Pluripotency Transcription Factor Oct4 Mediates Stepwise Nucleosome Demethylation and Depletion

Shakya, Arvind; Callister, Catherine; Goren, Alon; Yosef, Nir; Garg, Neha; Khoddami, Vahid; Nix, David A.; Regev, Aviv; Tantin, Dean

doi:10.1128/mcb.01105-14

Cited by 50 publications

(54 citation statements)

References 65 publications

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“…This suggests that FACT was important for keeping these genes in an "off" state by maintaining repressive chromatin. This is consistent with the known role of FACT in activating expression of the HO gene in yeast and the Oct4 gene in mouse cells (Biswas et al 2006;Takahata et al 2009a,b;Shakya et al 2015), where FACT promotes the eviction of specific nucleosomes in promoters prior to activation. However, in contrast to our expectation, the profile of nucleosome occupancy over the promoters of the upregulated class of genes did not change dramatically.…”

Section: Discussionsupporting

confidence: 87%

“…Consistent with this view, FACT can stabilize nucleosomes in vitro (Hsieh et al 2013;Chang et al 2014) and it is needed to restore nucleosome occupancy after transcription (Biswas et al 2007;Fleming et al 2008;Kaplan et al 2008;Ransom et al 2009;Hainer et al 2011Hainer et al , 2012Voth et al 2014;Feng et al 2016). However, FACT also has an established role in ejecting nucleosomes from promoters during transcriptional activation (Biswas et al 2006;Ransom et al 2009;Takahata et al 2009a,b;Shakya et al 2015). FACT can therefore either stabilize or destabilize nucleosomes, depending on the direction of the reorganization reaction being promoted.…”

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confidence: 91%

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Establishment and Maintenance of Chromatin Architecture Are Promoted Independently of Transcription by the Histone Chaperone FACT and H3-K56 Acetylation in Saccharomyces cerevisiae

et al. 2019

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FACT (FAcilitates Chromatin Transcription/Transactions) is a histone chaperone that can destabilize or assemble nucleosomes. Acetylation of histone H3-K56 weakens a histone-DNA contact that is central to FACT activity, suggesting that this modification could affect FACT functions. We tested this by asking how mutations of H3-K56 and FACT affect nucleosome reorganization activity in vitro, and chromatin integrity and transcript output in vivo. Mimics of unacetylated or permanently acetylated H3-K56 had different effects on FACT activity as expected, but the same mutations had surprisingly similar effects on global transcript levels. The results are consistent with emerging models that emphasize FACT's importance in establishing global chromatin architecture prior to transcription, promoting transitions among different states as transcription profiles change, and restoring chromatin integrity after it is disturbed. Optimal FACT activity required the availability of both modified and unmodified states of H3-K56. Perturbing this balance was especially detrimental for maintaining repression of genes with high nucleosome occupancy over their promoters and for blocking antisense transcription at the +1 nucleosome. The results reveal a complex collaboration between H3-K56 modification status and multiple FACT functions, and support roles for nucleosome reorganization by FACT before, during, and after transcription.

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Section: Discussionsupporting

confidence: 87%

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confidence: 91%

Establishment and Maintenance of Chromatin Architecture Are Promoted Independently of Transcription by the Histone Chaperone FACT and H3-K56 Acetylation in Saccharomyces cerevisiae

et al. 2019

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“…Although JMJD1C belongs to KDM3 family that in general catalyzes H3K9 demethylation, multiple independent studies published contradicting results that either succeeded 7,14,15,[22][23][24][25][26] or failed 5,6,[27][28][29] to detect the demethylating activities of JMJD1C at H3K9. Most if not all studies with negative results failed to detect H3K9 demethylating activities of JMJD1C in vitro, whereas studies with positive results detected H3K9 demethylating activities of JMJD1C in vivo using either western blot or chromatin immunoprecipitation assays.…”

Section: Discussionmentioning

confidence: 99%

Small molecular modulators of JMJD1C preferentially inhibit growth of leukemia cells

