Tumor necrosis factor alpha(TNF-a) is a cytokine that can potently stimulate the synthesis of a range of proinflammatory mediators in macrophages. The underlying epigenetic mechanism, however, is underexplored. Here w...Tumor necrosis factor alpha(TNF-a) is a cytokine that can potently stimulate the synthesis of a range of proinflammatory mediators in macrophages. The underlying epigenetic mechanism, however, is underexplored. Here we report that the transcriptional modulator megakaryocytic leukemia 1(MKL1) is associated with a histone H3 K4 methyltransferase activity. Re-ChIP assay suggests that MKL1 interacts with and recruits WDR5, a component of the COMPASS complex responsible for H3 K4 methylation, to the promoter regions of pro-inflammatory genes in macrophages treated with TNF-α. WDR5 enhances the ability of MKL1 to stimulate the promoter activities of proinflammatory genes. In contrast, silencing of WDR5 attenuates TNF-a induced production of pro-inflammatory mediators and erases the H3 K4 methylation from the gene promoters. Of interest, the chromatin remodeling protein BRG1 also plays an essential role in maintaining H3 K4 methylation on MKL1 target promoters by interacting with WDR5. MKL1 knockdown disrupts the interaction between BRG1 and WDR5. Together, our data illustrate a role for MKL1 in moderating the crosstalk between BRG1 and WDR5 to activate TNF-a induced pro-inflammatory transcription in macrophages.展开更多
MLL1 is a histone H3Lys4 methyltransferase and forms a complex with WDR5 and other components.It plays important roles in developmental events,transcriptional regulation,and leukemogenesis.MLL1-fusion proteins resulti...MLL1 is a histone H3Lys4 methyltransferase and forms a complex with WDR5 and other components.It plays important roles in developmental events,transcriptional regulation,and leukemogenesis.MLL1-fusion proteins resulting from chromosomal translocations are molecular hallmarks of a special type of leukemia,which occurs in over 70% infant leukemia patients and often accompanies poor prognosis.Investigations in the past years on leukemogenesis and the MLL1-WDR5 histone H3Lys4 methyltransferase complex demonstrate that epigenetic regulation is one of the key steps in development and human diseases.展开更多
Background:Breast cancer has become a severe threat to human health,making it imperative to identify effective drugs and therapeutic targets.Methods:Various molecular biology experiments,such as western blot analysis,...Background:Breast cancer has become a severe threat to human health,making it imperative to identify effective drugs and therapeutic targets.Methods:Various molecular biology experiments,such as western blot analysis,cytologic effect,co-immunoprecipitation,and immunofluorescence assays,as well as a nude mouse xenograft tumor model,were used to comprehensively analyze the impact of gamma-interferon-inducible lysosomal thiol reductase(GILT)on the malignant phenotype of breast cancer cells.This work was performed to examine GILT expression levels and explore the potential mechanism in breast cancer.Results:GILT protein expression levels were significantly lower in breast cancer cells than in normal breast epithelial cells.Overexpressing GILT inhibited breast cancer cell proliferation and migration and slowed tumor growth.GILT inhibited the interaction between the MYC and WDR5 transcription complex and played a tumor-suppressive role.The MYC/WDR5 transcription complex inhibitor OICR-9429 could synergize with GILT to inhibit breast cancer cell proliferation.Conclusion:This study reveals a potential mechanism by which GILT can slow breast cancer growth,as well as identifying the possible clinical application value of small molecule inhibitor OICR-9429.These data collectively provide novel treatment strategies for breast cancer therapy.展开更多
