Chromatin conformation remains stable upon extensive transcriptional changes driven by heat shock
Open accessPublished version of a preprint
Abstract
Heat shock (HS) initiates rapid, extensive, and evolutionarily conserved changes in transcription that are accompanied by chromatin decondensation and nucleosome loss at HS loci. Here we have employed in situ Hi-C to determine how heat stress affects long-range chromatin conformation in human and Drosophila cells. We found that compartments and topologically associating domains (TADs) remain unchanged by an acute HS. Knockdown of Heat Shock Factor 1 (HSF1), the master transcriptional regulator of the HS response, identified HSF1-dependent genes and revealed that up-regulation is often mediated by distal HSF1 bound enhancers. HSF1-dependent genes were usually found in the same TAD as the nearest HSF1 binding site. Although most interactions between HSF1 binding sites and target promoters were established in the nonheat shock (NHS) condition, a subset increased contact frequency following HS. Integrating information about HSF1 binding strength, RNA polymerase abundance at the HSF1 bound sites (putative enhancers), and contact frequency with a target promoter accurately predicted which up-regulated genes were direct targets of HSF1 during HS. Our results suggest that the chromatin conformation necessary for a robust HS response is preestablished in NHS cells of diverse metazoan species.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
This is not an inexorable chain of events; for example, stimulus-responsive enhancers may exhibit open chromatin and 3D interactions with their promoters before activation.
“However, it should be emphasized that this is not an inexorable chain of events. For example, stimulus-responsive enhancers may exhibit open chromatin and 3D interactions with their promoters before activation92,93.”
From Towards a comprehensive catalogue of validated and target-linked human enhancers (2020) · cites this paper as [93]
The section “Pre-programmed chromatin architecture is conserved across metazoans” (page unavailable) reports that contacts between heat-shock-regulated genes and distal HSF1-bound elements were preformed before heat shock, supporting the pre-activation 3D-interaction claim. Our copy does not establish that those enhancers had open chromatin before activation; the Introduction discusses changes in chromatin accessibility upon heat shock instead. (LLM, conf=0.87)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Topological domains in mammalian genomes identified by analysis of chromatin interactions
Dixon, J. R., Selvaraj, S., Yue, F., Kim, A., Li, Y., Shen, Y., Hu, M., Liu, J. S., & Ren, B. (2012) · Nature · doi:10.1038/nature11082 · Cited by 6,829 · see citing works
Cohesin Loss Eliminates All Loop Domains
Rao, S. S. P., Huang, S.-C., Glenn St Hilaire, B., Engreitz, J. M., Perez, E. M., Kieffer-Kwon, K.-R., Sanborn, A. L., Johnstone, S. E., Bascom, G. D., Bochkov, I. D., et al. (2017) · Cell · doi:10.1016/j.cell.2017.09.026 · Cited by 1,883 · see citing works
Sanborn, A. L., Rao, S. S. P., Huang, S.-C., Durand, N. C., Huntley, M. H., Jewett, A. I., Bochkov, I. D., Chinnappan, D., Cutkosky, A., Li, J., et al. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1518552112 · Cited by 1,730 · see citing works
Nora, E. P., Goloborodko, A., Valton, A.-L., Gibcus, J. H., Uebersohn, A., Abdennur, N., Dekker, J., Mirny, L. A., & Bruneau, B. G. (2017) · Cell · doi:10.1016/j.cell.2017.05.004 · Cited by 1,709 · see citing works
Chromatin architecture reorganization during stem cell differentiation
Dixon, J. R., Jung, I., Selvaraj, S., Shen, Y., Antosiewicz-Bourget, J. E., Lee, A. Y., Ye, Z., Kim, A., Rajagopal, N., Xie, W., et al. (2015) · Nature · doi:10.1038/nature14222 · Cited by 1,646 · see citing works
The long-range interaction landscape of gene promoters
Sanyal, A., Lajoie, B. R., Jain, G., & Dekker, J. (2012) · Nature · doi:10.1038/nature11279 · Cited by 1,489 · see citing works
Looping and Interaction between Hypersensitive Sites in the Active β-globin Locus
Tolhuis, B., Palstra, R.-J., Splinter, E., Grosveld, F., & de Laat, W. (2002) · Molecular Cell · doi:10.1016/s1097-2765(02)00781-5 · Cited by 1,344 · see citing works
Organization of the mitotic chromosome
Naumova, N., Imakaev, M., Fudenberg, G., Zhan, Y., Lajoie, B. R., Mirny, L. A., & Dekker, J. (2013) · Science · doi:10.1126/science.1236083 · Cited by 976 · cited 1× · see citing works
“250 Generally, TADs are highly conserved across cell types, but they disappear along with 251 compartments during mitosis (38).”
