Pleiotropic Functions of H3K27Me3 Demethylases in Immune Cell Differentiation

Bosselut, Rémy

doi:10.1016/j.it.2015.12.004

Cited by 43 publications

(38 citation statements)

References 86 publications

(139 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The recent demonstration that MPMs are in fact polyclonal tumors formed by the coalescence of different independent subclones highlights the need for new therapeutic approaches, as each clone may carry its own distinct set of molecular alterations, and the intratumoral heterogeneity arising may allow for the emergence of drug-resistant subpopulations, and as such multi-targeted approaches to therapy may be required to overcome the issue of clonality (37). EZH2 is associated with the H3K27me3 histone post-translational modification mark common to silenced chromatin or bivalent 'poised' promoters (20,38). The lysine demethylases that catalyze the removal of this mark have been identified as Kdm6a (Utx) and Kdm6b (Jmjd3).…”

Section: Discussionmentioning

confidence: 99%

“…In a recent analysis of MPM, a subset of genes was found to be silenced by histone H3 lysine 27 trimethylation (H3K27me3), a mark most often found at or near the promoters of silent genes (20,21). Polycomb repressive complex 2 (PRC2) catalyses tri-methylation of Histone H3 at lysine 27 (H3K27me2/3) (22), and contains the lysine methyltransferase EZH2.…”

Section: Introductionmentioning

confidence: 99%

“…The proteins which demethylate H3K27me3 have been collectively identified as the Kdm6 family (20) and include Kdm6a (also known as Utx) and Kdm6b (also known as JMJD3) both of which have been shown to catalyze the demethylation of H3K27me3 (25,26). The roles of these demethylases in cancer are less well defined.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Kdm6a and Kdm6b: Altered expression in malignant pleural mesothelioma

Cregan

Breslin

Roche

et al. 2017

International Journal of Oncology

View full text Add to dashboard Cite

Malignant pleural mesothelioma (MPM) is a rare aggressive cancer of the pleura primarily associated with prior exposure to asbestos. The current standard of care for patients suffering from MPM is a combination of cisplatin and pemetrexed (or alternatively cisplatin and raltitrexed). Most patients, however, die within 24 months of diagnosis. New therapies are therefore urgently required for this disease. Inflammation is thought to be a key element in the pathogenesis of MPM, and recently Kdm6 family members (Kdm6a and Kdm6b) have been identified as playing important roles in inflammatory processes. As such these genes could potentially represent novel candidate targets for intervention in MPM. Using RT-PCR we examined the expression of Kdm6aA and Kdm6b in a panel of MPM cell lines and in a cohort of snap-frozen patient samples isolated at surgery comprising benign, epithelial, biphasic and sarcomatoid histologies. Both Kdm6a and Kdm6b were found to be significantly overexpressed in MPM at the mRNA level. However, tests examining if targeting therapeutically Kdm6a/b using a specific small molecule inhibitor (GSK-J4) was potentially useful for treating MPM, revealed that anti-proliferative activity was higher at lower drug concentrations in cell lines derived from normal mesothelial cells compared to those derived from malignant cells. Treatments with GSK-J4 were found to be associated with the induction of apoptosis and increased expression of pro-inflammatory cytokines. As such our results demonstrate that whilst members of the Kdm6 family are overexpressed in MPM they may not be suitable candidates for therapy and may elicit a cytokine storm.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Kdm6a and Kdm6b: Altered expression in malignant pleural mesothelioma

Cregan

Breslin

Roche

et al. 2017

International Journal of Oncology

View full text Add to dashboard Cite

show abstract

“…Strikingly, HP1 promotes tumor suppressor BRCA1 functions during the DNA damage response [36]. The trimethylation of histone H3 lysine 27 (H3K27me3) contributes to gene repression [37]. NF-κB is involved in inflammation and tumor growth [38].…”

Section: Discussionmentioning

confidence: 99%

Inflammatory related gene IKKα, IKKβ, IKKγ cooperates to determine liver cancer stem cells progression by altering telomere via heterochromatin protein 1-HOTAIR axis

