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Conserved long noncoding RNAs transcriptionally regulated by Oct4 and Nanog modulate pluripotency in mouse embryonic stem cells

Mohamed, Jameelah Sheik; Gaughwin, Philip LU ; Lim, Bing; Robson, Paul and Lipovich, Leonard (2010) In RNA 16(2). p.324-337
Abstract
The genetic networks controlling stem cell identity are the focus of intense interest, due to their obvious therapeutic potential as well as exceptional relevance to models of early development. Genome-wide mapping of transcriptional networks in mouse embryonic stem cells (mESCs) reveals that many endogenous noncoding RNA molecules, including long noncoding RNAs (lncRNAs), may play a role in controlling the pluripotent state. We performed a genome-wide screen that combined full-length mESC transcriptome genomic mapping data with chromatin immunoprecipitation genomic location maps of the key mESC transcription factors Oct4 and Nanog. We henceforth identified four mESC-expressed, conserved lncRNA-encoding genes residing proximally to active... (More)
The genetic networks controlling stem cell identity are the focus of intense interest, due to their obvious therapeutic potential as well as exceptional relevance to models of early development. Genome-wide mapping of transcriptional networks in mouse embryonic stem cells (mESCs) reveals that many endogenous noncoding RNA molecules, including long noncoding RNAs (lncRNAs), may play a role in controlling the pluripotent state. We performed a genome-wide screen that combined full-length mESC transcriptome genomic mapping data with chromatin immunoprecipitation genomic location maps of the key mESC transcription factors Oct4 and Nanog. We henceforth identified four mESC-expressed, conserved lncRNA-encoding genes residing proximally to active genomic binding sites of Oct4 and Nanog. Accordingly, these four genes have potential roles in pluripotency. We show that two of these lncRNAs, AK028326 (Oct4-activated) and AK141205 (Nanog-repressed), are direct targets of Oct4 and Nanog. Most importantly, we demonstrate that these lncRNAs are not merely controlled by mESC transcription factors, but that they themselves regulate developmental state: knockdown and overexpression of these transcripts lead to robust changes in Oct4 and Nanog mRNA levels, in addition to alterations in cellular lineage-specific gene expression and in the pluripotency of mESCs. We further characterize AK028326 as a co-activator of Oct4 in a regulatory feedback loop. These results for the first time implicate lncRNAs in the modulation of mESC pluripotency and expand the established mESC regulatory network model to include functional lncRNAs directly controlled by key mESC transcription factors. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Gomafu, differentiation, ncRNA, mouse embryonic stem cells/mESCs, RNCR2, C18ORF22
in
RNA
volume
16
issue
2
pages
324 - 337
publisher
Cold Spring Harbor Laboratory Press
external identifiers
  • wos:000273868900010
  • scopus:75149163987
ISSN
1355-8382
DOI
10.1261/rna.1441510
language
English
LU publication?
yes
id
2dc78e56-0d9d-41ea-b03b-189a57d64f4a (old id 1547164)
date added to LUP
2010-02-24 11:02:44
date last changed
2018-07-15 03:43:09
@article{2dc78e56-0d9d-41ea-b03b-189a57d64f4a,
  abstract     = {The genetic networks controlling stem cell identity are the focus of intense interest, due to their obvious therapeutic potential as well as exceptional relevance to models of early development. Genome-wide mapping of transcriptional networks in mouse embryonic stem cells (mESCs) reveals that many endogenous noncoding RNA molecules, including long noncoding RNAs (lncRNAs), may play a role in controlling the pluripotent state. We performed a genome-wide screen that combined full-length mESC transcriptome genomic mapping data with chromatin immunoprecipitation genomic location maps of the key mESC transcription factors Oct4 and Nanog. We henceforth identified four mESC-expressed, conserved lncRNA-encoding genes residing proximally to active genomic binding sites of Oct4 and Nanog. Accordingly, these four genes have potential roles in pluripotency. We show that two of these lncRNAs, AK028326 (Oct4-activated) and AK141205 (Nanog-repressed), are direct targets of Oct4 and Nanog. Most importantly, we demonstrate that these lncRNAs are not merely controlled by mESC transcription factors, but that they themselves regulate developmental state: knockdown and overexpression of these transcripts lead to robust changes in Oct4 and Nanog mRNA levels, in addition to alterations in cellular lineage-specific gene expression and in the pluripotency of mESCs. We further characterize AK028326 as a co-activator of Oct4 in a regulatory feedback loop. These results for the first time implicate lncRNAs in the modulation of mESC pluripotency and expand the established mESC regulatory network model to include functional lncRNAs directly controlled by key mESC transcription factors.},
  author       = {Mohamed, Jameelah Sheik and Gaughwin, Philip and Lim, Bing and Robson, Paul and Lipovich, Leonard},
  issn         = {1355-8382},
  keyword      = {Gomafu,differentiation,ncRNA,mouse embryonic stem cells/mESCs,RNCR2,C18ORF22},
  language     = {eng},
  number       = {2},
  pages        = {324--337},
  publisher    = {Cold Spring Harbor Laboratory Press},
  series       = {RNA},
  title        = {Conserved long noncoding RNAs transcriptionally regulated by Oct4 and Nanog modulate pluripotency in mouse embryonic stem cells},
  url          = {http://dx.doi.org/10.1261/rna.1441510},
  volume       = {16},
  year         = {2010},
}