The Histone Demethylase KDM5b/JARID1b Plays a Role in Cell Fate Decisions by Blocking Terminal Differentiation ᰔ †

Stem Cell and Cancer Institute, MDCL Rm. 5030, Faculty of Health Sciences, McMaster University, 1200 Main St. W, Hamilton, ON, Canada.
Molecular and Cellular Biology (Impact Factor: 4.78). 07/2008; 28(17):5312-27. DOI: 10.1128/MCB.00128-08
Source: PubMed


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), 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.

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Available from: Bijan K Dey, Oct 08, 2015
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    • "Our results also support a role for KDM5B in regulating H3K4 methylation at developmental genes during differentiation. Previous studies have shown that lineage-specific genes are underexpressed following EB differentiation of KDM5B-depleted ES cells [25-27]. These studies underscore the importance of KDM5B for differentiation. "
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    ABSTRACT: Pluripotency of embryonic stem (ES) cells is controlled in part by chromatin-modifying factors that regulate histone H3 lysine 4 (H3K4) methylation. However, it remains unclear how H3K4 demethylation contributes to ES cell function. Here, we show that KDM5B, which demethylates lysine 4 of histone H3, co-localizes with H3K4me3 near promoters and enhancers of active genes in ES cells; its depletion leads to spreading of H3K4 methylation into gene bodies and enhancer shores, indicating that KDM5B functions to focus H3K4 methylation at promoters and enhancers. Spreading of H3K4 methylation to gene bodies and enhancer shores is linked to defects in gene expression programs and enhancer activity, respectively, during self-renewal and differentiation of KDM5B-depleted ES cells. KDM5B critically regulates H3K4 methylation at bivalent genes during differentiation in the absence of LIF or Oct4. We also show that KDM5B and LSD1, another H3K4 demethylase, co-regulate H3K4 methylation at active promoters but they retain distinct roles in demethylating gene body regions and bivalent genes. Our results provide global and functional insight into the role of KDM5B in regulating H3K4 methylation marks near promoters, gene bodies, and enhancers in ES cells and during differentiation.
    Genome biology 02/2014; 15(2):R32. DOI:10.1186/gb-2014-15-2-r32 · 10.81 Impact Factor
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    • "A de novo splicing mutation (NM_006618.3, c.283-2A>G) involving KDM5B was identified in trio 2. This gene encodes for a Lysine-specific demethylase 5B protein belonging to the H3K4 demethylase family, involved in cancer progression and playing a role in cell fate decisions [Dey et al., 2008; Shackleton, 2010]. Interestingly, in regard to X-linked variants, three of them were located within members of the Plexins family, "
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    American Journal of Medical Genetics Part A 01/2014; 164(1). DOI:10.1002/ajmg.a.36274 · 2.16 Impact Factor
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    • "Knockdown of PLU1 or MRG15 increased intragenic H3K4me3 that produces cryptic intragenic transcription and inhibited the transcriptional elongation [145]. Another study showed that constitutive overexpression of PLU1 blocked neural terminal differentiation [146]. On the contrary, Schmitz et al. has provided evidence that PLU1 is required for the neural differentiation of ES cells but is dispensable for self-renewal [147]. "
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    ABSTRACT: Epigenetic mechanisms are fundamental to understanding the regulatory networks of gene expression that govern stem cell maintenance and differentiation. Methylated histone H3 lysine 4 (H3K4) has emerged as a key epigenetic signal for gene transcription; it is dynamically modulated by several specific H3K4 methyltransferases and demethylases. Recent studies have described new epigenetic mechanisms by which H3K4 methylation modifiers control self-renewal and lineage commitments of stem cells. Such advances in stem cell biology would have a high impact on the research fields of cancer stem cell and regenerative medicine. In this review, we discuss the recent progress in understanding the roles of H3K4 methylation modifiers in regulating embryonic and adult stem cells’ fates.
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