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Molecular and Cellular Biology, September 2008, p. 5312-5327, Vol. 28, No. 17
0270-7306/08/$08.00+0     doi:10.1128/MCB.00128-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

The Histone Demethylase KDM5b/JARID1b Plays a Role in Cell Fate Decisions by Blocking Terminal Differentiation {triangledown} ,{dagger}

Bijan K. Dey,1 Leanne Stalker,1,2 Angelique Schnerch,1,2 Mickie Bhatia,1,2 Joyce Taylor-Papidimitriou,3 and Christopher Wynder1,2*

Stem Cell and Cancer Research Institute, McMaster University, Hamilton, Ontario, Canada L8N 3Z5,1 Department of Biochemistry and Biomedical Sciences, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada L8N 3Z5,2 Kings College Medical School, Breast Cancer Biology Lab, 3rd floor Thomas Guy House, Guys Hospital, London SE1 9RT, United Kingdom3

Received 23 January 2008/ Returned for modification 5 April 2008/ Accepted 20 June 2008

The histone demethylase lysine demethylase 5b (KDM5b) specifically demethylates lysine 4 of histone H3 (meH3K4), thereby repressing gene transcription. KDM5b regulates cell cycle control genes in cancer and is expressed in the early epiblast. This suggests that KDM5b plays a developmental role by maintaining uncommitted progenitors. Here we show that transient overexpression of KDM5b in embryonic stem cells decreases the expression of at least three different modulators of cell fate decisions, Egr1, p27KIP1, and BMI1, by demethylation of their promoters. Constitutively increased KDM5b expression results in an increased mitotic rate and a decreased global 3meH3K4 but no change in cell identity. Results of two separate differentiation assays, neural differentiation and embryoid body EB (EB) formation, showed that KDM5b reduced the terminally differentiated cells and increased proliferating progenitors. These were achieved by two mechanisms, blocking of the upregulation of cell lineage markers and maintenance of cyclins, that allowed cells to escape differentiation and remain uncommitted. Additionally, EBs maintain high levels of Oct4 and Nanog and can be dissociated to reestablish highly proliferative cultures. The persistence of uncommitted progenitors may be due to the direct regulation of the Tcf/Lef family member mTcf3/hTcf7L1, an upstream regulator of Nanog expression. These findings demonstrate a role for KDM5b in the choice between proliferation and differentiation during development.

* Corresponding author. Mailing address: Stem Cell and Cancer Institute, MDCL Rm. 5030, Faculty of Health Sciences, McMaster University, 1200 Main St. W, Hamilton, ON, Canada L8N 3Z5. Phone: (905) 525-9140, ext. 28649. Fax: (905) 522-7772. E-mail: wynderc{at}mcmaster.ca

{triangledown} Published ahead of print on 30 June 2008.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, September 2008, p. 5312-5327, Vol. 28, No. 17
0270-7306/08/$08.00+0     doi:10.1128/MCB.00128-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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