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Cell. Author manuscript; available in PMC 2009 February 8.
Published in final edited form as:
Cell. 2008 August 8; 134(3): 521–533.
doi: 10.1016/j.cell.2008.07.020.
PMCID: PMC2586071
NIHMSID: NIHMS65551
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Connecting microRNA genes to the core transcriptional regulatory circuitry of embryonic stem cells
Alexander Marson,1,2* Stuart S. Levine,1* Megan F. Cole,1,2 Garrett M. Frampton,1,2 Tobias Brambrink,1 Sarah Johnstone,1,2 Matthew G. Guenther,1 Wendy K. Johnston,1,3 Marius Wernig,1 Jamie Newman,1,2 J. Mauro Calabrese,2,4 Lucas M. Dennis,1,2 Thomas L. Volkert,1 Sumeet Gupta,1 Jennifer Love,1 Nancy Hannett,1 Phillip A. Sharp,2,4 David P. Bartel,1,2,3 Rudolf Jaenisch,1,2 and Richard A. Young1,2
1Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA
2Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts 02139, USA
3Howard Hughes Medical Insititute, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts 02139, USA
4Koch Institute, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts 02139
*These authors contributed equally to this work
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SUMMARY
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 a new map of the transcriptional regulatory circuitry of ES cells that incorporates both protein-coding and miRNA genes, and which is 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 most 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 expressed in a tissue-specific fashion in differentiated cells. These data reveal how key ES cell transcription factors promote the miRNA expression program that contributes to normal self-renewal and cellular differentiation, and integrate miRNAs and their targets into an expanded model of the regulatory circuitry controlling ES cell identity.

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