CoChat
Sign Up
Cited by 1,253Cancer-related molecular mechanisms researchGenomics and Chromatin DynamicsRNA Research and Splicing

Local regulation of gene expression by lncRNA promoters, transcription and splicing

Open access
Engreitz, Jesse M., Haines, Jenna E., Perez, Elizabeth M., Munson, Glen, Chen, Jenny, Kane, Michael, McDonel, Patrick E., Guttman, Mitchell +1 more·2016·Nature
DOI 10.1038/nature20149PMC PMC6853796
Open this paper in CoChat — free accountOpen PDF

Abstract

Mammalian genomes are pervasively transcribed to produce thousands of long non-coding RNAs (lncRNAs). A few of these lncRNAs have been shown to recruit regulatory complexes through RNA-protein interactions to influence the expression of nearby genes, and it has been suggested that many other lncRNAs can also act as local regulators. Such local functions could explain the observation that lncRNA expression is often correlated with the expression of nearby genes. However, these correlations have been challenging to dissect and could alternatively result from processes that are not mediated by the lncRNA transcripts themselves. For example, some gene promoters have been proposed to have dual functions as enhancers, and the process of transcription itself may contribute to gene regulation by recruiting activating factors or remodelling nucleosomes. Here we use genetic manipulation in mouse cell lines to dissect 12 genomic loci that produce lncRNAs and find that 5 of these loci influence the expression of a neighbouring gene in cis. Notably, none of these effects requires the specific lncRNA transcripts themselves and instead involves general processes associated with their production, including enhancer-like activity of gene promoters, the process of transcription, and the splicing of the transcript. Furthermore, such effects are not limited to lncRNA loci: we find that four out of six protein-coding loci also influence the expression of a neighbour. These results demonstrate that cross-talk among neighbouring genes is a prevalent phenomenon that can involve multiple mechanisms and cis-regulatory signals, including a role for RNA splice sites. These mechanisms may explain the function and evolution of some genomic loci that produce lncRNAs and broadly contribute to the regulation of both coding and non-coding genes.

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.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/nature20149

Cites

10 of 10 references verified0 citation errors · 0 not checkable

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.

A few free checks a day · papers already verified open instantly · results are public

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?

  • Certain promoters, termed epromoters, can also function as enhancers.

    “Finally, evidence from multiple sources including reporter assays [169, 175, 239, 240], CRISPR [240–242], chromatin mapping [243, 244] and population genetics analysis [207, 245] suggests that certain promoters, termed ‘epromoters’, can also function as enhancers (reviewed in [246]).”

    From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [241]

