Core Transcriptional Regulatory Circuitry in Human Embryonic Stem Cells

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2005 Sep 13

PMID 16153702

Citations 2095

Authors

Laurie A Boyer

Tong Ihn Lee

Megan F Cole

Sarah E Johnstone

Stuart S Levine

Jacob P Zucker

Matthew G Guenther

Roshan M Kumar

Heather L Murray

Richard G Jenner

David K Gifford

Douglas A Melton

Rudolf Jaenisch

Richard A Young

Affiliations

Soon will be listed here.

Abstract

The transcription factors OCT4, SOX2, and NANOG have essential roles in early development and are required for the propagation of undifferentiated embryonic stem (ES) cells in culture. To gain insights into transcriptional regulation of human ES cells, we have identified OCT4, SOX2, and NANOG target genes using genome-scale location analysis. We found, surprisingly, that OCT4, SOX2, and NANOG co-occupy a substantial portion of their target genes. These target genes frequently encode transcription factors, many of which are developmentally important homeodomain proteins. Our data also indicate that OCT4, SOX2, and NANOG collaborate to form regulatory circuitry consisting of autoregulatory and feedforward loops. These results provide new insights into the transcriptional regulation of stem cells and reveal how OCT4, SOX2, and NANOG contribute to pluripotency and self-renewal.

Citing Articles

Structure-function relationship of ASH1L and histone H3K36 and H3K4 methylation.

Vann K, Sharma R, Hsu C, Devoucoux M, Tencer A, Zeng L Nat Commun. 2025; 16(1):2235.

PMID: 40044670 PMC: 11883000. DOI: 10.1038/s41467-025-57556-5.

Unveiling distinctions between mesenchymal stromal cells and stem cells by single-cell transcriptomic analysis.

Yan K, Ma F, Song X, Wang H, Liu P, Zhang J Heliyon. 2025; 11(4):e42311.

PMID: 40034318 PMC: 11872483. DOI: 10.1016/j.heliyon.2025.e42311.

Key roles of ubiquitination in regulating critical regulators of cancer stem cell functionality.

Guo Q, Qin H, Chen Z, Zhang W, Zheng L, Qin T Genes Dis. 2025; 12(3):101311.

PMID: 40034124 PMC: 11875185. DOI: 10.1016/j.gendis.2024.101311.

Enhancer reprogramming: critical roles in cancer and promising therapeutic strategies.

Yang J, Zhou F, Luo X, Fang Y, Wang X, Liu X Cell Death Discov. 2025; 11(1):84.

PMID: 40032852 PMC: 11876437. DOI: 10.1038/s41420-025-02366-3.

Pluripotency factor Tex10 finetunes Wnt signaling for spermatogenesis and primordial germ cell development.

Yuan F, Yang J, Ma F, Hu Z, Malik V, Zang R Nat Commun. 2025; 16(1):1900.

PMID: 39988597 PMC: 11847947. DOI: 10.1038/s41467-025-57165-2.

References

Milo R, Itzkovitz S, Kashtan N, Chklovskii D, Alon U . Network motifs: simple building blocks of complex networks. Science. 2002; 298(5594):824-7. DOI: 10.1126/science.298.5594.824. View

Rodda D, Chew J, Lim L, Loh Y, Wang B, Ng H . Transcriptional regulation of nanog by OCT4 and SOX2. J Biol Chem. 2005; 280(26):24731-7. DOI: 10.1074/jbc.M502573200. View

Avilion A, Nicolis S, Pevny L, Perez L, Vivian N, Lovell-Badge R . Multipotent cell lineages in early mouse development depend on SOX2 function. Genes Dev. 2003; 17(1):126-40. PMC: 195970. DOI: 10.1101/gad.224503. View

Bortvin A, Eggan K, Skaletsky H, Akutsu H, Berry D, Yanagimachi R . Incomplete reactivation of Oct4-related genes in mouse embryos cloned from somatic nuclei. Development. 2003; 130(8):1673-80. DOI: 10.1242/dev.00366. View

