Open AccessThe Histone Demethylase KDM5b/JARID1b Plays a Role in Cell Fate Decisions by Blocking Terminal Differentiation
Author(s) -
Bijan K. Dey,
Leanne Stalker,
Angelique Schnerch,
Mickie Bhatia,
Joyce Taylor-Papidimitriou,
Christopher Wynder
Publication year - 2008
Publication title -
molecular and cellular biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.14
H-Index - 327
eISSN - 1067-8824
pISSN - 0270-7306
DOI - 10.1128/mcb.00128-08
Subject(s) - demethylase , biology , microbiology and biotechnology , homeobox protein nanog , cellular differentiation , histone , cell fate determination , nanog homeobox protein , embryonic stem cell , transcription factor , h3k4me3 , histone methylation , genetics , gene expression , sox2 , dna methylation , promoter , gene , induced pluripotent stem cell
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 ,p27 KIP1 , andBMI1 , 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 ofOct4 andNanog 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 membermTcf3 /hTcf7L1 , an upstream regulator ofNanog expression. These findings demonstrate a role for KDM5b in the choice between proliferation and differentiation during development.