Connecting microRNA genes to the core transcriptional regulatory circuitry of embryonic stem cells.
MicroRNAs (miRNAs) are crucial for normal embryonic stem (ES) cell self-renewal and cellular differentiation, but how miRNA gene expression is controlled by the key transcriptional regulators of ES cells has not been established. We describe here the transcriptional regulatory circuitry of ES cells that incorporates protein-coding and miRNA genes based on high-resolution ChIP-seq data, systematic identification of miRNA promoters, and quantitative sequencing of short transcripts in multiple cell types. We find that the key ES cell transcription factors are associated with promoters for miRNAs that are preferentially expressed in ES cells and with promoters for a set of silent miRNA genes. This silent set of miRNA genes is co-occupied by Polycomb group proteins in ES cells and shows tissue-specific expression in differentiated cells. These data reveal how key ES cell transcription factors promote the ES cell miRNA expression program and integrate miRNAs into the regulatory circuitry controlling ES cell identity.
Marson
Alexander
A
Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA.
Levine
Stuart S
SS
Cole
Megan F
MF
Frampton
Garrett M
GM
Brambrink
Tobias
T
Johnstone
Sarah
S
Guenther
Matthew G
MG
Johnston
Wendy K
WK
Wernig
Marius
M
Newman
Jamie
J
Calabrese
J Mauro
JM
Dennis
Lucas M
LM
Volkert
Thomas L
TL
Gupta
Sumeet
S
Love
Jennifer
J
Hannett
Nancy
N
Sharp
Phillip A
PA
Bartel
David P
DP
Jaenisch
Rudolf
R
Young
Richard A
RA
D000818:Animals; D053595:Embryonic Stem Cells / Q000378:metabolism*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic
D035683:MicroRNAs; D014157:Transcription Factors