BackgroundA compendium of chromatin contact maps reveals spatially active regions in the human genome
Schmitt, A. D., Hu, M., Jung, I., Xu, Z., Qiu, Y., Tan, C. L., Li, Y., Lin, S., Lin, Y., Barr, C. L., et al. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.10.061 · Cited by 866 · see citing works
Systematic mapping of functional enhancer–promoter connections with CRISPR interference
Fulco, C. P., Munschauer, M., Anyoha, R., Munson, G., Grossman, S. R., Perez, E. M., Kane, M., Cleary, B., Lander, E. S., & Engreitz, J. M. (2016) · Science · doi:10.1126/science.aag2445 · Cited by 643 · see citing works
The Energetics and Physiological Impact of Cohesin Extrusion
Vian, L., Pękowska, A., Rao, S. S. P., Kieffer-Kwon, K.-R., Jung, S., Baranello, L., Huang, S.-C., El Khattabi, L., Dose, M., Pruett, N., et al. (2018) · Cell · doi:10.1016/j.cell.2018.03.072 · Cited by 581 · see citing works
Enhancer loops appear stable during development and are associated with paused polymerase
Ghavi-Helm, Y., Klein, F. A., Pakozdi, T., Ciglar, L., Noordermeer, D., Huber, W., & Furlong, E. E. M. (2014) · Nature · doi:10.1038/nature13417 · Cited by 536 · see citing works
HiCRep: assessing the reproducibility of Hi-C data using a stratum-adjusted correlation coefficient
Yang, T., Zhang, F., Yardımcı, G. G., Song, F., Hardison, R. C., Noble, W. S., Yue, F., & Li, Q. (2017) · Genome Research · doi:10.1101/gr.220640.117 · Cited by 533 · see citing works
Rubin, 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 1× · see citing works
“Although it has been shown that regulatory contacts are newly formed or strengthened while cells are undergoing transcriptional changes (45–47), there is also evidence of preestablished enhancer–promoter interactions during stimuli activation, differentiation, development, and stress (31, 45, 48, 49).”
BackgroundDynamic Rewiring of Promoter-Anchored Chromatin Loops during Adipocyte Differentiation
Siersbæk, R., Madsen, J. G. S., Javierre, B. M., Nielsen, R., Bagge, E. K., Cairns, J., Wingett, S. W., Traynor, S., Spivakov, M., Fraser, P., et al. (2017) · Molecular Cell · doi:10.1016/j.molcel.2017.04.010 · Cited by 243 · see citing works
Transcriptional response to stress is pre-wired by promoter and enhancer architecture
Vihervaara, A., Mahat, D. B., Guertin, M. J., Chu, T., Danko, C. G., Lis, J. T., & Sistonen, L. (2017) · Nature Communications · doi:10.1038/s41467-017-00151-0 · Cited by 164 · see citing works
Self-citation
Flagged first, then by citations
Research works printed but not linked: 32
- Ritossa F (1962) A new puffing pattern induced by temperature shock and DNP in drosophila. Experientia 18(12):571-573.
- Yao J, Munson KM, Webb WW, & Lis JT (2006) Dynamics of heat shock factor association with native gene loci in living cells. Nature 442(7106):1050-1053.
