a framework to comprehensively understand lineage-specific transcriptional behaviors.
Identifiants
pubmed: 38053013
doi: 10.1038/s41594-023-01130-4
pii: 10.1038/s41594-023-01130-4
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.
Références
Alberio, R. Regulation of cell fate decisions in early mammalian embryos. Annu. Rev. Anim. Biosci. 8, 377–393, https://doi.org/10.1146/annurev-animal-021419-083841 (2020).
doi: 10.1146/annurev-animal-021419-083841
pubmed: 31730400
Bardot, E. S. & Hadjantonakis, A. K. Mouse gastrulation: coordination of tissue patterning, specification and diversification of cell fate. Mech. Dev. 163, 103617, https://doi.org/10.1016/j.mod.2020.103617 (2020).
doi: 10.1016/j.mod.2020.103617
pubmed: 32473204
pmcid: 7534585
Rossant, J. Making the mouse blastocyst: past, present, and future. Curr. Top. Dev. Biol. 117, 275–288, https://doi.org/10.1016/bs.ctdb.2015.11.015 (2016).
doi: 10.1016/bs.ctdb.2015.11.015
pubmed: 26969983
Rossant, J. & Tam, P. P. L. Blastocyst lineage formation, early embryonic asymmetries and axis patterning in the mouse. Development 136, 701–713, https://doi.org/10.1242/dev.017178 (2009).
doi: 10.1242/dev.017178
pubmed: 19201946
Grabarek, J. B. et al. Differential plasticity of epiblast and primitive endoderm precursors within the ICM of the early mouse embryo. Development 139, 129–39 (2012).
pubmed: 22096072
pmcid: 3231774
doi: 10.1242/dev.067702
Cui, W. & Mager, J. Transcriptional regulation and genes involved in first lineage specification during preimplantation development. Adv. Anat. Embryol. Cell Biol. 229, 31–46, https://doi.org/10.1007/978-3-319-63187-5_4 (2018).
doi: 10.1007/978-3-319-63187-5_4
pubmed: 29177763
pmcid: 7558833
Frum, T. & Ralston, A. Cell signaling and transcription factors regulating cell fate during formation of the mouse blastocyst. Trends Genet. 31, 402–410, https://doi.org/10.1016/j.tig.2015.04.002 (2015).
doi: 10.1016/j.tig.2015.04.002
pubmed: 25999217
pmcid: 4490046
Muñoz-Descalzo, S., Hadjantonakis, A. K. & Arias, A. M. Wnt/ß-catenin signalling and the dynamics of fate decisions in early mouse embryos and embryonic stem (ES) cells. Semin. Cell Dev. Biol. 47, 101–109 (2015).
pubmed: 26321498
doi: 10.1016/j.semcdb.2015.08.011
Lim, B. & Levine, M. S. Enhancer–promoter communication: hubs or loops? Curr. Opin. Genet. Dev. 67, 5–9 (2021).
pubmed: 33202367
doi: 10.1016/j.gde.2020.10.001
Schoenfelder, S. & Fraser, P. Long-range enhancer–promoter contacts in gene expression control. Nat. Rev. Genet. 20, 437–455, https://doi.org/10.1038/s41576-019-0128-0 (2019).
doi: 10.1038/s41576-019-0128-0
pubmed: 31086298
Creyghton, M. P. et al. Histone H3K27ac separates active from poised enhancers and predicts developmental state. Proc. Natl Acad. Sci. USA 110, 21931–21936 (2010).
doi: 10.1073/pnas.1016071107
Wu, J. et al. Chromatin analysis in human early development reveals epigenetic transition during ZGA. Nature 557, 256–260 (2018).
pubmed: 29720659
doi: 10.1038/s41586-018-0080-8
Birney, E. et al. Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature 447, 799–816 (2007).
pubmed: 17571346
doi: 10.1038/nature05874
Roadmap Epigenomics Consortium, et al.Integrative analysis of 111 reference human epigenomes. Nature 518, 317–330, https://doi.org/10.1038/nature14248 (2015).
doi: 10.1038/nature14248
pmcid: 4530010
Yue, F. et al. A comparative encyclopedia of DNA elements in the mouse genome. Nature 515, 355–364, https://doi.org/10.1038/nature13992 (2014).
doi: 10.1038/nature13992
pubmed: 25409824
pmcid: 4266106
Arnold, C. D. et al. Genome-wide quantitative enhancer activity maps identified by STARR-seq. Science 339, 1074–1077, https://doi.org/10.1126/science.1232542 (2013).
doi: 10.1126/science.1232542
pubmed: 23328393
Lopes, R., Korkmaz, G. & Agami, R. Applying CRISPR-Cas9 tools to identify and characterize transcriptional enhancers. Nat. Rev. Mol. Cell Biol. 17, 597–604, https://doi.org/10.1038/nrm.2016.79 (2016).
