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Neighborhood regulation by lncRNA promoters, transcription, and splicing

Engreitz, Jesse M. and Haines, Jenna E. and Munson, Glen and Chen, Jenny and Perez, Elizabeth M. and Kane, Michael and McDonel, Patrick E. and Guttman, Mitchell and Lander, Eric S. (2016) Neighborhood regulation by lncRNA promoters, transcription, and splicing. . (Submitted)

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Mammalian genomes are pervasively transcribed to produce thousands of spliced long noncoding RNAs (lncRNAs), whose functions remain poorly understood. Because recent evidence has implicated several specific lncRNA loci in the local regulation of gene expression, we sought to determine whether such local regulation is a property of many lncRNA loci. We used genetic manipulations to dissect 12 genomic loci that produce lncRNAs and found that 5 of these loci influence the expression of a neighboring gene in cis. Surprisingly, however, none of these effects required the specific lncRNA transcripts themselves and instead involved general processes associated with their production, including enhancer-like activity of gene promoters, the process of transcription, and the splicing of the transcript. Interestingly, such effects are not limited to lncRNA loci: we found similar effects on local gene expression at 4 of 6 protein-coding loci. These results demonstrate that 'crosstalk' among neighboring genes is a prevalent phenomenon that can involve multiple mechanisms and cis regulatory signals, including a novel role for RNA splicing. These mechanisms may explain the function and evolution of some genomic loci that produce lncRNAs.

Item Type:Report or Paper (Discussion Paper)
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URLURL TypeDescription Paper Paper
Engreitz, Jesse M.0000-0002-5754-1719
Chen, Jenny0000-0002-6664-2597
Guttman, Mitchell0000-0003-4748-9352
Lander, Eric S.0000-0003-2662-4631
Additional Information:he copyright holder for this preprint is the author/funder. All rights reserved. No reuse allowed without permission. Posted April 29, 2016. This article is a preprint and has not been peer-reviewed. We thank Shari Grossman, John Rinn, Moran Yassour, Phil Sharp, Laurie Boyer, Millie Ray, Charlie Fulco, Mathias Munschauer, Tim Wang, and Nir Friedman for discussions; Alex Shishkin for technical advice and reagents; and Jason Flannick for computational tools. J.M.E. is supported by the Fannie and John Hertz Foundation and the National Defense Science and Engineering Graduate Fellowship. This work was supported by funds from the Broad Institute (E.S.L.), the NIH Director’s Early Independence Award (DP5OD012190 to M.G.), the Edward Mallinckrodt Foundation (M.G.), the Sontag Foundation (M.G.), and the Searle Scholars Program (M.G.). Author contributions: J.M.E., M.G., and E.S.L. conceived and designed the study. J.M.E., J.E.H., G.M., and P.E.M. developed experimental protocols. J.M.E., J.E.H., G.M., E.M.P., and M.K. performed experiments. J.M.E. developed computational tools and performed data analysis. J.M.E. and J.C. performed evolutionary analysis. J.M.E. and E.S.L. wrote the manuscript with input from all authors.
Funding AgencyGrant Number
Fannie and John Hertz FoundationUNSPECIFIED
National Defense Science and Engineering Graduate (NDSEG) FellowshipUNSPECIFIED
Broad Institute of MIT and HarvardUNSPECIFIED
Edward Mallinckrodt FoundationUNSPECIFIED
Sontag FoundationUNSPECIFIED
Searle Scholars ProgramUNSPECIFIED
Record Number:CaltechAUTHORS:20160513-141401565
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:67089
Deposited By: Ruth Sustaita
Deposited On:16 May 2016 19:30
Last Modified:11 Nov 2021 00:27

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