- Guertin MJ & Lis JT (2010) Chromatin landscape dictates HSF binding to target DNA elements. PLoS Genet 6(9):e1001114.
- Duarte FM, et al. (2016) Transcription factors GAF and HSF act at distinct regulatory steps to modulate stress-induced gene activation. Genes Dev 30(15):1731-1746.
- Mahat DB, Salamanca HH, Duarte FM, Danko CG, & Lis JT (2016) Mammalian Heat Shock Response and Mechanisms Underlying Its Genome-wide Transcriptional Regulation. Mol Cell 62(1):63-78.
- Vihervaara A, et al. (2013) Transcriptional response to stress in the dynamic chromatin environment of cycling and mitotic cells. Proc Natl Acad Sci U S A 110(36):E3388-3397.
- Hahn JS, Hu Z, Thiele DJ, & Iyer VR (2004) Genome-wide analysis of the biology of stress responses through heat shock transcription factor. Mol Cell Biol 24(12):5249-5256.
- Ashburner M (1970) Patterns of puffing activity in the salivary gland chromosomes of Drosophila. V. Responses to environmental treatments. Chromosoma 31(3):356-376.
- Boehm AK, Saunders A, Werner J, & Lis JT (2003) Transcription factor and polymerase recruitment, modification, and movement on dhsp70 in vivo in the minutes following heat shock. Mol Cell Biol 23(21):7628-7637.
- Petesch SJ & Lis JT (2008) Rapid, transcription-independent loss of nucleosomes over a large chromatin domain at Hsp70 loci. Cell 134(1):74-84.
- Wu C, Wong YC, & Elgin SC (1979) The chromatin structure of specific genes: II. Disruption of chromatin structure during gene activity. Cell 16(4):807-814.
- Saunders A, et al. (2003) Tracking FACT and the RNA polymerase II elongation complex through chromatin in vivo. Science 301(5636):1094-1096.
- Petesch SJ & Lis JT (2012) Overcoming the nucleosome barrier during transcript elongation. Trends Genet 28(6):285-294.
- Rao SS, et al. (2014) A 3D map of the human genome at kilobase resolution reveals principles of chromatin looping. Cell 159(7):1665-1680.
- Lieberman-Aiden E, et al. (2009) Comprehensive mapping of long-range interactions reveals folding principles of the human genome. Science 326(5950):289-293.
- Li L, et al. (2015) Widespread rearrangement of 3D chromatin organization underlies polycomb-mediated stress-induced silencing. Mol Cell 58(2):216-231.
- Ramirez F, et al. (2018) High-resolution TADs reveal DNA sequences underlying genome organization in flies. Nat Commun 9(1):189.
- Danko CG, et al. (2015) Identification of active transcriptional regulatory elements from GRO-seq data. Nat Methods 12(5):433-438.
- Henriques T, et al. (2018) Widespread transcriptional pausing and elongation control at enhancers. Genes Dev 32(1):26-41.
- Mikhaylichenko O, et al. (2018) The degree of enhancer or promoter activity is reflected by the levels and directionality of eRNA transcription. Genes Dev 32(1):42-57.
- Core LJ, et al. (2014) Analysis of nascent RNA identifies a unified architecture of initiation regions at mammalian promoters and enhancers. Nat Genet 46(12):1311- 1320.
- Hou C, Li L, Qin ZS, & Corces VG (2012) Gene density, transcription, and insulators contribute to the partition of the Drosophila genome into physical domains. Mol Cell 48(3):471-484.
- Jin F, et al. (2013) A high-resolution map of the three-dimensional chromatin interactome in human cells. Nature 503(7475):290-294.
- Mifsud B, et al. (2015) Mapping long-range promoter contacts in human cells with high-resolution capture Hi-C. Nat Genet 47(6):598-606.
- Li G, et al. (2012) Extensive promoter-centered chromatin interactions provide a topological basis for transcription regulation. Cell 148(1-2):84-98.