doi: 10.1038/nrm.2016.79
pubmed: 27381243
Apostolou, E. et al. Genome-wide chromatin interactions of the Nanog locus in pluripotency, differentiation, and reprogramming. Cell Stem Cell 12, 699–712, https://doi.org/10.1016/j.stem.2013.04.013 (2013).
doi: 10.1016/j.stem.2013.04.013
pubmed: 23665121
pmcid: 3725985
Beagan, J. A. et al. Local genome topology can exhibit an incompletely rewired 3D-folding state during somatic cell reprogramming. Cell Stem Cell 18, 611–624, https://doi.org/10.1016/j.stem.2016.04.004 (2016).
Dekker, J. et al. The 4D nucleome project. Nature 549, 219–226, https://doi.org/10.1038/nature23884 (2017).
doi: 10.1038/nature23884
pubmed: 28905911
pmcid: 5617335
Denholtz, M. et al. Long-range chromatin contacts in embryonic stem cells reveal a role for pluripotency factors and polycomb proteins in genome organization. Cell Stem Cell 13, 602–616, https://doi.org/10.1016/j.stem.2013.08.013 (2013).
doi: 10.1016/j.stem.2013.08.013
pubmed: 24035354
Dixon, J. R. et al. Topological domains in mammalian genomes identified by analysis of chromatin interactions. Nature 485, 376–380, https://doi.org/10.1038/nature11082 (2012).
doi: 10.1038/nature11082
pubmed: 22495300
pmcid: 3356448
Di Giammartino, D. C. & Apostolou, E. The chromatin signature of pluripotency: establishment and maintenance. Curr. Stem Cell Rep. 2, 255–262, https://doi.org/10.1007/s40778-016-0055-3 (2016).
doi: 10.1007/s40778-016-0055-3
pubmed: 27547710
pmcid: 4972866
Gorkin, D. U., Leung, D. & Ren, B. The 3D genome in transcriptional regulation and pluripotency. Cell Stem Cell 14, 762–775, https://doi.org/10.1016/j.stem.2014.05.017 (2014).
doi: 10.1016/j.stem.2014.05.017
pubmed: 24905166
pmcid: 4107214
Allahyar, A. et al. Enhancer hubs and loop collisions identified from single-allele topologies. Nat. Genet. 50, 1151–1160, https://doi.org/10.1038/s41588-018-0161-5 (2018).
doi: 10.1038/s41588-018-0161-5
pubmed: 29988121
Beagrie, R. A. et al. Complex multi-enhancer contacts captured by genome architecture mapping. Nature 543, 519–524, https://doi.org/10.1038/nature21411 (2017).
doi: 10.1038/nature21411
pubmed: 28273065
pmcid: 5366070
Dowen, J. M. et al. Control of cell identity genes occurs in insulated neighborhoods in mammalian chromosomes. Cell 159, 374–387, https://doi.org/10.1016/j.cell.2014.09.030 (2014).
doi: 10.1016/j.cell.2014.09.030
pubmed: 25303531
pmcid: 4197132
Li, G. et al. Extensive promoter-centered chromatin interactions provide a topological basis for transcription regulation. Cell 148, 84–98, https://doi.org/10.1016/j.cell.2011.12.014 (2012).
doi: 10.1016/j.cell.2011.12.014
pubmed: 22265404
pmcid: 3339270
Sun, F. et al. Promoter–enhancer communication occurs primarily within insulated neighborhoods. Mol. Cell 73, 250–263.e5, https://doi.org/10.1016/j.molcel.2018.10.039 (2019).
doi: 10.1016/j.molcel.2018.10.039
pubmed: 30527662
Lieberman-Aiden, E. et al. Comprehensive mapping of long-range interactions reveals folding principles of the human genome. Science 326, 289–293 (2009).
pubmed: 19815776
pmcid: 2858594
doi: 10.1126/science.1181369
Downes, D. J. et al. High-resolution targeted 3C interrogation of cis-regulatory element organization at genome-wide scale. Nat. Commun. 12, 531, https://doi.org/10.1038/s41467-020-20809-6 (2021).
doi: 10.1038/s41467-020-20809-6
pubmed: 33483495
pmcid: 7822813
Hughes, J. R. et al. Analysis of hundreds of cis-regulatory landscapes at high resolution in a single, high-throughput experiment. Nat. Genet. 46, 205–212, https://doi.org/10.1038/ng.2871 (2014).
doi: 10.1038/ng.2871
pubmed: 24413732
Hsieh, T. H. S. et al. Resolving the 3D landscape of transcription-linked mammalian chromatin folding. Mol. Cell 78, 539–553.e8, https://doi.org/10.1016/j.molcel.2020.03.002 (2020).
