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See detailNuclear export of histone deacetylase 7 during thymic selection is required for immune self-tolerance.
Kasler, Herbert G.; Lim, Hyung W.; Mottet, Denis ULg et al

in EMBO Journal (2012)

Histone deacetylase 7 (HDAC7) is a T-cell receptor (TCR) signal-dependent regulator of differentiation that is highly expressed in CD4/CD8 double-positive (DP) thymocytes. Here, we examine the effect of ... [more ▼]

Histone deacetylase 7 (HDAC7) is a T-cell receptor (TCR) signal-dependent regulator of differentiation that is highly expressed in CD4/CD8 double-positive (DP) thymocytes. Here, we examine the effect of blocking TCR-dependent nuclear export of HDAC7 during thymic selection, through expression of a signal-resistant mutant of HDAC7 (HDAC7-DeltaP) in thymocytes. We find that HDAC7-DeltaP transgenic thymocytes exhibit a profound block in negative thymic selection, but can still undergo positive selection, resulting in the escape of autoreactive T cells into the periphery. Gene expression profiling reveals a comprehensive suppression of the negative selection-associated gene expression programme in DP thymocytes, associated with a defect in the activation of MAP kinase pathways by TCR signals. The consequence of this block in vivo is a lethal autoimmune syndrome involving the exocrine pancreas and other abdominal organs. These experiments establish a novel molecular model of autoimmunity and cast new light on the relationship between thymic selection and immune self-tolerance. [less ▲]

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See detailHDAC5 is required for maintenance of pericentric heterochromatin, and controls cell-cycle progression and survival of human cancer cells
Peixoto, Paul ULg; Castronovo, Vincenzo ULg; Matheus, Nicolas ULg et al

in Cell Death & Differentiation (2012)

Histone deacetylases (HDACs) form a family of enzymes, which have fundamental roles in the epigenetic regulation of gene expression and contribute to the growth, differentiation, and apoptosis of cancer ... [more ▼]

Histone deacetylases (HDACs) form a family of enzymes, which have fundamental roles in the epigenetic regulation of gene expression and contribute to the growth, differentiation, and apoptosis of cancer cells. In this study, we further investigated the biological function of HDAC5 in cancer cells. We found HDAC5 is associated with actively replicating pericentric heterochromatin during late S phase. We demonstrated that specific depletion of HDAC5 by RNA interference resulted in profound changes in the heterochromatin structure and slowed down ongoing replication forks. This defect in heterochromatin maintenance and assembly are sensed by DNA damage checkpoint pathways, which triggered cancer cells to autophagy and apoptosis, and arrested their growth both in vitro and in vivo. Finally, we also demonstrated that HDAC5 depletion led to enhanced sensitivity of DNA to DNA-damaging agents, suggesting that heterochromatin de-condensation induced by histone HDAC5 silencing may enhance the efficacy of cytotoxic agents that act by targeting DNA in vitro. Together, these results highlighted for the first time an unrecognized link between HDAC5 and the maintenance/assembly of heterochromatin structure, and demonstrated that its specific inhibition might contribute to increase the efficacy of DNA alteration-based cancer therapies in clinic. [less ▲]

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See detailHistone Deacetylase 7 Regulates Cell Survival and TCR Signaling in CD4/CD8 Double-Positive Thymocytes.
Kasler, Herbert G; Young, Bryan D; Mottet, Denis ULg et al

in Journal of Immunology (2011), 186(8), 4782-93

CD4/CD8 double-positive thymocytes express the transcriptional repressor histone deacetylase (HDAC)7, a class IIa HDAC that is exported from the cell nucleus after TCR engagement. Through signal-dependent ... [more ▼]

