Embryonic stem (ES) cells are unique in their ability to self-renew indefinitely and maintain pluripotency. These properties require transcription factors that specify the gene expression programme of ES cells. It has been possible to reverse the highly differentiated state of somatic cells back to a pluripotent state with a combination of four transcription factors: Klf4 is one of the reprogramming factors required, in conjunction with Oct4, Sox2 and c-Myc. Maintenance of self-renewal and pluripotency of ES cells requires Oct4, Sox2 and c-Myc, but Klf4 is dispensable. Here, we show that Krüppel-like factors are required for the self-renewal of ES cells. Simultaneous depletion of Klf2, Klf4 and Klf5 lead to ES cell differentiation. Chromatin immunoprecipitation coupled to microarray assay reveals that these Klf proteins share many common targets of Nanog, suggesting a close functional relationship between these factors. Expression analysis after triple RNA interference (RNAi) of the Klfs shows that they regulate key pluripotency genes, such as Nanog. Taken together, our study provides new insight into how the core Klf circuitry integrates into the Nanog transcriptional network to specify gene expression that is unique to ES cells.

1. Gene Regulation Laboratory, Genome Institute of Singapore, 60 Biopolis Street, #02-01, Genome Building, Singapore 138672.
2. Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, Singapore 117543.
3. Department of Bioengineering, University of Illinois at Urbana-Champaign, 1304 W. Springfield Avenue, Urbana, IL 61801, USA.
4. Stem Cell and Developmental Biology, Genome Institute of Singapore, 60 Biopolis Street, 02-01, Genome Building, Singapore 138672.
5. Department of Obstetrics and Gynecology, Nanjing Maternal and Child Health Care Hospital, Nanjing Medical University, 123 Tian Fei Road, PR China 210004.
6. These authors contributed equally to this work.

Correspondence to: Huck-Hui Ng^1,2 e-mail: nghh@gis.a-star.edu.sg

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