doi: 10.1016/j.molcel.2020.03.002
pubmed: 32213323
pmcid: 7703524
Krietenstein, N. et al. Ultrastructural details of mammalian chromosome architecture. Mol. Cell 78, 554–565.e7, https://doi.org/10.1016/j.molcel.2020.03.003 (2020).
doi: 10.1016/j.molcel.2020.03.003
pubmed: 32213324
pmcid: 7222625
Crispatzu, G. et al. The chromatin, topological and regulatory properties of pluripotency-associated poised enhancers are conserved in vivo. Nat. Commun. 12, 4344, https://doi.org/10.1038/s41467-021-24641-4 (2021).
doi: 10.1038/s41467-021-24641-4
pubmed: 34272393
pmcid: 8285398
Mumbach, M. R. et al. HiChIP: efficient and sensitive analysis of protein-directed genome architecture. Nat. Methods 13, 919–922, https://doi.org/10.1038/nmeth.3999 (2016).
doi: 10.1038/nmeth.3999
pubmed: 27643841
pmcid: 5501173
Lee, R. et al. CTCF-mediated chromatin looping provides a topological framework for the formation of phase-separated transcriptional condensates. Nucleic Acids Res. 50, 207–226, https://doi.org/10.1093/nar/gkab1242 (2022).
doi: 10.1093/nar/gkab1242
pubmed: 34931241
Fulco, C. P. et al. Activity-by-contact model of enhancer–promoter regulation from thousands of CRISPR perturbations. Nat. Genet. 51, 1664–1669, https://doi.org/10.1038/s41588-019-0538-0 (2019).
doi: 10.1038/s41588-019-0538-0
pubmed: 31784727
pmcid: 6886585
Galouzis, C. C. & Furlong, E. E. M. Regulating specificity in enhancer–promoter communication. Curr. Opin. Cell Biol. 75, 102065, https://doi.org/10.1016/j.ceb.2022.01.010 (2022).
doi: 10.1016/j.ceb.2022.01.010
pubmed: 35240372
Shlyueva, D., Stampfel, G. & Stark, A. Transcriptional enhancers: from properties to genome-wide predictions. Nat. Rev. Genet. 15, 272–286, https://doi.org/10.1038/nrg3682 (2014).
doi: 10.1038/nrg3682
pubmed: 24614317
Collombet, S. et al. Parental-to-embryo switch of chromosome organization in early embryogenesis. Nature 580, 142–146 (2020).
pubmed: 32238933
doi: 10.1038/s41586-020-2125-z
Guo, F. et al. Single-cell multi-omics sequencing of mouse early embryos and embryonic stem cells. Cell Res. 27, 967–988, https://doi.org/10.1038/cr.2017.82 (2017).
doi: 10.1038/cr.2017.82
pubmed: 28621329
pmcid: 5539349
Mittnenzweig, M. et al. A single-embryo, single-cell time-resolved model for mouse gastrulation. Cell 184, 2825–2842.e22, https://doi.org/10.1016/j.cell.2021.04.004 (2021).
doi: 10.1016/j.cell.2021.04.004
pubmed: 33932341
pmcid: 8162424
Pijuan-Sala, B. et al. Single-cell chromatin accessibility maps reveal regulatory programs driving early mouse organogenesis. Nat. Cell Biol. 22, 487–497, https://doi.org/10.1038/s41556-020-0489-9 (2020).
doi: 10.1038/s41556-020-0489-9
pubmed: 32231307
pmcid: 7145456
Nowotschin, S. et al. The emergent landscape of the mouse gut endoderm at single-cell resolution. Nature 569, 361–367, https://doi.org/10.1038/s41586-019-1127-1 (2019).
doi: 10.1038/s41586-019-1127-1
pubmed: 30959515
pmcid: 6724221
Tanaka, S., Kunath, T., Hadjantonakis, A. K., Nagy, A. & Rossant, J. Promotion to trophoblast stem cell proliferation by FGF4. Science 282, 2072–2075, https://doi.org/10.1126/science.282.5396.2072 (1998).
doi: 10.1126/science.282.5396.2072
pubmed: 9851926
Tesar, P. J. et al. New cell lines from mouse epiblast share defining features with human embryonic stem cells. Nature 448, 196–199, https://doi.org/10.1038/nature05972 (2007).
doi: 10.1038/nature05972
pubmed: 17597760
Evans, M. J. & Kaufman, M. H. Establishment in culture of pluripotential cells from mouse embryos. Nature 292, 154–156, https://doi.org/10.1038/292154a0 (1981).
