Evidence map›Paper›PMID 27831498›Full record

ArticleGenome research2017

A systematic comparison reveals substantial differences in chromosomal versus episomal encoding of enhancer activity.

Fumitaka Inoue, Martin Kircher, Beth Martin, Gregory M Cooper, Daniela M Witten, Michael T McManus, Nadav Ahituv, Jay Shendure

Erratum issuedAbstract read
In one paragraph

Article in Genome research, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 206 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
206citing papers in PubMed, 1 pooled it
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

206 citing papers in PubMed, 1 synthesis or guideline pooled it.

  1. Pooled it
  2. Article
  3. Article
  4. Article
  5. Review
  6. Article
  7. Article
  8. Article
  9. Review
  10. Synthetic Regulatory Genomics.Annual review of genomics and human genetics · 2026
    Review
  11. Article
  12. Article
  13. Article
  14. Article
  15. Review
  16. Article
  17. Article
  18. Article
  19. Article
  20. Facilitators may represent a new class of regulatory elements.Current opinion in genetics & development · 2026
    Review

146 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

8 authors.

Fumitaka InoueDepartment of Bioengineering and Therapeutic Sciences, Institute for Human Genetics, University of California San Francisco, San Francisco, California 94158, USA.ORCID 0000-0002-1396-6168
Martin KircherDepartment of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.ORCID 0000-0001-9278-5471
Beth MartinDepartment of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.ORCID 0000-0002-9661-014X
Gregory M CooperHudsonAlpha Institute for Biotechnology, Huntsville, Alabama 35806, USA.ORCID 0000-0001-5509-9923
Daniela M WittenDepartments of Statistics and Biostatistics, University of Washington, Seattle, Washington 98195, USA.
Michael T McManusDepartment of Microbiology and Immunology, UCSF Diabetes Center, Keck Center for Noncoding RNA, University of California, San Francisco, San Francisco, California 94143, USA.
Nadav AhituvDepartment of Bioengineering and Therapeutic Sciences, Institute for Human Genetics, University of California San Francisco, San Francisco, California 94158, USA.ORCID 0000-0002-7434-8144
Jay ShendureDepartment of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.ORCID 0000-0002-1516-1865

Funding

Massively parallel dissection of psychiatric regulatory networksR01MH109907 · NIMH · J. DAVID GLADSTONE INSTITUTES · PI AHITUV, NADAV, POLLARD, KATHERINE S. · 2016 to 2020
$3.4M
Integrative interpretation of the organismal consequences of non-coding variationR01CA197139 · NCI · UNIVERSITY OF WASHINGTON · PI COOPER, GREGORY MICHAEL, SHENDURE, JAY ASHOK · 2015 to 2017
$1.9M
Massively parallel, in vivo functional testing of regulatory elementsR01HG006768 · NHGRI · UNIVERSITY OF WASHINGTON · PI AHITUV, NADAV, SHENDURE, JAY ASHOK · 2012 to 2014
$1.8M
NCI NIH HHS R01 CA197139NHGRI NIH HHS R01 HG006768NIMH NIH HHS R01 MH109907
6 · The paper itself

Abstract

Candidate enhancers can be identified on the basis of chromatin modifications, the binding of chromatin modifiers and transcription factors and cofactors, or chromatin accessibility. However, validating such candidates as bona fide enhancers requires functional characterization, typically achieved through reporter assays that test whether a sequence can increase expression of a transcriptional reporter via a minimal promoter. A longstanding concern is that reporter assays are mainly implemented on episomes, which are thought to lack physiological chromatin. However, the magnitude and determinants of differences in cis-regulation for regulatory sequences residing in episomes versus chromosomes remain almost completely unknown. To address this systematically, we developed and applied a novel lentivirus-based massively parallel reporter assay (lentiMPRA) to directly compare the functional activities of 2236 candidate liver enhancers in an episomal versus a chromosomally integrated context. We find that the activities of chromosomally integrated sequences are substantially different from the activities of the identical sequences assayed on episomes, and furthermore are correlated with different subsets of ENCODE annotations. The results of chromosomally based reporter assays are also more reproducible and more strongly predictable by both ENCODE annotations and sequence-based models. With a linear model that combines chromatin annotations and sequence information, we achieve a Pearson's R

Indexed as

ChromatinChromatin Assembly and DisassemblyChromosomesEnhancer Elements, GeneticGene Expression RegulationGenes, ReporterHigh-Throughput Nucleotide SequencingHumansPlasmidsPromoter Regions, GeneticRegulatory Sequences, Nucleic AcidTranscription FactorsChromatinTranscription Factors

Identifiers

PMID27831498
PMCPMC5204343

What OpenQuestion holds

Textmetadata
LicenceCC BY-NC
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.