In vitro, mouse embryonic stem （ES） cells can differentiate into many somatic cell types, including neurons and glial cells. When cultured in serum-free medium, ES cells convert spontaneously and efficiently to a ne...In vitro, mouse embryonic stem （ES） cells can differentiate into many somatic cell types, including neurons and glial cells. When cultured in serum-free medium, ES cells convert spontaneously and efficiently to a neural fate. Previous studies have shown that the neural conversion of mouse ES cells includes both the participation of neural-specific transcription factors and the regulation of epigenetic modifications. However, the intracellular mechanism underlying this intrinsic transition still re- mains to be further elucidated. Herein, we describe a long intergenic non-coding RNA, LincRNA1230, which participates in the regulation of the neural lineage specification of mouse ES cells. The ectopic forced expression of LincRNAI230 dramatically inhibited mouse ES cells from adopting a neural cell fate, while LincRNA1230 knockdown promoted the conversion of mouse ES cells towards neural progenitors. Mechanistic studies have shown that LincRNA1230 inhibits the activation of early neural genes, such as Pax6 and Soxl, through the modulation of bivalent modifications （tri-methylation of histone3 lysine4 and his- tone3 lysine27） at the promoters of these genes. The interaction of LincRNA1230 with Wdr5 blocked the localization of Wdr5 at the promoters of early neural genes, thereby inhibiting the enrichment of H3K4me3 modifications at these loci. Collectively, these findings revealed a crucial role for LincRNA1230 in the regulation of the neural differentiation of mouse ES cells.展开更多
The MLL/SET family of histone H3 lysine 4 methyltransferases form enzyme complexes with core subunits ASH2L, WDR5, RbBP5, and DPY-30 （often abbreviated WRAD）, and are responsible for global histone H3 iysine 4 methy...The MLL/SET family of histone H3 lysine 4 methyltransferases form enzyme complexes with core subunits ASH2L, WDR5, RbBP5, and DPY-30 （often abbreviated WRAD）, and are responsible for global histone H3 iysine 4 methylation, a hallmark of actively transcribed chromatin in mammalian cells. Accordingly, the function of these proteins is required for a wide variety of processes including stem cell differentiation, cell growth and division, body segmentation, and hematopoiesis. While most work on MLL-WRAD has focused on the function this core complex in histone methylation, recent studies indicate that MLL-WRAD proteins interact with a variety of other proteins and IncRNAs and can localize to cellular organelles beyond the nucleus. In this review, we focus on the recently described activities and interacting partners of MLL-WRAD both inside and outside the nucleus.展开更多
基金the National Natural Science Foundation of China (81570420) supported by the Qinglan Project of the Education Commission of Jiangsu Province
文摘Tumor necrosis factor alpha(TNF-a) is a cytokine that can potently stimulate the synthesis of a range of proinflammatory mediators in macrophages. The underlying epigenetic mechanism, however, is underexplored. Here we report that the transcriptional modulator megakaryocytic leukemia 1(MKL1) is associated with a histone H3 K4 methyltransferase activity. Re-ChIP assay suggests that MKL1 interacts with and recruits WDR5, a component of the COMPASS complex responsible for H3 K4 methylation, to the promoter regions of pro-inflammatory genes in macrophages treated with TNF-α. WDR5 enhances the ability of MKL1 to stimulate the promoter activities of proinflammatory genes. In contrast, silencing of WDR5 attenuates TNF-a induced production of pro-inflammatory mediators and erases the H3 K4 methylation from the gene promoters. Of interest, the chromatin remodeling protein BRG1 also plays an essential role in maintaining H3 K4 methylation on MKL1 target promoters by interacting with WDR5. MKL1 knockdown disrupts the interaction between BRG1 and WDR5. Together, our data illustrate a role for MKL1 in moderating the crosstalk between BRG1 and WDR5 to activate TNF-a induced pro-inflammatory transcription in macrophages.
文摘MLL1 is a histone H3Lys4 methyltransferase and forms a complex with WDR5 and other components.It plays important roles in developmental events,transcriptional regulation,and leukemogenesis.MLL1-fusion proteins resulting from chromosomal translocations are molecular hallmarks of a special type of leukemia,which occurs in over 70% infant leukemia patients and often accompanies poor prognosis.Investigations in the past years on leukemogenesis and the MLL1-WDR5 histone H3Lys4 methyltransferase complex demonstrate that epigenetic regulation is one of the key steps in development and human diseases.