doi: 10.1038/292154a0
pubmed: 7242681
Li, Q. V., Rosen, B. P. & Huangfu, D. Decoding pluripotency: genetic screens to interrogate the acquisition, maintenance, and exit of pluripotency. Wiley Interdiscip. Rev. Syst. Biol. Med. 12, e1464, https://doi.org/10.1002/wsbm.1464 (2020).
doi: 10.1002/wsbm.1464
pubmed: 31407519
Pelham-Webb, B., Murphy, D. & Apostolou, E. Dynamic 3D chromatin reorganization during establishment and maintenance of pluripotency. Stem Cell Rep. 15, 1176–1195, https://doi.org/10.1016/j.stemcr.2020.10.012 (2020).
doi: 10.1016/j.stemcr.2020.10.012
Loof, G. et al. 3D genome topologies distinguish pluripotent epiblast and primitive endoderm cells in the mouse blastocyst. Preprint at bioRxiv https://doi.org/10.1101/2022.10.19.512781 (2022).
Schoenfelder, S. et al. Divergent wiring of repressive and active chromatin interactions between mouse embryonic and trophoblast lineages. Nat. Commun. 9, 4189, https://doi.org/10.1038/s41467-018-06666-4 (2018).
doi: 10.1038/s41467-018-06666-4
pubmed: 30305613
pmcid: 6180096
Lee, B. K. et al. Super-enhancer-guided mapping of regulatory networks controlling mouse trophoblast stem cells. Nat. Commun. 10, 4749, https://doi.org/10.1038/s41467-019-12720-6 (2019).
doi: 10.1038/s41467-019-12720-6
pubmed: 31628347
pmcid: 6802173
Thompson, J. J. et al. Extensive co-binding and rapid redistribution of NANOG and GATA6 during emergence of divergent lineages. Nat. Commun. 13, 4257, https://doi.org/10.1038/s41467-022-31938-5 (2022).
doi: 10.1038/s41467-022-31938-5
pubmed: 35871075
pmcid: 9308780
Tomikawa, J. et al. Exploring trophoblast-specific Tead4 enhancers through chromatin conformation capture assays followed by functional screening. Nucleic Acids Res. 48, 278–289, https://doi.org/10.1093/nar/gkz1034 (2020).
doi: 10.1093/nar/gkz1034
pubmed: 31777916
Wamaitha, S. E. et al. Gata6 potently initiates reprograming of pluripotent and differentiated cells to extraembryonic endoderm stem cells. Genes Dev. 29, 1239–1255, https://doi.org/10.1101/gad.257071.114 (2015).
doi: 10.1101/gad.257071.114
pubmed: 26109048
pmcid: 4495396
Zhang, Y. et al. Dynamic epigenomic landscapes during early lineage specification in mouse embryos. Nat. Genet. 50, 96–105, https://doi.org/10.1038/s41588-017-0003-x (2018).
doi: 10.1038/s41588-017-0003-x
pubmed: 29203909
Jia, R. et al. Super enhancer profiles identify key cell identity genes during differentiation from embryonic stem cells to trophoblast stem cells super enhencers in trophoblast differentiation. Front. Genet. 12, 762529, https://doi.org/10.3389/fgene.2021.762529 (2021).
doi: 10.3389/fgene.2021.762529
pubmed: 34712273
pmcid: 8546299
Ye, S., Li, P., Tong, C. & Ying, Q. L. Embryonic stem cell self-renewal pathways converge on the transcription factor Tfcp2l1. EMBO J. 32, 2548–2560, https://doi.org/10.1038/emboj.2013.175 (2013).
doi: 10.1038/emboj.2013.175
pubmed: 23942238
pmcid: 3791365
Sun, H. et al. Tfcp2l1 safeguards the maintenance of human embryonic stem cell self-renewal. J. Cell. Physiol. 233, 6944–6951, https://doi.org/10.1002/jcp.26483 (2018).
doi: 10.1002/jcp.26483
pubmed: 29323720
Yeo, J. C. et al. Klf2 is an essential factor that sustains ground state pluripotency. Cell Stem Cell 14, 864–872 (2014).
pubmed: 24905170
doi: 10.1016/j.stem.2014.04.015
Chappell, J. & Dalton, S. Roles for MYC in the establishment and maintenance of pluripotency. Cold Spring Harb. Perspect. Med. 3, a014381, https://doi.org/10.1101/cshperspect.a014381 (2013).
doi: 10.1101/cshperspect.a014381
pubmed: 24296349
pmcid: 3839598
Kim, Y., Zheng, X. & Zheng, Y. Proliferation and differentiation of mouse embryonic stem cells lacking all lamins. Cell Res. 23, 1420–1423, https://doi.org/10.1038/cr.2013.118 (2013).