CD4/CD8 double-positive thymocytes express the transcriptional repressor histone deacetylase (HDAC)7, a class IIa HDAC that is exported from the cell nucleus after TCR engagement. Through signal-dependent nuclear export, class IIa HDACs such as HDAC7 mediate signal-dependent changes in gene expression that are important to developmental fate decisions in multiple tissues. We report that HDAC7 is exported from the cell nucleus during positive selection in mouse thymocytes and that it regulates genes mediating the coupling between TCR engagement and downstream events that determine cell survival. Thymocytes lacking HDAC7 are inefficiently positively selected due to a severely shortened lifespan and exhibit a truncated repertoire of TCR Jalpha segments. The expression of multiple important mediators and modulators of the response to TCR engagement is altered in HDAC7-deficient thymocytes, resulting in increased tonic MAPK activity that contributes to the observed loss of viability. Remarkably, the activity of protein kinase D, the kinase that mediates nuclear export of HDAC7 in response to TCR signaling, is also increased in HDAC7-deficient thymocytes, suggesting that HDAC7 nuclear export governs a self-sustaining autoexcitatory loop. These experiments add to the understanding of the life/death decision in thymic T cell development, define a novel function for class IIa HDACs, and point to a novel feed-forward mechanism whereby these molecules regulate their own state and mediate stable developmental transitions. [less ▲]

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See detailHDAC4 represses p21(WAF1/Cip1) expression in human cancer cells through a Sp1-dependent, p53-independent mechanism.
Mottet, Denis ULg; Pirotte, Sophie ULg; Lamour, Virginie ULg et al

in Oncogene (2009), 28(2), 243-56

Cancer cells have complex, unique characteristics that distinguish them from normal cells, such as increased growth rates and evasion of anti-proliferative signals. Global inhibition of class I and II ... [more ▼]

Cancer cells have complex, unique characteristics that distinguish them from normal cells, such as increased growth rates and evasion of anti-proliferative signals. Global inhibition of class I and II histone deacetylases (HDACs) stops cancer cell proliferation in vitro and has proven effective against cancer in clinical trials, at least in part, through transcriptional reactivation of the p21(WAF1/Cip1)gene. The HDACs that regulate p21(WAF1/Cip1) are not fully identified. Using small interfering RNAs, we found that HDAC4 participates in the repression of p21(WAF1/Cip1) through Sp1/Sp3-, but not p53-binding sites. HDAC4 interacts with Sp1, binds and reduces histone H3 acetylation at the Sp1/Sp3 binding site-rich p21(WAF1/Cip1) proximal promoter, suggesting a key role for Sp1 in HDAC4-mediated repression of p21(WAF1/Cip1). Induction of p21(WAF1/Cip1) mediated by silencing of HDAC4 arrested cancer cell growth in vitro and inhibited tumor growth in an in vivo human glioblastoma model. Thus, HDAC4 could be a useful target for new anti-cancer therapies based on selective inhibition of specific HDACs. [less ▲]

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See detailRegulation of insulin secretion by SIRT4, a mitochondrial ADP-ribosyltransferase
Ahuja, Nidhi; Schwer, Bjoern; Carobbio, Stefania et al

in Journal of Biological Chemistry (2007), 282(46),

Sirtuins are homologues of the yeast transcriptional repressor Sir2p and are conserved from bacteria to humans. We report that human SIRT4 is localized to the mitochondria. SIRT4 is a matrix protein and ... [more ▼]

Sirtuins are homologues of the yeast transcriptional repressor Sir2p and are conserved from bacteria to humans. We report that human SIRT4 is localized to the mitochondria. SIRT4 is a matrix protein and becomes cleaved at amino acid 28 after import into mitochondria. Mass spectrometry analysis of proteins that coimmunoprecipitate with SIRT4 identified insulin degrading enzyme and the ADP/ATP carrier proteins, ANT2 and ANT3. SIRT4 exhibits no histone deacetylase activity but functions as an efficient ADP-ribosyltransferase on histones and bovine serum albumin. SIRT4 is expressed in islets of Langerhans and colocalizes with insulin-expressing beta cells. Depletion of SIRT4 from insulin-producing INS-1E cells results in increased insulin secretion in response to glucose. These observations define a new role for mitochondrial SIRT4 in the regulation of insulin secretion. [less ▲]

