scholarly journals Functional and physical interaction between the histone methyl transferase Suv39H1 and histone deacetylases

2002 ◽  
Vol 30 (2) ◽  
pp. 475-481 ◽  
Author(s):  
O. Vaute
Keyword(s):  
Histone Deacetylases ◽  
Physical Interaction ◽  
Methyl Transferase ◽  
Histone Methyl Transferase

PLZF-RARα Utilizes the Histone Methyl Transferase G9a/GLP and the Histone Demethylase LSD1 to Repress RARα Target Genes and Block Myeloid Differentiation

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 198-198
Author(s):  
Itsaso Hormaeche ◽  
Kim L. Rice ◽  
Arthur Zelent ◽  
Melanie J. McConnell ◽  
Jonathan D. Licht
Keyword(s):  
Fusion Protein ◽  
Transcriptional Repression ◽  
Histone Deacetylases ◽  
Target Genes ◽  
Myeloid Cell ◽  
Gene Repression ◽  
Methyl Transferase ◽  
Histone 3 ◽  
Histone Methyl Transferase

Abstract As a result of the t(11;17) translocation in retinoic acid resistant subtype of acute promyelocytic leukemia (APL), the transcriptional repression domains of the Promyelocytic Leukemia Zinc Finger protein (PLZF) are fused to the ligand binding and DNA binding domains of the Retinoic Acid Receptor α (RARα). The expression of PLZF-RARα as well as the reciprocal RARα-PLZF protein both appear to contribute to leukemogenesis. While the mode of action of PML-RARα has been studied in detail, less is known about transcriptional repression mediated by PLZF-RARα. We and others previously showed an important role of histone deacetylases in PLZF and PLZF-RARα mediated gene repression. We now find that expression of PLZF-RARα also modulates gene expression through changes in the state of histone methylation at target promoters. PLZF-RARα co-precipitated in vivo with endogenous G9a, a histone methyl transferase responsible for the mono and di-methylation of euchromatic histone 3 lysine tail residue 9 (H3K9me1/2), a covalent modification associated with gene repression. Deletion analysis of the PLZF-RARα fusion protein showed that the BTB/POZ domain of PLZF fused to RARα was sufficient to mediate this interaction. PLZF-RARα also bound in vivo to LSD1, a histone demethylase that removes methyl groups from mono or di-methylated Histone 3 lysine 4 (H3K4me1/2), a change generally associated with gene repression. As with G9a the BTB/POZ domain of PLZF was implicated in binding to LSD1. Co-precipitation experiments showed a robust interaction between PLZF-RARα and G9a and LSD1 while RARα, PML-RARα and NPM-RARα bound much more weakly, suggesting that the interaction with these histone modifying enzymes may be a mechanism relatively specific to t(11;17)-associated APL. To identify genes modulated by PLZF-RARα and determine how PLZF-RARα affects the chromatin of such genes we induced expression of PLZF-RARα in a U937 tetracycline-regulated system. PLZF-RARα directly repressed known RARα target genes such as NFE2, PRAM1 and C/EBPε. As a result of PLZF-RARα expression, U937T cells were blocked in differentiation characterized by decreased expression of the myeloid cell surface markers CD11b, CD14 and CD33. Chromatin immunoprecipitation experiments in this cell line showed that PLZF-RARα expression was associated with an increase in H3K9me1/me2 at the NFE2, PRAM1 and C/EBPε promoters. Knockdown of endogenous G9a by shRNA transduction reversed transcriptional repression mediated by the fusion protein on all three promoters. Both results are consistent with the presence of G9a in PLZF-RARα transcriptional complex. By contrast, the H3K4 methylation changes in response to PLZF-RARα were promoter specific and complex: while NFE2 exhibited a decrease in H3K4me1/2, consistent with the recruitment of LSD1 and demethylation, PRAM1 and C/EBPε showed an increase in these two modifications. Inhibition of LSD1 by tranylcypromine treatment as well as knockdown of LSD1 by shRNA only reverted PLZF-RARα repression of NFE2. PLZF-RARα recruitment to all three genes was associated with a decrease in H3K4trimethylation, a modification only accomplished by jumanji-class histone demethylases. Consistent with the biochemical information, knockdown of G9a or its heterodimeric partner GLP, showed a strong biological phenotype, reverting the block in myeloid differentiation caused by PLZF-RARα as measured by the expression of the myeloid cell surface markers CD11b and CD14. Depletion of LSD1 only modestly interfered with the differentiation block mediated by the fusion protein. Gene regulation by PLZF-RARα is associated with a complex set of chromatin changes mediated by a combination of histone deacetylases, methyl transferase and demethylases. All three classes of enzymes may represent therapeutic targets in t(11;17)-APL.