doi: 10.1038/cr.2013.118
pubmed: 23979018
pmcid: 3847566
Sehgal, P., Chaturvedi, P., Kumaran, R. I., Kumar, S. & Parnaik, V. K. Lamin A/C haploinsufficiency modulates the differentiation potential of mouse embryonic stem cells. PLoS One 8, e57891, https://doi.org/10.1371/journal.pone.0057891 (2013).
doi: 10.1371/journal.pone.0057891
pubmed: 23451281
pmcid: 3581495
Rideout, W. M. et al. Generation of mice from wild-type and targeted ES cells by nuclear cloning. Nat. Genet. 24, 109–110, https://doi.org/10.1038/72753 (2000).
doi: 10.1038/72753
pubmed: 10655052
Kunath, T. et al. Imprinted X-inactivation in extra-embryonic endoderm cell lines from mouse blastocysts. Development 132, 1649–1661, https://doi.org/10.1242/dev.01715 (2005).
doi: 10.1242/dev.01715
pubmed: 15753215
McLean, C. Y. et al. GREAT improves functional interpretation of cis-regulatory regions. Nat. Biotechnol. 28, 495–501, https://doi.org/10.1038/nbt.1630 (2010).
doi: 10.1038/nbt.1630
pubmed: 20436461
pmcid: 4840234
Whyte, W. A. et al. Master transcription factors and mediator establish super-enhancers at key cell identity genes. Cell 153, 307–319, https://doi.org/10.1016/j.cell.2013.03.035 (2013).
doi: 10.1016/j.cell.2013.03.035
pubmed: 23582322
pmcid: 3653129
Zhou, H. Y. et al. A Sox2 distal enhancer cluster regulates embryonic stem cell differentiation potential. Genes Dev. 28, 2699–2711, https://doi.org/10.1101/gad.248526.114 (2014).
doi: 10.1101/gad.248526.114
pubmed: 25512558
pmcid: 4265674
Hnisz, D. et al. Super-enhancers in the control of cell identity and disease.Cell 155, 934–947 (2013).
pubmed: 24119843
doi: 10.1016/j.cell.2013.09.053
Artus, J., Piliszek, A. & Hadjantonakis, A. K. The primitive endoderm lineage of the mouse blastocyst: sequential transcription factor activation and regulation of differentiation by Sox17. Dev. Biol. 350, 393–404, https://doi.org/10.1016/j.ydbio.2010.12.007 (2011).
doi: 10.1016/j.ydbio.2010.12.007
pubmed: 21146513
Ling, K. W. et al. GATA-2 plays two functionally distinct roles during the ontogeny of hematopoietic stem cells. J. Exp. Med. 200, 871–882, https://doi.org/10.1084/jem.20031556 (2004).
doi: 10.1084/jem.20031556
pubmed: 15466621
pmcid: 2213282
Takahashi, K. & Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663–676, https://doi.org/10.1016/j.cell.2006.07.024 (2006).
doi: 10.1016/j.cell.2006.07.024
pubmed: 16904174
Renaud, S. J., Kubota, K., Rumi, M. A. K. & Soares, M. J. The FOS transcription factor family differentially controls trophoblast migration and invasion. J. Biol. Chem. 289, 5025–5039, https://doi.org/10.1074/jbc.M113.523746 (2014).
doi: 10.1074/jbc.M113.523746
pubmed: 24379408
Knöfler, M., Vasicek, R. & Schreiber, M. Key regulatory transcription factors involved in placental trophoblast development—a review. Placenta 22, S83–S92, https://doi.org/10.1053/plac.2001.0648 (2001).
doi: 10.1053/plac.2001.0648
pubmed: 11312636
Benchetrit, H. et al. Direct induction of the three pre-implantation blastocyst cell types from fibroblasts. Cell Stem Cell 24, 983–994.e7, https://doi.org/10.1016/j.stem.2019.03.018 (2019).
doi: 10.1016/j.stem.2019.03.018
pubmed: 31031139
pmcid: 6561721
Fujikura, J. et al. Differentiation of embryonic stem cells is induced by GATA factors. Genes Dev. 16, 784–789, https://doi.org/10.1101/gad.968802 (2002).
doi: 10.1101/gad.968802
pubmed: 11937486
pmcid: 186328
Fraser, J. et al. Hierarchical folding and reorganization of chromosomes are linked to transcriptional changes in cellular differentiation. Mol. Syst. Biol. 11, 852 (2015).
pubmed: 26700852
pmcid: 4704492
doi: 10.15252/msb.20156492
Dixon, J. R. et al. Chromatin architecture reorganization during stem cell differentiation. Nature 518, 331–336, https://doi.org/10.1038/nature14222 (2015).