Xin

et al. 2016

Oncotarget

View full text Add to dashboard Cite

Cancer stem cells are associated with tumor recurrence. IKK is a protein kinase that is composed of IKKα, IKKβ, IKKγ. Herein, we demonstrate that IKKα plus IKKβ promoted and IKKγ inhibited liver cancer stem cell growth in vitro and in vivo. Mechanistically, IKKα plus IKKβ enhanced and IKKγ inhibited the interplay among HP1α, HP1β and HP1γ that competes for the interaction among HP1α, SUZ12, HEZ2. Therefore, IKKα plus IKKβ inhibited and IKKγ enhanced the activity of H3K27 methyltransferase SUZ12 and EZH2, which methylates H3K27 immediately sites on HOTAIR promoter region. Therefore, IKKα plus IKKβ increased and IKKγ decreased the HOTAIR expression. Strikingly, IKKα plus IKKβ decreases and IKKγ increases the HP1α interplays with DNA methyltransferase DNMT3b, which increases or decreases TERRA promoter DNA methylation. Thus IKKα plus IKKβ reduces and IKKγ increases to recruit TRF1 and RNA polymerase II deposition and elongation on the TERRA promoter locus, which increases or decreases TERRA expression. Furthermore, IKKα plus IKKβ decreases/increases and IKKγ increases/decreases the interplay between TERT and TRRRA/between TERT and TREC. Ultimately, IKKα plus IKKβ increases and IKKγ decreases the telomerase activity. On the other hand, at the telomere locus, IKKα plus IKKβ increases/drcreases and IKKγ decreases/increases TRF2, POT1, pPOT1, Exo1, pExo1, SNM1B, pSNM1B/CST-AAF binding, which keep active telomere regulatory genes and poised for telomere length. Strikingly, HOTAIR is required for IKKα plus IKKβ and IKKγ to control telomerase activity and telomere length. These observations suggest that HOTAIR operates the action of IKKα, IKKβ, IKKγ in liver cancer stem cells. This study provides a novel basis to elucidate the oncogenic action of IKKα, IKKβ, IKKγ and prompts that IKKα, IKKβ, IKKγ cooperate to HOTAR to be used as a novel therapeutic targets for liver cancer.

show abstract

“…We were interested in the mechanism by which deoxycholate or C. scindens increased GMPs. Due to the persistent nature of immunity to E. histolytica following bone marrow transplant we examined the epigenetic mediator JMJD3 (21,29) . C. scindens colonization or deoxycholate administration increased expression of JMJD3 specifically in sorted GMPs (Figure 3 A, QPCR of sorted marrow GMPs demonstrated that genes associated with histone H3, including the demethylase JMJD3 are enriched in mice exposed to C. scindens (Figure S3 A, B, C,).…”

Section: Main Textmentioning

confidence: 99%

Gut microbiome communication with bone marrow regulates susceptibility to amebiasis

Burgess

Leslie

Uddin

et al. 2018

Preprint

View full text Add to dashboard Cite

AbstractThe gut microbiome provides resistance to infection. However, the mechanisms for this are poorly understood. Colonization with the intestinal bacterium Clostridium scindens provided protection from the parasite Entamoeba histolytica via innate immunity. Introduction of C. scindens into the gut microbiota epigenetically altered and expanded bone marrow granulocyte-monocyte-progenitors (GMPs) and provided neutrophil-mediated protection against subsequent challenge with E. histolytica. Adoptive transfer of bone-marrow from C. scindens colonized-mice into naïve-mice protected against ameba infection and increased intestinal neutrophils. Because of the known ability of C. scindens to metabolize the bile salt cholate, we measured deoxycholate and discovered that it was increased in the sera of C. scindens colonized mice, as well as in children protected from amebiasis. Administration of deoxycholate alone (in the absence of C. scindens) increased the epigenetic mediator JMJD3 and GMPs and provided protection from amebiasis. In conclusion the microbiota was shown to communicate to the bone marrow via microbially-metabolized bile salts to train innate immune memory to provide antigen-nonspecific protection from subsequent infection. This represents a novel mechanism by which the microbiome protects from disease.One Sentence SummaryIntroduction of the human commensal bacteria Clostridium scindens into the intestinal microbiota epigenetically alters bone marrow and protects from future parasite infection.

show abstract

Pleiotropic Functions of H3K27Me3 Demethylases in Immune Cell Differentiation

Cited by 43 publications

References 86 publications

Kdm6a and Kdm6b: Altered expression in malignant pleural mesothelioma

Kdm6a and Kdm6b: Altered expression in malignant pleural mesothelioma

Inflammatory related gene IKKα, IKKβ, IKKγ cooperates to determine liver cancer stem cells progression by altering telomere via heterochromatin protein 1-HOTAIR axis

Gut microbiome communication with bone marrow regulates susceptibility to amebiasis

Contact Info

Product

Resources

About