- Criscione SW, et al. (2016) Reorganization of chromosome architecture in replicative cellular senescence. Sci Adv 2(2):e1500882.
- Vihervaara A, Duarte FM, & Lis JT (2018) Molecular mechanisms driving transcriptional stress responses. Nat Rev Genet 19(6):385-397.
- Li W, et al. (2013) Functional roles of enhancer RNAs for oestrogen-dependent transcriptional activation. Nature 498(7455):516-520.
- Platt JL, et al. (2016) Capture-C reveals preformed chromatin interactions between HIF-binding sites and distant promoters. EMBO Rep 17(10):1410-1421.
- Kerpedjiev P, et al. (2017) HiGlass: Web-based Visual Comparison And Exploration Of Genome Interaction Maps. bioRxiv.
- Feng J, Liu T, Qin B, Zhang Y, & Liu XS (2012) Identifying ChIP-seq enrichment using MACS. Nat Protoc 7(9):1728-1740.
- Brent RP (1971) An algorithm with guaranteed convergence for finding a zero of a function. The Computer Journal 14(4):422-425. [0 -70] [0 -70] [1 -4] [1 -4] [-20 -20] [-20 -20] ~100 [0 -150] [0 -150] [1 -16] [1 -16] [-50 -50] [-50 -50]
Cited by
Sorted by citations
Towards a comprehensive catalogue of validated and target-linked human enhancers
Gasperini, M., Tome, J. M., & Shendure, J. (2020) · Nature Reviews Genetics · doi:10.1038/s41576-019-0209-0 · Cited by 396 · see citing works
Radiation-induced DNA damage and repair effects on 3D genome organization
Sanders, J. T., Freeman, T. F., Xu, Y., Golloshi, R., Stallard, M. A., Hill, A. M., San Martin, R., Balajee, A. S., & McCord, R. P. (2020) · Nature Communications · doi:10.1038/s41467-020-20047-w · Cited by 134 · see citing works
Functional characterization of Alzheimer’s disease genetic variants in microglia
Yang, X., Wen, J., Yang, H., Jones, I. R., Zhu, X., Liu, W., Li, B., Clelland, C. D., Luo, W., Wong, M. Y., et al. (2023) · Nature Genetics · doi:10.1038/s41588-023-01506-8 · Cited by 71 · see citing works
Chen, L., Cao, W., Aita, R., Aldea, D., Flores, J., Gao, N., Bonder, E. M., Ellison, C. E., & Verzi, M. P. (2021) · Cell Reports · doi:10.1016/j.celrep.2020.108679 · Cited by 27 · see citing works
- Authors
- Ray, J., Munn, P. R., Vihervaara, A., Lewis, J. J., Ozer, A., Danko, C. G., & Lis, J. T.
- Affiliations
- Cornell University (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2019-09-10
- Volume
- 116
- Issue
- 39
- Pages
- 19431-19439
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC6765289
- OpenAlex
- W2972670629
- Cited by
- 109
- References
- 16
- Citations by year
- 2026: 10 · 2025: 11 · 2024: 15 · 2023: 13 · 2022: 18 · 2021: 21 · 2020: 15 · 2019: 5 · 2018: 1
- FWCI
- 4.88
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- HHS | NIH | National Heart, Lung, and Blood Institute (U01HL129958)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- heat shock, chromatin conformation, long-range chromatin interactions, topologically associating domains, HSF1, heat shock response, enhancers, RNA polymerase II, gene expression regulation, Drosophila cells, human cells, chromatin decondensation
- MeSH terms
- Heat Shock Transcription Factors, Animals, Binding Sites, Cell Line, Chromatin, Chromosomes, Drosophila, Enhancer Elements, Genetic, Biological Evolution, Gene Expression Regulation, Heat-Shock Proteins, Humans, Molecular Conformation, Promoter Regions, Genetic, Heat-Shock Response, K562 Cells, Gene Knockdown Techniques
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