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

Flagged first, then by citations

Research works printed but not linked: 52

  1. [1]Okazaki Y. Analysis of the mouse transcriptome based on functional annotation of 60,770 full-length cDNAs. Nature 420, 563– 573 (2002). 12466851
  2. [2]Kapranov P. RNA maps reveal new RNA classes and a possible function for pervasive transcription. Science 316, 1484– 1488 (2007). 17510325
  3. [4]Carninci P. The transcriptional landscape of the mammalian genome. Science 309, 1559– 1563 (2005). 16141072
  4. [5]Lee JT Lessons from X-chromosome inactivation: long ncRNA as guides and tethers to the epigenome. Genes Dev 23, 1831– 1842 (2009). 19684108 PMC2725936
  5. [6]Nagano T. The Air noncoding RNA epigenetically silences transcription by targeting G9a to chromatin. Science 322, 1717– 1720 (2008). 18988810
  6. [7]Wang KC A long noncoding RNA maintains active chromatin to coordinate homeotic gene expression. Nature 472, 120– 124 (2011). 21423168 PMC3670758
  7. [8]Ørom UA Long noncoding RNAs with enhancer-like function in human cells. Cell 143, 46– 58 (2010). 20887892 PMC4108080
  8. [9]Guil S. & Esteller M. Cis-acting noncoding RNAs: friends and foes. Nat Struct Mol Biol 19, 1068– 1075 (2012). 23132386
  9. [10]Ebisuya M, Yamamoto T, Nakajima M. & Nishida E. Ripples from neighbouring transcription. Nat. Cell Biol. 10, 1106– 1113 (2008). 19160492
  10. [11]Cabili MN Integrative annotation of human large intergenic noncoding RNAs reveals global properties and specific subclasses. Genes Dev 25, 1915– 1927 (2011). 21890647 PMC3185964
  11. [12]Bassett AR Considerations when investigating lncRNA function in vivo. Elife 3, e03058 (2014). 25124674 PMC4132285
  12. [13]Li G. Extensive promoter-centered chromatin interactions provide a topological basis for transcription regulation. Cell 148, 84– 98 (2012). 22265404 PMC3339270
  13. [14]Rajagopal N. High-throughput mapping of regulatory DNA. Nat Biotechnol 34, 167– 174 (2016). 26807528 PMC5108523
  14. [15]Yin Y. Opposing Roles for the lncRNA Haunt and Its Genomic Locus in Regulating HOXA Gene Activation during Embryonic Stem Cell Differentiation. Cell Stem Cell 16, 504– 516 (2015). 25891907
  15. [16]Paralkar VR Unlinking an lncRNA from Its Associated cis Element. Mol Cell 62, 104– 110 (2016). 27041223 PMC4877494
  16. [17]Martens JA, Laprade L. & Winston F. Intergenic transcription is required to repress the Saccharomyces cerevisiae SER3 gene. Nature 429, 571– 574 (2004). 15175754
  17. [18]Shearwin KE, Callen BP & Egan JB Transcriptional interference--a crash course. Trends Genet 21, 339– 345 (2005). 15922833 PMC2941638
  18. [19]Purmann A. Genomic organization of transcriptomes in mammals: Coregulation and cofunctionality. Genomics 89, 580– 587 (2007). 17369017
  19. [20]Kosak ST Coordinate gene regulation during hematopoiesis is related to genomic organization. PLoS Biol 5, e309 (2007). 18031200 PMC2080650
  20. [21]Brinster RL, Allen JM, Behringer RR, Gelinas RE & Palmiter RD Introns increase transcriptional efficiency in transgenic mice. Proc Natl Acad Sci U S A 85, 836– 840 (1988). 3422466 PMC279650
  21. [22]Fong YW & Zhou Q. Stimulatory effect of splicing factors on transcriptional elongation. Nature 414, 929– 933 (2001). 11780068
  22. [23]Calo E. & Wysocka J. Modification of enhancer chromatin: what, how, and why? Mol Cell 49, 825– 837 (2013). 23473601 PMC3857148
  23. [24]Andersson R, Sandelin A. & Danko CG A unified architecture of transcriptional regulatory elements. Trends Genet 31, 426– 433 (2015). 26073855
  24. [25]Kim T-K & Shiekhattar R. Architectural and Functional Commonalities between Enhancers and Promoters. Cell 162, 948– 959 (2015). 26317464 PMC4556168
  25. [27]Hezroni H. Principles of long noncoding RNA evolution derived from direct comparison of transcriptomes in 17 species. Cell Rep 11, 1110– 1122 (2015). 25959816 PMC4576741
  26. [28]Chen J. Evolutionary analysis across mammals reveals distinct classes of long non-coding RNAs. Genome Biol 17, 19 (2016). 26838501 PMC4739325
  27. [29]Bhatt DM Transcript dynamics of proinflammatory genes revealed by sequence analysis of subcellular RNA fractions. Cell 150, 279– 290 (2012). 22817891 PMC3405548
  28. [30]Engreitz JM RNA-RNA interactions enable specific targeting of noncoding RNAs to nascent Pre-mRNAs and chromatin sites. Cell 159, 188– 199 (2014). 25259926 PMC4177037
  29. [32]Wang T, Wei JJ, Sabatini DM & Lander ES Genetic screens in human cells using the CRISPR-Cas9 system. Science 343, 80– 84 (2014). 24336569 PMC3972032
  30. [33]Keane TM Mouse genomic variation and its effect on phenotypes and gene regulation. Nature 477, 289– 294 (2011). 21921910 PMC3276836
  31. [35]Chen B. Dynamic imaging of genomic loci in living human cells by an optimized CRISPR/Cas system. Cell 155, 1479– 1491 (2013). 24360272 PMC3918502
  32. [36]Shishkin AA Simultaneous generation of many RNA-seq libraries in a single reaction. Nat Methods 12, 323– 325 (2015). 25730492 PMC4712044
  33. [37]Engreitz J, Lander ES & Guttman M. RNA antisense purification (RAP) for mapping RNA interactions with chromatin. Methods Mol Biol 1262, 183– 197 (2015). 25555582
  34. [38]Engreitz JM The Xist lncRNA exploits three-dimensional genome architecture to spread across the X chromosome. Science 341, 1237973 (2013). 23828888 PMC3778663
  35. [40]Huang S, Holt J, Kao C-Y, McMillan L. & Wang W. A novel multi-alignment pipeline for high-throughput sequencing data. Database (Oxford) 2014, bau057– bau057 (2014). 24948510 PMC4062837
  36. [41]Guttman M. Ab initio reconstruction of cell type-specific transcriptomes in mouse reveals the conserved multi-exonic structure of lincRNAs. Nat Biotechnol 28, 503– 510 (2010). 20436462 PMC2868100
  37. [42]Levitt N, Briggs D, Gil A. & Proudfoot NJ Definition of an efficient synthetic poly(A) site. Genes Dev 3, 1019– 1025 (1989). 2570734
  38. [43]Kwak H, Fuda NJ, Core LJ & Lis JT Precise maps of RNA polymerase reveal how promoters direct initiation and pausing. Science 339, 950– 953 (2013). 23430654 PMC3974810
  39. [44]Core LJ, Waterfall JJ & Lis JT Nascent RNA sequencing reveals widespread pausing and divergent initiation at human promoters. Science 322, 1845– 1848 (2008). 19056941 PMC2833333
  40. [45]Mahat DB Base-pair-resolution genome-wide mapping of active RNA polymerases using precision nuclear run-on (PRO-seq). Nat Protoc 11, 1455– 1476 (2016). 27442863 PMC5502525
  41. [46]Adelman K. & Lis JT Promoter-proximal pausing of RNA polymerase II: emerging roles in metazoans. Nat Rev Genet 13, 720– 731 (2012). 22986266 PMC3552498
  42. [47]Buenrostro JD, Giresi PG, Zaba LC, Chang HY & Greenleaf WJ Transposition of native chromatin for fast and sensitive epigenomic profiling of open chromatin, DNA-binding proteins and nucleosome position. Nat Methods 10, 1213– 1218 (2013). 24097267 PMC3959825
  43. [48]Langmead B. & Salzberg SL Fast gapped-read alignment with Bowtie 2. Nat Methods 9, 357– 359 (2012). 22388286 PMC3322381
  44. [49]Busby M. Systematic comparison of monoclonal versus polyclonal antibodies for mapping histone modifications by ChIP-seq. (2016). doi: 10.1101/054387 PMC5097419 27826357 · DOI
  45. [53]Fort A. Deep transcriptome profiling of mammalian stem cells supports a regulatory role for retrotransposons in pluripotency maintenance. Nat Genet 46, 558– 566 (2014). 24777452
  46. [55]Garber M. Identifying novel constrained elements by exploiting biased substitution patterns. Bioinformatics 25, i54– 62 (2009). 19478016 PMC2687944
  47. [56]Lindblad-Toh K. A high-resolution map of human evolutionary constraint using 29 mammals. Nature 478, 476– 482 (2011). 21993624 PMC3207357
  48. [57]Gentleman RC Bioconductor: open software development for computational biology and bioinformatics. Genome Biol 5, R80 (2004). 15461798 PMC545600
  49. [58]Lawrence M. Software for computing and annotating genomic ranges. PLoS Comput Biol 9, e1003118 (2013). 23950696 PMC3738458
  50. [59]Lawrence M, Gentleman R. & Carey V. rtracklayer: an R package for interfacing with genome browsers. Bioinformatics 25, 1841– 1842 (2009). 19468054 PMC2705236
  51. [61]Robinson JT Integrative genomics viewer. Nat Biotechnol 29, 24– 26 (2011). 21221095 PMC3346182
  52. [62]Danecek P. The variant call format and VCFtools. Bioinformatics 27, 2156– 2158 (2011). 21653522 PMC3137218