doi: 10.1038/nature14222
pubmed: 25693564
pmcid: 4515363
Hu, G. et al. Transformation of accessible chromatin and 3D nucleome underlies lineage commitment of early T cells. Immunity 48, 227–242.e8, https://doi.org/10.1016/j.immuni.2018.01.013 (2018).
doi: 10.1016/j.immuni.2018.01.013
pubmed: 29466755
pmcid: 5847274
Bhattacharyya, S., Chandra, V., Vijayanand, P. & Ay, F. Identification of significant chromatin contacts from HiChIP data by FitHiChIP. Nat. Commun. 10, 4221 (2019).
pubmed: 31530818
pmcid: 6748947
doi: 10.1038/s41467-019-11950-y
Tang, L., Hill, M. C., Ellinor, P. T. & Li, M. Bacon: a comprehensive computational benchmarking framework for evaluating targeted chromatin conformation capture-specific methodologies. Genome Biol. 23, 30 (2022).
pubmed: 35063001
pmcid: 8780810
doi: 10.1186/s13059-021-02597-4
Shohat, S. & Shifman, S. Genes essential for embryonic stem cells are associated with neurodevelopmental disorders. Genome Res. 29, 1910–1918 (2019).
pubmed: 31649057
pmcid: 6836742
doi: 10.1101/gr.250019.119
Tzelepis, K. et al. A CRISPR dropout screen identifies genetic vulnerabilities and therapeutic targets in acute myeloid leukemia. Cell Rep. 17, 1193–1205 (2016).
pubmed: 27760321
pmcid: 5081405
doi: 10.1016/j.celrep.2016.09.079
Di Giammartino, D. C. et al. KLF4 is involved in the organization and regulation of pluripotency-associated three-dimensional enhancer networks. Nat. Cell Biol. 21, 1179–1190 (2019).
pubmed: 31548608
pmcid: 7339746
doi: 10.1038/s41556-019-0390-6
Krijger, P. H. L. & De Laat, W. Regulation of disease-associated gene expression in the 3D genome. Nat. Rev. Mol. Cell Biol. 17, 771–782 (2016).
pubmed: 27826147
doi: 10.1038/nrm.2016.138
Miguel-Escalada, I. et al. Human pancreatic islet three-dimensional chromatin architecture provides insights into the genetics of type 2 diabetes. Nat. Genet. 51, 1137–1148 (2019).
pubmed: 31253982
pmcid: 6640048
doi: 10.1038/s41588-019-0457-0
Madsen, J. G. S. et al. Highly interconnected enhancer communities control lineage-determining genes in human mesenchymal stem cells. Nat. Genet. 52, 1227–1238 (2020).
pubmed: 33020665
doi: 10.1038/s41588-020-0709-z
Dejosez, M. et al. Regulatory architecture of housekeeping genes is driven by promoter assemblies. Cell Rep. 42, 112505 (2023).
pubmed: 37182209
pmcid: 10329844
doi: 10.1016/j.celrep.2023.112505
Sheffield, N. C. & Bock, C. LOLA: enrichment analysis for genomic region sets and regulatory elements in R and bioconductor. Bioinformatics 32, 587–589 (2016).
pubmed: 26508757
doi: 10.1093/bioinformatics/btv612
Zuin, J. et al. Nonlinear control of transcription through enhancer–promoter interactions. Nature 604, 571–577 (2022).
pubmed: 35418676
pmcid: 9021019
doi: 10.1038/s41586-022-04570-y
Luo, R. et al. Dynamic network-guided CRISPRi screen identifies CTCF-loop-constrained nonlinear enhancer gene regulatory activity during cell state transitions. Nat. Genet. 55, 1336–1346 (2023).
pubmed: 37488417
doi: 10.1038/s41588-023-01450-7
Wang, X. et al. The transcription factor TFCP2L1 induces expression of distinct target genes and promotes self-renewal of mouse and human embryonic stem cells. J. Biol. Chem. 294, 6007–6016 (2019).
pubmed: 30782842
pmcid: 6463713
doi: 10.1074/jbc.RA118.006341
Qiu, D. et al. Klf2 and Tfcp2l1, two Wnt/β-catenin targets, act synergistically to induce and maintain naive pluripotency. Stem Cell Rep. 5, 314–322 (2015).
doi: 10.1016/j.stemcr.2015.07.014
Papathanasiou, M. et al. Identification of a dynamic gene regulatory network required for pluripotency factor‐induced reprogramming of mouse fibroblasts and hepatocytes. EMBO J. 40, 102236 (2021).
doi: 10.15252/embj.2019102236
Li, Y. et al. Gene expression profiling reveals the heterogeneous transcriptional activity of Oct3/4 and its possible interaction with Gli2 in mouse embryonic stem cells. Genomics 102, 456–467 (2013).