基金Fundamental Research Funds for the Central Universities(Grant No:2042022FK1209)National Natural Science Funds of China(Grant No:81972833)Basic and Clinical Medical Research Joint Fund of Zhongnan Hospital of Wuhan University(Grant No:JCZN2022008).
文摘Background:Breast cancer has become a severe threat to human health,making it imperative to identify effective drugs and therapeutic targets.Methods:Various molecular biology experiments,such as western blot analysis,cytologic effect,co-immunoprecipitation,and immunofluorescence assays,as well as a nude mouse xenograft tumor model,were used to comprehensively analyze the impact of gamma-interferon-inducible lysosomal thiol reductase(GILT)on the malignant phenotype of breast cancer cells.This work was performed to examine GILT expression levels and explore the potential mechanism in breast cancer.Results:GILT protein expression levels were significantly lower in breast cancer cells than in normal breast epithelial cells.Overexpressing GILT inhibited breast cancer cell proliferation and migration and slowed tumor growth.GILT inhibited the interaction between the MYC and WDR5 transcription complex and played a tumor-suppressive role.The MYC/WDR5 transcription complex inhibitor OICR-9429 could synergize with GILT to inhibit breast cancer cell proliferation.Conclusion:This study reveals a potential mechanism by which GILT can slow breast cancer growth,as well as identifying the possible clinical application value of small molecule inhibitor OICR-9429.These data collectively provide novel treatment strategies for breast cancer therapy.
基金supported by National Natural Science Foundation of China (81530042, 31571529, 31210103905, 31571519, 31571390, 31371510, 31301208, 31471250, 31401257)the Ministry of Science and Technology (2012CB966603, 2013CB967600, 2013CB967401)+2 种基金Science and Technology Commission of Shanghai Municipality (15JC1403200, 15JC1403201)Shanghai Rising-Star Program (14QA1403900)the Fundamental Research Funds for the Central Universities (2000219099)
文摘In vitro, mouse embryonic stem （ES） cells can differentiate into many somatic cell types, including neurons and glial cells. When cultured in serum-free medium, ES cells convert spontaneously and efficiently to a neural fate. Previous studies have shown that the neural conversion of mouse ES cells includes both the participation of neural-specific transcription factors and the regulation of epigenetic modifications. However, the intracellular mechanism underlying this intrinsic transition still re- mains to be further elucidated. Herein, we describe a long intergenic non-coding RNA, LincRNA1230, which participates in the regulation of the neural lineage specification of mouse ES cells. The ectopic forced expression of LincRNAI230 dramatically inhibited mouse ES cells from adopting a neural cell fate, while LincRNA1230 knockdown promoted the conversion of mouse ES cells towards neural progenitors. Mechanistic studies have shown that LincRNA1230 inhibits the activation of early neural genes, such as Pax6 and Soxl, through the modulation of bivalent modifications （tri-methylation of histone3 lysine4 and his- tone3 lysine27） at the promoters of these genes. The interaction of LincRNA1230 with Wdr5 blocked the localization of Wdr5 at the promoters of early neural genes, thereby inhibiting the enrichment of H3K4me3 modifications at these loci. Collectively, these findings revealed a crucial role for LincRNA1230 in the regulation of the neural differentiation of mouse ES cells.
文摘The MLL/SET family of histone H3 lysine 4 methyltransferases form enzyme complexes with core subunits ASH2L, WDR5, RbBP5, and DPY-30 （often abbreviated WRAD）, and are responsible for global histone H3 iysine 4 methylation, a hallmark of actively transcribed chromatin in mammalian cells. Accordingly, the function of these proteins is required for a wide variety of processes including stem cell differentiation, cell growth and division, body segmentation, and hematopoiesis. While most work on MLL-WRAD has focused on the function this core complex in histone methylation, recent studies indicate that MLL-WRAD proteins interact with a variety of other proteins and IncRNAs and can localize to cellular organelles beyond the nucleus. In this review, we focus on the recently described activities and interacting partners of MLL-WRAD both inside and outside the nucleus.