SIRT1 regulates the histone methyl-transferase SUV39H1 during heterochromatin formation

Nature ◽  
2007 ◽  
Vol 450 (7168) ◽  
pp. 440-444 ◽  
Author(s):  
Alejandro Vaquero ◽  
Michael Scher ◽  
Hediye Erdjument-Bromage ◽  
Paul Tempst ◽  
Lourdes Serrano ◽  
...  
Keyword(s):  
Methyl Transferase ◽  
Heterochromatin Formation ◽  
Histone Methyl Transferase

scholarly journals Krüppel-like factor 4, Elk-1, and histone deacetylases cooperatively suppress smooth muscle cell differentiation markers in response to oxidized phospholipids

2008 ◽  
Vol 295 (5) ◽  
pp. C1175-C1182 ◽  
Author(s):  
Tadashi Yoshida ◽  
Qiong Gan ◽  
Gary K. Owens
Keyword(s):  
Smooth Muscle ◽  
Histone Deacetylases ◽  
Molecular Mechanisms ◽  
Phenotypic Switching ◽  
Marker Genes ◽  
Physical Interaction ◽  
Oxidized Phospholipids ◽  
Differentiation Markers ◽  
Differentiation Marker

Phenotypic switching of vascular smooth muscle cells (SMCs), such as increased proliferation, enhanced migration, and downregulation of SMC differentiation marker genes, is known to play a key role in the development of atherosclerosis. However, the factors and mechanisms controlling this process are not fully understood. We recently showed that oxidized phospholipids, including 1-palmitoyl-2-(5-oxovaleroyl)- sn-glycero-3-phosphocholine (POVPC), which accumulate in atherosclerotic lesions, are potent repressors of expression of SMC differentiation marker genes in cultured SMCs as well as in rat carotid arteries in vivo. Here, we examined the molecular mechanisms whereby POVPC induces suppression of SMC differentiation marker genes in cultured SMCs. Results showed that POVPC induced phosphorylation of ERK1/2 and Elk-1. The MEK inhibitors U-0126 and PD-98059 attenuated POVPC-induced suppression of smooth muscle ( SM) α-actin and SM-myosin heavy chain. POVPC also induced expression of Krüppel-like factor 4 (Klf4). Chromatin immunoprecipitation assays revealed that POVPC caused simultaneous binding of Elk-1 and Klf4 to the promoter region of the SM α-actin gene. Moreover, coimmunoprecipitation assays showed a physical interaction between Elk-1 and Klf4. Results in Klf4-null SMCs showed that blockade of both Klf4 induction and Elk-1 phosphorylation completely abolished POVPC-induced suppression of SMC differentiation marker genes. POVPC-induced suppression of SMC differentiation marker genes was also accompanied by hypoacetylation of histone H4 at the SM α-actin promoter, which was mediated by the recruitment of histone deacetylases (HDACs), HDAC2 and HDAC5. Coimmunoprecipitation assays showed that Klf4 interacted with HDAC5. Results provide evidence that Klf4, Elk-1, and HDACs coordinately mediate POVPC-induced suppression of SMC differentiation marker genes.