pubmed: 24121003
doi: 10.1016/j.ygeno.2013.09.004
Higgs, D. R. Enhancer–promoter interactions and transcription. Nat. Genet. 52, 470–471 (2020).
pubmed: 32377019
doi: 10.1038/s41588-020-0620-7
Spitz, F. & Furlong, E. E. M. Transcription factors: from enhancer binding to developmental control. Nat. Rev. Genet. 13, 613–626 (2012).
pubmed: 22868264
doi: 10.1038/nrg3207
Li, J. & Pertsinidis, A. New insights into promoter–enhancer communication mechanisms revealed by dynamic single-molecule imaging. Biochem. Soc. Trans. 49, 1299–1309 (2021).
pubmed: 34060610
pmcid: 8325597
doi: 10.1042/BST20200963
Schmitt, A. D. et al. A compendium of chromatin contact maps reveals spatially active regions in the human genome. Cell Rep. 17, 2042–2059 (2016).
pubmed: 27851967
pmcid: 5478386
doi: 10.1016/j.celrep.2016.10.061
Di Giammartino, D. C., Polyzos, A. & Apostolou, E. Transcription factors: building hubs in the 3D space. Cell Cycle 19, 2395–2410 (2020).
pubmed: 32783593
pmcid: 7553511
doi: 10.1080/15384101.2020.1805238
Bergman, D. T. et al. Compatibility rules of human enhancer and promoter sequences. Nature 607, 176–184 (2022).
pubmed: 35594906
pmcid: 9262863
doi: 10.1038/s41586-022-04877-w
Osterwalder, M. et al. Enhancer redundancy provides phenotypic robustness in mammalian development. Nature 554, 239–243 (2018).
pubmed: 29420474
pmcid: 5808607
doi: 10.1038/nature25461
Kvon, E. Z., Waymack, R., Gad, M. & Wunderlich, Z. Enhancer redundancy in development and disease. Nat. Rev. Genet. 22, 324–336 (2021).
pubmed: 33442000
pmcid: 8068586
doi: 10.1038/s41576-020-00311-x
Beer, M. A., Shigaki, D. & Huangfu, D. Enhancer predictions and genome-wide regulatory circuits. Annu. Rev. Genomics Hum. Genet. 21, 37–54 (2020).
pubmed: 32443951
pmcid: 7644210
doi: 10.1146/annurev-genom-121719-010946
Tobias, I. C. et al. Transcriptional enhancers: from prediction to functional assessment on a genome-wide scale. Genome 64, 426–448 (2021).
pubmed: 32961076
doi: 10.1139/gen-2020-0104
Ernst, J. & Kellis, M. ChromHMM: automating chromatin-state discovery and characterization. Nat. Methods 9, 215–216 (2012).
pubmed: 22373907
pmcid: 3577932
doi: 10.1038/nmeth.1906
Tippens, N. D. et al. Transcription imparts architecture, function and logic to enhancer units. Nat. Genet. 52, 1067–1075 (2020).
pubmed: 32958950
pmcid: 7541647
doi: 10.1038/s41588-020-0686-2
Cao, Q. et al. Reconstruction of enhancer-target networks in 935 samples of human primary cells, tissues and cell lines. Nat. Genet. 49, 1428–1436 (2017).
pubmed: 28869592
doi: 10.1038/ng.3950
Whalen, S., Truty, R. M. & Pollard, K. S. Enhancer–promoter interactions are encoded by complex genomic signatures on looping chromatin. Nat. Genet. 48, 488–496 (2016).
pubmed: 27064255
pmcid: 4910881
doi: 10.1038/ng.3539
Karbalayghareh, A., Sahin, M. & Leslie, C. S. Chromatin interaction-aware gene regulatory modeling with graph attention networks. Genome Res. 32, 930–944 (2022).
pubmed: 35396274
pmcid: 9104700
Bigness, J., Loinaz, X., Patel, S., Larschan, E. & Singh, R. Integrating long-range regulatory interactions to predict gene expression using graph convolutional networks. J. Comput. Biol. 29, 409–424 (2022).
pubmed: 35325548
pmcid: 9125570
doi: 10.1089/cmb.2021.0316
Uyehara, C. M. & Apostolou, E. 3D Enhancer–promoter interactions and multi-connected hubs: organizational principles and functional roles. Cell Rep. 42, 112068 (2023).
pubmed: 37059094
pmcid: 10556201
doi: 10.1016/j.celrep.2023.112068
Garg, V. et al. Single-cell analysis of bidirectional reprogramming between early embryonic states reveals mechanisms of differential lineage plasticities. Preprint at bioRxiv https://doi.org/10.1101/2023.03.28.534648 (2023).