Wang

et al. 2019

Intl Journal of Cancer

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Histone demethylases are promising therapeutic targets as they play fundamental roles for survival of Mixed lineage leukemia rearranged acute leukemia (MLLr AL). Here we focused on the catalytic Jumonji domain of histone H3 lysine 9 (H3K9) demethylase JMJD1C to screen for potential small molecular modulators from 149,519 natural products and 33,765 Chinese medicine components via virtual screening. JMJD1C Jumonji domain inhibitor 4 (JDI‐4) and JDI‐12 that share a common structural backbone were detected within the top 15 compounds. Surface plasmon resonance analysis showed that JDI‐4 and JDI‐12 bind to JMJD1C and its family homolog KDM3B with modest affinity. In vitro demethylation assays showed that JDI‐4 can reverse the H3K9 demethylation conferred by KDM3B. In vivo demethylation assays indicated that JDI‐4 and JDI‐12 could induce the global increase of H3K9 methylation. Cell proliferation and colony formation assays documented that JDI‐4 and JDI‐12 kill MLLr AL and other malignant hematopoietic cells, but not leukemia cells resistant to JMJD1C depletion or cord blood cells. Furthermore, JDI‐16, among multiple compounds structurally akin to JDI‐4/JDI‐12, exhibits superior killing activities against malignant hematopoietic cells compared to JDI‐4/JDI‐12. Mechanistically, JDI‐16 not only induces apoptosis but also differentiation of MLLr AL cells. RNA sequencing and quantitative PCR showed that JDI‐16 induced gene expression associated with cell metabolism; targeted metabolomics revealed that JDI‐16 downregulates lactic acids, NADP+ and other metabolites. Moreover, JDI‐16 collaborates with all‐trans retinoic acid to repress MLLr AML cells. In summary, we identified bona fide JMJD1C inhibitors that induce preferential death of MLLr AL cells.

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“…In line with the role of LOCKs in the maintenance of differentiated phenotypes, the generation of induced pluripotent stem cells involves the genome-wide reprogramming of DNA methylation and histone modifications 75 . Reprogramming of chromatin states are induced in part by the OCT4-mediated recruitment of H3K9me2 histone demethylase and chromatin remodelling complexes 76 .…”

Section: Epigenetic Mediatorsmentioning

confidence: 99%

Epigenetic modulators, modifiers and mediators in cancer aetiology and progression

2016

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This year is the tenth anniversary of the publication in this journal of a model suggesting the existence of ‘tumour progenitor genes’. These genes are epigenetically disrupted at the earliest stages of malignancies, even before mutations, and thus cause altered differentiation throughout tumour evolution. The past decade of discovery in cancer epigenetics has revealed a number of similarities between cancer genes and stem cell reprogramming genes, widespread mutations in epigenetic regulators, and the part played by chromatin structure in cellular plasticity in both development and cancer. In the light of these discoveries, we suggest here a framework for cancer epigenetics involving three types of genes: ‘epigenetic mediators’, corresponding to the tumour progenitor genes suggested earlier; ‘epigenetic modifiers’ of the mediators, which are frequently mutated in cancer; and ‘epigenetic modulators’ upstream of the modifiers, which are responsive to changes in the cellular environment and often linked to the nuclear architecture. We suggest that this classification is helpful in framing new diagnostic and therapeutic approaches to cancer.

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Pluripotency Transcription Factor Oct4 Mediates Stepwise Nucleosome Demethylation and Depletion

Cited by 50 publications

References 65 publications

Establishment and Maintenance of Chromatin Architecture Are Promoted Independently of Transcription by the Histone Chaperone FACT and H3-K56 Acetylation in Saccharomyces cerevisiae

Establishment and Maintenance of Chromatin Architecture Are Promoted Independently of Transcription by the Histone Chaperone FACT and H3-K56 Acetylation in Saccharomyces cerevisiae

Small molecular modulators of JMJD1C preferentially inhibit growth of leukemia cells

Epigenetic modulators, modifiers and mediators in cancer aetiology and progression

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