The noncoding RNA linc-ADAMTS5 cooperates with RREB1 to protect from intervertebral disc degeneration through inhibiting ADAMTS5 expression

2017 ◽  
Vol 131 (10) ◽  
pp. 965-979 ◽  
Author(s):  
Kun Wang ◽  
Yu Song ◽  
Wei Liu ◽  
Xinghuo Wu ◽  
Yukun Zhang ◽  
...  
Keyword(s):  
Intervertebral Disc ◽  
Disc Degeneration ◽  
Histone Deacetylases ◽  
Noncoding Rna ◽  
Intervertebral Disc Degeneration ◽  
Physical Interaction ◽  
Loss Of Function ◽  
Element Binding Protein ◽  
Long Intergenic Noncoding Rna

Previous studies have indicated the important roles of ADAMTS5 in intervertebral disc degeneration (IDD). However, the mechanisms that regulate ADAMTS5 expression in nuclear pulposus (NP) cells remain largely unknown. Evidence suggests that intergenic transcription may be associated with genes that encode transcriptional regulators. Here, we identified a long intergenic noncoding RNA, linc-ADAMTS5, which was transcribed in the opposite direction to ADAMTS5. In the present study, through mining computational algorithm programs, and publicly available data sets, we identified Ras-responsive element-binding protein 1 (RREB1) as a crucial transcription factor regulating the expression of ADAMTS5 in NP cells. RNA pull-down, RNA immunoprecipitation (RIP), in vitro binding assays, and gain- and loss-of-function studies indicated that a physical interaction between linc-ADAMTS5 and splicing factor proline/glutamine-rich (SFPQ) facilitated the recruitment of RREB1 to binding sites within the ADAMTS5 promoter to induce chromatin remodeling. This resulted in subdued ADAMTS5 levels in cultured NP cells involving histone deacetylases (HDACs). In clinical NP tissues, linc-ADAMTS5 and RREB1 were correlated negatively with ADAMTS5 expression. Taken together, these results demonstrate that RREB1 cooperates with noncoding RNA linc-ADAMTS5 to inhibit ADAMTS5 expression, thereby affecting degeneration of the extracellular matrix (ECM) of the intervertebral disc (IVD).

scholarly journals Phase 1 first-in-human study of the enhancer of zeste-homolog 2 (EZH2) histone methyl transferase inhibitor E7438

2015 ◽  
Vol 26 ◽  
pp. ii10 ◽  
Author(s):  
V. Ribrag ◽  
J.-C. Soria ◽  
L. Reyderman ◽  
R. Chen ◽  
P. Salazar ◽  
...  
Keyword(s):  
Phase 1 ◽  
Human Study ◽  
Methyl Transferase ◽  
Enhancer Of Zeste ◽  
Histone Methyl Transferase

scholarly journals Cauliflower mosaic virus P6 Dysfunctions Histone Deacetylase HD2C to Promote Virus Infection

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2278
Author(s):  
Shun Li ◽  
Shanwu Lyu ◽  
Yujuan Liu ◽  
Ming Luo ◽  
Suhua Shi ◽  
...  
Keyword(s):  
Histone Acetylation ◽  
Mosaic Virus ◽  
Histone Deacetylase ◽  
Plant Development ◽  
Stress Responses ◽  
Biotic Stress ◽  
Histone Deacetylases ◽  
Cauliflower Mosaic Virus ◽  
Physical Interaction ◽  
Epigenetic Modifiers

Histone deacetylases (HDACs) are vital epigenetic modifiers not only in regulating plant development but also in abiotic- and biotic-stress responses. Though to date, the functions of HD2C—an HD2-type HDAC—In plant development and abiotic stress have been intensively explored, its function in biotic stress remains unknown. In this study, we have identified HD2C as an interaction partner of the Cauliflower mosaic virus (CaMV) P6 protein. It functions as a positive regulator in defending against CaMV infection. The hd2c mutants show enhanced susceptibility to CaMV infection. In support, the accumulation of viral DNA, viral transcripts, and the deposition of histone acetylation on the viral minichromosomes are increased in hd2c mutants. P6 interferes with the interaction between HD2C and HDA6, and P6 overexpression lines have similar phenotypes with hd2c mutants. In further investigations, P6 overexpression lines, together with CaMV infection plants, are more sensitive to ABA and NaCl with a concomitant increasing expression of ABA/NaCl-regulated genes. Moreover, the global levels of histone acetylation are increased in P6 overexpression lines and CaMV infection plants. Collectively, our results suggest that P6 dysfunctions histone deacetylase HD2C by physical interaction to promote CaMV infection.

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