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

Xinan H Yang; Rangarajan D Nadadur; Catharina Re Hilvering; Valerio Bianchi; Michael Werner; Stefan R Mazurek; Margaret Gadek; Kaitlyn M Shen; Joseph Aaron Goldman; Leonid Tyan; Jenna Bekeny; Johnathan M Hall; Nutishia Lee; Carlos Perez-Cervantes; Ozanna Burnicka-Turek; Kenneth D Poss; Christopher R Weber; Wouter de Laat; Alexander J Ruthenburg; Ivan P Moskowitz

doi:10.7554/eLife.31683

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

Xinan H Yang, Rangarajan D Nadadur, Catharina Re Hilvering, Valerio Bianchi, Michael Werner, Stefan R Mazurek, Margaret Gadek, Kaitlyn M Shen, Joseph Aaron Goldman, Leonid Tyan, Jenna Bekeny, Johnathan M Hall, Nutishia Lee, Carlos Perez-Cervantes, Ozanna Burnicka-Turek, Kenneth D Poss, Christopher R Weber, Wouter de Laat, Alexander J Ruthenburg, Ivan P Moskowitz

Hubrecht Institute

Research output: Contribution to journal/periodical › Article › Scientific › peer-review

30 Citations (Scopus)

Abstract

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.

Original language	English
Journal	eLife
Volume	6
DOIs	https://doi.org/10.7554/eLife.31683
Publication status	Published - 27 Dec 2017

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Journal Article

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10.7554/eLife.31683

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Yang, X. H., Nadadur, R. D., Hilvering, C. R., Bianchi, V., Werner, M., Mazurek, S. R., Gadek, M., Shen, K. M., Goldman, J. A., Tyan, L., Bekeny, J., Hall, J. M., Lee, N., Perez-Cervantes, C., Burnicka-Turek, O., Poss, K. D., Weber, C. R., de Laat, W., Ruthenburg, A. J., & Moskowitz, I. P. (2017). Transcription-factor-dependent enhancer transcription defines a gene regulatory network for cardiac rhythm. eLife, 6. https://doi.org/10.7554/eLife.31683

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title = "Transcription-factor-dependent enhancer transcription defines a gene regulatory network for cardiac rhythm",

abstract = "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.",

keywords = "Journal Article",

author = "Yang, {Xinan H} and Nadadur, {Rangarajan D} and Hilvering, {Catharina Re} and Valerio Bianchi and Michael Werner and Mazurek, {Stefan R} and Margaret Gadek and Shen, {Kaitlyn M} and Goldman, {Joseph Aaron} and Leonid Tyan and Jenna Bekeny and Hall, {Johnathan M} and Nutishia Lee and Carlos Perez-Cervantes and Ozanna Burnicka-Turek and Poss, {Kenneth D} and Weber, {Christopher R} and {de Laat}, Wouter and Ruthenburg, {Alexander J} and Moskowitz, {Ivan P}",

year = "2017",

month = dec,

day = "27",

doi = "10.7554/eLife.31683",

language = "English",

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Yang, XH, Nadadur, RD, Hilvering, CR, Bianchi, V, Werner, M, Mazurek, SR, Gadek, M, Shen, KM, Goldman, JA, Tyan, L, Bekeny, J, Hall, JM, Lee, N, Perez-Cervantes, C, Burnicka-Turek, O, Poss, KD, Weber, CR, de Laat, W, Ruthenburg, AJ & Moskowitz, IP 2017, 'Transcription-factor-dependent enhancer transcription defines a gene regulatory network for cardiac rhythm', eLife, vol. 6. https://doi.org/10.7554/eLife.31683

TY - JOUR

T1 - Transcription-factor-dependent enhancer transcription defines a gene regulatory network for cardiac rhythm

AU - Yang, Xinan H

AU - Nadadur, Rangarajan D

AU - Hilvering, Catharina Re

AU - Bianchi, Valerio

AU - Werner, Michael

AU - Mazurek, Stefan R

AU - Gadek, Margaret

AU - Shen, Kaitlyn M

AU - Goldman, Joseph Aaron

AU - Tyan, Leonid

AU - Bekeny, Jenna

AU - Hall, Johnathan M

AU - Lee, Nutishia

AU - Perez-Cervantes, Carlos

AU - Burnicka-Turek, Ozanna

AU - Poss, Kenneth D

AU - Weber, Christopher R

AU - de Laat, Wouter

AU - Ruthenburg, Alexander J

AU - Moskowitz, Ivan P

PY - 2017/12/27

Y1 - 2017/12/27

N2 - 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.

AB - 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.

KW - Journal Article

U2 - 10.7554/eLife.31683

DO - 10.7554/eLife.31683

M3 - Article

C2 - 29280435

SN - 2050-084X

VL - 6

JO - eLife

JF - eLife

ER -

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

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