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LSD1 regulates the balance between self-renewal and differentiation in human embryonic stem cells

Nature Cell Biology volume 13, pages 652–659 (2011)Cite this article

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Abstract

We identify LSD1 (lysine-specific demethylase 1; also known as KDM1A and AOF2) as a key histone modifier that participates in the maintenance of pluripotency through the regulation of bivalent domains, a chromatin environment present at the regulatory regions of developmental genes that contains both H3K4 di/trimethylation and H3K27 trimethylation marks. LSD1 occupies the promoters of a subset of developmental genes that contain bivalent domains and are co-occupied by OCT4 and NANOG in human embryonic stem cells, where it controls the levels of H3K4 methylation through its demethylase activity. Thus, LSD1 has a role in maintaining the silencing of several developmental genes in human embryonic stem cells by regulating the critical balance between H3K4 and H3K27 methylation at their regulatory regions.

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Figure 1: LSD1 knockdown causes differentiation of human embryonic stem cells.
Figure 2: LSD1 knockdown causes the induction of developmental gene expression.
Figure 3: LSD1 enzymatic activity is essential to maintain its repressive potential.
Figure 4: The BMP2 pathway partially mediates the effects of LSD1 knockdown in human embryonic stem cells.
Figure 5: LSD1 knockdown causes earlier differentiation of human embryonic stem cells.
Figure 6: LSD1 knockdown causes an increase in the levels of H3K4 tri- and dimethylation at target genes, where it is recruited independently of REST (NRSF).
Figure 7: LSD1 overlaps with OCT4 and NANOG on genes preferably containing bivalent domains.

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Acknowledgements

We thank S. Malik and I. Martinez for critical reading of the manuscript, D. Trono for plasmids pLVTHM and psPAX2, T. Pratt for plasmid pTP6, A. Consiglio for assistance with viral preparations and infection, R. Vassena, I. Rodriguez and A. Sanchez for help with the differentiation experiments, B. Christen for advice on cell treatments and V. Astro for assistance with movie preparation. M.J.B. was partially supported by the Ramón y Cajal programme. B.S. is a predoctoral fellow from the Ministerio de Ciencia e Innovación of Spain. This work was partially supported by grants RYC-2007-01510 and SAF2009-08588 from the Ministerio de Ciencia e Innovación of Spain to M.J.B. and grants from the G. Harold and Leila Y. Mathers Charitable Foundation, Sanofi-Aventis, MICINN, CIBER and Fundacion Cellex to J.C.I.B.

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Authors and Affiliations

  1. Center of Regenerative Medicine in Barcelona, Dr. Aiguader, 88, 08003 Barcelona, Spain

    Antonio Adamo, Borja Sesé, Stephanie Boue, Julio Castaño, Ida Paramonov, Maria J. Barrero & Juan Carlos Izpisua Belmonte

  2. Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA

    Juan Carlos Izpisua Belmonte

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Contributions

A.A. set up techniques, designed and carried out the experiments with the assistance of B.S., J.C. and M.J.B. and wrote the paper. S.B. and I.P. carried out the bioinformatics analysis. M.J.B. conceived and supervised the project and wrote the paper. J.C.I.B. supervised the project and wrote the paper.

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Correspondence to Juan Carlos Izpisua Belmonte.

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Adamo, A., Sesé, B., Boue, S. et al. LSD1 regulates the balance between self-renewal and differentiation in human embryonic stem cells. Nat Cell Biol 13, 652–659 (2011). https://doi.org/10.1038/ncb2246

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