Niakan, K. K. et al. Novel role for the orphan nuclear receptor Dax1 in embryogenesis, different from steroidogenesis. Mol. Genet. Metab. 88, 261–271, https://doi.org/10.1016/j.ymgme.2005.12.010 (2006).
doi: 10.1016/j.ymgme.2005.12.010
pubmed: 16466956
Concordet, J. P. & Haeussler, M. CRISPOR: intuitive guide selection for CRISPR/Cas9 genome editing experiments and screens. Nucleic Acids Res. 46, W242–W245, https://doi.org/10.1093/nar/gky354 (2018).
doi: 10.1093/nar/gky354
pubmed: 29762716
pmcid: 6030908
Buenrostro, J. D., Wu, B., Chang, H. Y. & Greenleaf, W. J. ATAC-seq: a method for assaying chromatin accessibility genome-wide. Curr. Protoc. Mol. Biol. 109, 21.29.1–21.29.9, https://doi.org/10.1002/0471142727.mb2129s109 (2015).
doi: 10.1002/0471142727.mb2129s109
pubmed: 25559105
Krijger, P. H. L., Geeven, G., Bianchi, V., Hilvering, C. R. E. & de Laat, W. 4C-seq from beginning to end: a detailed protocol for sample preparation and data analysis. Methods 170, 17–32, https://doi.org/10.1016/j.ymeth.2019.07.014 (2020).
doi: 10.1016/j.ymeth.2019.07.014
pubmed: 31351925
Anders, S., Pyl, P. T. & Huber, W. HTSeq-A Python framework to work with high-throughput sequencing data. Bioinformatics 31, 166–169, https://doi.org/10.1093/bioinformatics/btu638 (2015).
doi: 10.1093/bioinformatics/btu638
pubmed: 25260700
Hounkpe, B. W., Chenou, F., de Lima, F. & de Paula, E. V. HRT Atlas v1.0 database: redefining human and mouse housekeeping genes and candidate reference transcripts by mining massive RNA-seq datasets. Nucleic Acids Res. 49, D947–D955, https://doi.org/10.1093/nar/gkaa609 (2021).
doi: 10.1093/nar/gkaa609
pubmed: 32663312
Langmead, B. & Salzberg, S. L. Fast gapped-read alignment with Bowtie 2. Nat. Methods 9, 357–359, https://doi.org/10.1038/nmeth.1923 (2012).
doi: 10.1038/nmeth.1923
pubmed: 22388286
pmcid: 3322381
Li, H. et al. The sequence alignment/map format and SAMtools. Bioinformatics 25, 2078–2079, https://doi.org/10.1093/bioinformatics/btp352 (2009).
doi: 10.1093/bioinformatics/btp352
pubmed: 19505943
pmcid: 2723002
Quinlan, A. R. & Hall, I. M. BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics 26, 841–842, https://doi.org/10.1093/bioinformatics/btq033 (2010).
doi: 10.1093/bioinformatics/btq033
pubmed: 20110278
pmcid: 2832824
Lazaris, C., Kelly, S., Ntziachristos, P., Aifantis, I. & Tsirigos, A. HiC-bench: comprehensive and reproducible Hi-C data analysis designed for parameter exploration and benchmarking. BMC Genomics 18, 22, https://doi.org/10.1186/s12864-016-3387-6 (2017).
doi: 10.1186/s12864-016-3387-6
pubmed: 28056762
pmcid: 5217551
Durand, N. C. et al. Juicer provides a one-click system for analyzing loop-resolution Hi-C experiments. Cell Syst. 3, 95–98, https://doi.org/10.1016/j.cels.2016.07.002 (2016).
doi: 10.1016/j.cels.2016.07.002
pubmed: 27467249
pmcid: 5846465
Zheng, X. & Zheng, Y. CscoreTool: fast Hi-C compartment analysis at high resolution. Bioinformatics 34, 1568–1570, https://doi.org/10.1093/bioinformatics/btx802 (2018).
doi: 10.1093/bioinformatics/btx802
pubmed: 29244056
Kent, W. J., Zweig, A. S., Barber, G., Hinrichs, A. S. & Karolchik, D. BigWig and BigBed: enabling browsing of large distributed datasets. Bioinformatics 26, 224–7 (2010).
doi: 10.1093/bioinformatics/btq351
Mumbach, M. R. et al. Enhancer connectome in primary human cells identifies target genes of disease-associated DNA elements. Nat. Genet. 49, 1602–1612 (2017).
pubmed: 28945252
pmcid: 5805393
doi: 10.1038/ng.3963
Rubin, A. J. et al. Coupled single-cell CRISPR screening and epigenomic profiling reveals causal gene regulatory networks. Cell 176, 361–376.e17 (2019).
pubmed: 30580963
doi: 10.1016/j.cell.2018.11.022