Biological Sciences Division
Published December 27, 2017 | Version v1
Journal article Open

Transcription-factor-dependent enhancer transcription defines a gene regulatory network for cardiac rhythm

Creators

  • 1. University of Chicago
  • 2. University Medical Center Utrecht
  • 3. Duke University

Description

The noncoding genome is pervasively transcribed. Noncoding RNAs (ncRNAs) generated from enhancers have been proposed as a general facet of enhancer function and some have been shown to be required for enhancer activity. Here we examine the transcription-factor- (TF)-dependence of ncRNA expression to define enhancers and enhancer-associated ncRNAs that are involved in a TF-dependent regulatory network. TBX5, a cardiac TF, regulates a network of cardiac channel genes to maintain cardiac rhythm. We deep sequenced wildtype and Tbx5-mutant mouse atria, identifying ~2600 novel Tbx5-dependent ncRNAs. Tbx5-dependent ncRNAs were enriched for tissue-specific marks of active enhancers genome-wide. Tbx5-dependent ncRNAs emanated from regions that are enriched for TBX5-binding and that demonstrated Tbx5- dependent enhancer activity. Tbx5-dependent ncRNA transcription provided a quantitative metric of Tbx5-dependent enhancer activity, correlating with target gene expression. We identified RACER, a novel Tbx5-dependent long noncoding RNA (lncRNA) required for the expression of the calcium-handling gene Ryr2. We illustrate that TF-dependent enhancer transcription can illuminate components of TF-dependent gene regulatory networks.

Data availability

The following previously published data sets were used:

He A Gu F Hu Y Ma Q Ye L Visel A Pennacchio LA Pu WT (2014) Reinstatement of developmental stage-specific GATA4 enhancers controls the gene expression program in heart disease Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE52123). https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE52123

Kong S He A Pu WT (2011) Cardiac transcription factors in HL-1 cells: gene expression and genome binding profiling Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE21529). https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE21529

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Additional details

Identifiers

DOI
10.7554/eLife.31683
Other
oai:uchicago.tind.io:9996

Funding

National Institutes of Health
National Institutes of Health
R21LM012619
National Institutes of Health
F30HL131298
Fondation Leducq
American Heart Association
National Institutes of Health
R01 HL092153
National Institutes of Health
R01HL124836
National Institutes of Health
R33 HL123857

UChicago Information

Division(s)
Biological Sciences Division
Department(s)
Biochemistry and Molecular Biology, Human Genetics, Molecular Genetics and Cell Biology, Pathology, Pediatrics