Mitsui K, Tokuzawa Y, Itoh H, Segawa K, Murakami M, Takahashi K . The homeoprotein Nanog is required for maintenance of pluripotency in mouse epiblast and ES cells. Cell. 2003; 113(5):631-42. DOI: 10.1016/s0092-8674(03)00393-3. View

Chambers I, Colby D, Robertson M, Nichols J, Lee S, Tweedie S . Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells. Cell. 2003; 113(5):643-55. DOI: 10.1016/s0092-8674(03)00392-1. View

He J, Tegen S, Krawitz A, Martin G, Luo K . The transforming activity of Ski and SnoN is dependent on their ability to repress the activity of Smad proteins. J Biol Chem. 2003; 278(33):30540-7. DOI: 10.1074/jbc.M304016200. View

Sato N, Sanjuan I, Heke M, Uchida M, Naef F, Brivanlou A . Molecular signature of human embryonic stem cells and its comparison with the mouse. Dev Biol. 2003; 260(2):404-13. DOI: 10.1016/s0012-1606(03)00256-2. View

Mangan S, Alon U . Structure and function of the feed-forward loop network motif. Proc Natl Acad Sci U S A. 2003; 100(21):11980-5. PMC: 218699. DOI: 10.1073/pnas.2133841100. View

10.

Mangan S, Zaslaver A, Alon U . The coherent feedforward loop serves as a sign-sensitive delay element in transcription networks. J Mol Biol. 2003; 334(2):197-204. DOI: 10.1016/j.jmb.2003.09.049. View

11.

Castelli-Gair Hombria J, Lovegrove B . Beyond homeosis--HOX function in morphogenesis and organogenesis. Differentiation. 2003; 71(8):461-76. DOI: 10.1046/j.1432-0436.2003.7108004.x. View

12.

Sato N, Meijer L, Skaltsounis L, Greengard P, Brivanlou A . Maintenance of pluripotency in human and mouse embryonic stem cells through activation of Wnt signaling by a pharmacological GSK-3-specific inhibitor. Nat Med. 2004; 10(1):55-63. DOI: 10.1038/nm979. View

13.

Bartel D . MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004; 116(2):281-97. DOI: 10.1016/s0092-8674(04)00045-5. View

14.

Thieffry D, Salgado H, Huerta A, Collado-Vides J . Prediction of transcriptional regulatory sites in the complete genome sequence of Escherichia coli K-12. Bioinformatics. 1998; 14(5):391-400. DOI: 10.1093/bioinformatics/14.5.391. View

15.

Thomson J, Itskovitz-Eldor J, Shapiro S, Waknitz M, Swiergiel J, Marshall V . Embryonic stem cell lines derived from human blastocysts. Science. 1998; 282(5391):1145-7. DOI: 10.1126/science.282.5391.1145. View

16.

Nichols J, Zevnik B, Anastassiadis K, Niwa H, Chambers I, Scholer H . Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4. Cell. 1998; 95(3):379-91. DOI: 10.1016/s0092-8674(00)81769-9. View

17.

Nishimoto M, Fukushima A, Okuda A, Muramatsu M . The gene for the embryonic stem cell coactivator UTF1 carries a regulatory element which selectively interacts with a complex composed of Oct-3/4 and Sox-2. Mol Cell Biol. 1999; 19(8):5453-65. PMC: 84387. DOI: 10.1128/MCB.19.8.5453. View

18.

Ma H, Kumar B, Ditges U, Gunzer F, Buer J, Zeng A . An extended transcriptional regulatory network of Escherichia coli and analysis of its hierarchical structure and network motifs. Nucleic Acids Res. 2004; 32(22):6643-9. PMC: 545451. DOI: 10.1093/nar/gkh1009. View

19.

Lee J, Hart S, Skalnik D . Histone deacetylase activity is required for embryonic stem cell differentiation. Genesis. 2004; 38(1):32-8. DOI: 10.1002/gene.10250. View

20.

Abeyta M, Clark A, Rodriguez R, Bodnar M, Pera R, Firpo M . Unique gene expression signatures of independently-derived human embryonic stem cell lines. Hum Mol Genet. 2004; 13(6):601-8. DOI: 10.1093/hmg/ddh068. View