Cited by

Sorted by citations

Authors
Engreitz, J. M., Haines, J. E., Perez, E. M., Munson, G., Chen, J., Kane, M., McDonel, P. E., Guttman, M., & Lander, E. S.
Affiliations
  • Broad Institute (US)
  • California Institute of Technology (US)
Corresponding author
Lander, Eric S.
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2016-10-26
Volume
539
Issue
7629
Pages
452-455
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/nature20149
PMC
PMC6853796
OpenAlex
W2540381357
Cited by
1,253
References
10
Citations by year
2026: 51 · 2025: 54 · 2024: 130 · 2023: 126 · 2022: 124 · 2021: 211 · 2020: 172 · 2019: 171 · 2018: 123 · 2017: 86 · 2016: 5
FWCI
53.61
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • CaltechAUTHORS (California Institute of Technology) (submittedVersion)
  • Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
Funders
  • Edward Mallinckrodt, Jr. Foundation
  • Broad Institute
  • Searle Scholars Program
  • National Institutes of Health (DP50D012190, DP5OD012190)
  • National Defense Science and Engineering Graduate
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
Keywords
long non-coding RNA, cis-regulatory elements, pervasive transcription, RNA splicing, transcriptional regulation, gene expression regulation, protein-coding genes, RNA-protein interactions, CRISPR/Cas9 gene deletion, mouse cell lines, nucleosome remodeling, RNA-DNA interactions, lncRNA evolution
MeSH terms
Mouse Embryonic Stem Cells, Animals, Cell Line, Female, Gene Expression Regulation, Genes, Male, Promoter Regions, Genetic, RNA Splicing, RNA, Messenger, Transcription, Genetic, Conserved Sequence, Evolution, Molecular, RNA Splice Sites, Genomics, Mice, Genetic Loci, RNA, Long Noncoding

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