Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA252502 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR1378340_1.fastq.gz | Fastqsanger.gz | |||
| SRR1378340_2.fastq.gz | Fastqsanger.gz | |||
| SRR1378341_1.fastq.gz | Fastqsanger.gz | |||
| SRR1378341_2.fastq.gz | Fastqsanger.gz | |||
| SRR1378338_1.fastq.gz | Fastqsanger.gz |
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Project description:Histone lysine demethylase JMJD3/KDM6B is required for the establishment of adult hippocampal neurogenesis
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Project description:Recent studies have delineated cancer type-specific roles of histone 3 lysine 27 (H3K27) demethylase KDM6B/JMJD3 depending on its H3K27 demethylase activity. Here we show that KDM6B is expressed in multiple myeloma (MM); and that shRNA-mediated knockdown and CRISPR-mediated knockout of KDM6B abrogate MM cell growth and survival. TNFα or bone marrow stromal cell culture supernatants induce KDM6B, which is blocked by IKKβ inhibitor MLN120B, suggesting KDM6B is regulated by NF-κB signaling in MM cells. RNA-sequencing and subsequent ChIP-qPCR analyses reveal that KDM6B is recruited to the loci of genes encoding components of MAPK signaling pathway including ELK1 and FOS, and upregulates these genes expression without affecting H3K27 methylation level. Overexpression of catalytically-inactive KDM6B activates expression of MAPK pathway-related genes, confirming its function independent of demethylase activity. We further demonstrate that downstream targets of KDM6B, ELK1 and FOS, confer MM cell growth. Our study therefore delineates KDM6B function that links NF-κB and MAPK signaling pathway mediating MM cell growth and survival, and validates KDM6B as a novel therapeutic target in MM.
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Project description:The discovery of the first histone demethylase in 2004 (LSD1/KDM1) opened new avenues for the understanding of how histone methylation impacts cellular functions. A great number of histone demethylases have been identified since, which are potentially linked to gene regulation as well as to stem cell self-renewal and differentiation. KDM6A/UTY and KDM6B/JMJD3 are both H3K27me3/2-specific histone demethylases, which are known to play a central role in regulation of posterior development, by regulating HOX gene expression. So far nothing is known about the role of histone lysine demethylases (KDMs) during early hematopoiesis. We are studying the role of KDM6A and KDM6B on self-renewal, global gene expression and on local and global chromatin states in embryonic stem cells (ESCs) and during differentiation. In order to completely abrogate KDM6 demethylase activity in ESCs we employed a specific inhibitor (GSK-J4, Kruidenier et al. 2012). Treatment of ESCs with GSK-J4 had no effect on viability and proliferation . However, ESC differentiation in the presence of GSK-J4 was completely abrogated. In conclusion we show that ESC differentiation is completely blockend in the absence of any H3K27 demethylase activity. We used microarrays to detail the global gene expression program of genes which are differentially expressed during the early differentiation of ESC derived embryoid bodies (EBs) in the presence of GSK-J4 (KDM6 Inhibitor). ESCs (R1) have been cultured and differentiated in the presence of GSK-J4 a KDM6 specific inhibitor.
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Project description:The histone H3 lysine 27 (H3K27) demethylase Kdm6b (Jmjd3) can promote cellular differentiation, however its physiological functions in neurons remain to be fully determined. We studied the expression and function of Kdm6b in differentiating granule neurons of the developing postnatal mouse cerebellum. At postnatal day 7, Kdm6b is expressed throughout the layers of the developing cerebellar cortex, but its expression is upregulated in newborn cerebellar granule neurons (CGNs). Atoh1-Cre mediated conditional knockout of Kdm6b in CGN precursors either alone or in combination with Kdm6a did not disturb the gross morphological development of the cerebellum. Furthermore, RNAi-mediated knockdown of Kdm6b in cultured CGN precursors did not alter the induced expression of early neuronal marker genes upon cell cycle exit. By contrast, knockdown of Kdm6b significantly impaired the induction of a mature neuronal gene expression program, which includes gene products required for functional synapse maturation. Loss of Kdm6b also impaired the ability of Brain-Derived Neurotrophic Factor (BDNF) to induce expression of Grin2c and Tiam1 in maturing CGNs. Taken together, these data reveal a previously unknown role for Kdm6b in the postmitotic stages of CGN maturation and suggest that Kdm6b may work, at least in part, by a transcriptional mechanism that promotes gene sensitivity to regulation by BDNF.
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Project description:Regulatory T cells (Tregs) expressing Forkhead Box P3 (Foxp3) play crucial roles in maintaining immune tolerance and tissue integrity. Ezh2, a Histone H3 lysine 27 (H3K27) methyltransferase, is known as a crucial regulator of Treg cell identity and suppressive function upon activation, raising a question about whether overactivation of this pathway would further boost Treg cell function. Here, we demonstrate that lysine demethylase Kdm6b catalyzing the reverse reaction to Ezh2 is also required for Treg cell identity and function after activation. Treg-specific deletion of Kdm6b impairs tissue Treg cell fate and function, such as in the lung after injury or adipose tissue during animal aging. Mechanistically, T cell receptor (TCR) signaling upregulates Kdm6b expression and recruits it to Foxp3-bound chromatin to restrict H3K27me3. This antagonism helps suppress the expression of inflammatory cytokines and promote the expression of Treg functional genes, thus supporting tissue Treg cells.
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