In Vivo Characterization of Linc-p21 Reveals Functional cis-Regulatory DNA Elements

Abigail F. Groff; Diana B. Sanchez-Gomez; Marcela M.L. Soruco; Chiara Gerhardinger; A. Rasim Barutcu; Eric Li; Lara Elcavage; Olivia Plana; Lluvia V. Sanchez; James C. Lee; Martin Sauvageau; John L. Rinn

doi:10.1016/j.celrep.2016.07.050

Cell Reports (Aug 2016)

In Vivo Characterization of Linc-p21 Reveals Functional cis-Regulatory DNA Elements

Abigail F. Groff,
Diana B. Sanchez-Gomez,
Marcela M.L. Soruco,
Chiara Gerhardinger,
A. Rasim Barutcu,
Eric Li,
Lara Elcavage,
Olivia Plana,
Lluvia V. Sanchez,
James C. Lee,
Martin Sauvageau,
John L. Rinn

Affiliations

Abigail F. Groff: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA
Diana B. Sanchez-Gomez: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA
Marcela M.L. Soruco: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA
Chiara Gerhardinger: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA
A. Rasim Barutcu: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA
Eric Li: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA
Lara Elcavage: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA
Olivia Plana: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA
Lluvia V. Sanchez: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA
James C. Lee: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA
Martin Sauvageau: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA
John L. Rinn: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA

DOI: https://doi.org/10.1016/j.celrep.2016.07.050
Journal volume & issue: Vol. 16, no. 8
pp. 2178 – 2186

Abstract

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The Linc-p21 locus, encoding a long non-coding RNA, plays an important role in p53 signaling, cell-cycle regulation, and tumor suppression. However, despite extensive study, confusion exists regarding its mechanism of action: is activity driven by the transcript acting in trans, in cis, or by an underlying functional enhancer? Here, using a knockout mouse model and a massively parallel enhancer assay, we delineate the functional elements at this locus. We observe that, even in tissues with no detectable Linc-p21 transcript, deletion of the locus significantly affects local gene expression, including of the cell-cycle regulator Cdkn1a. To characterize this RNA-independent regulatory effect, we systematically interrogated the underlying DNA sequence for enhancer activity at nucleotide resolution and confirmed the existence of multiple enhancer elements. Together, these data suggest that, in vivo, the cis-regulatory effects mediated by Linc-p21, in the presence or absence of transcription, are due to DNA enhancer elements.

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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