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See detailHistone deacetylase HDAC8 associates with smooth muscle alpha–actin and is essential for smooth muscle cell contractility
Glénisson, Wendy; Waltregny, David ULg; Tran, Syv Li et al

Conference (2006)

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See detailEffect Of Inhibitors Of Histone Deacetylase On The Induction Of Cell Differentiation In Murine And Human Erythroleukemia Cell Lines
Wittich, S.; Scherf, H.; Xie, Cp. et al

in Anti-Cancer Drugs (2005), 16(6),

Histone deacetylase (HDAC) inhibitors are a novel class of promising anti-cancer agents. Little information is available on the capacity of structurally different HDAC inhibitors to induce terminal cell ... [more ▼]

Histone deacetylase (HDAC) inhibitors are a novel class of promising anti-cancer agents. Little information is available on the capacity of structurally different HDAC inhibitors to induce terminal cell differentiation in different cell types in relation to enzyme inhibition and subtype selectivity. Consequently, the aim of this study was to provide a comprehensive comparison of these effects. New biarylalanine inhibitors of HDAC were synthesized and compared to a series of standard inhibitors from different laboratories. Chromatographically purified rat liver and immunoprecipitated FLAG-tagged recombinant human HDACs were used as sources of HDAC activity. Enzyme inhibition was studied using a fluorescent substrate and its conversion was monitored by high-performance liquid chromatography. The ability to induce cell differentiation was compared in murine (Friend DS-19) and human (K562) erythroleukemic cell lines, and was quantified by benzidine staining. Inhibition of cell proliferation was evaluated by cell counting. All HDAC inhibitors were identified as potent inhibitors of erythroleukemic cell proliferation. However, we observed a complex pattern of differentiation induction: structurally similar inhibitors resulted in disparate activity profiles, whereas similar profiles were detected within distinct structural classes. Among the newly synthesized biarylalanine compounds, a 3'-methoxy derivative was identified as a very effective inducer of terminal cell differentiation. We conclude that investigation of subtype selectivity of selected HDAC inhibitors does not provide a clear link between selectivity and the observed cellular activity profile. The predictive value of in vitro HDAC inhibition assays for identifying anti-proliferative compounds has been emphasized. [less ▲]

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See detailHistone deacetylase HDAC8 associates with smooth muscle alpha-actin and is essential for smooth muscle cell contractility
Waltregny, David ULg; Glenisson, Wendy; Tran, Syv Li et al

in FASEB Journal (2005), 19(8), 966-968

Although originally characterized as nuclear enzymes controlling the stability of nucleosomes, histone deacetylases (HDACs) may also exert their activity within the cytosol. Recently, we have demonstrated ... [more ▼]

Although originally characterized as nuclear enzymes controlling the stability of nucleosomes, histone deacetylases (HDACs) may also exert their activity within the cytosol. Recently, we have demonstrated that HDAC8, a class I HDAC, is a novel, prominently cytosolic marker of smooth muscle differentiation. As HDAC8 displays a striking stress fiber-like pattern of distribution and is coexpressed in vivo with smooth muscle alpha-actin (alpha-SMA) and smooth muscle myosin heavy chain, we have explored the possible participation of this HDAC in smooth muscle cytoskeleton regulation. Cell fractionation assays performed with primary human smooth muscle cells (HSMCs) showed that HDAC8, in contrast to HDAC1 and HDAC3, was enriched in cytoskeleton-bound protein fractions and insoluble cell pellets, suggesting an association of HDAC8 with the cystoskeleton. Coimmunoprecipitation experiments using HSMCs, NIH-3T3 cells, and human prostate tissue lysates further demonstrated that HDAC8 associates with alpha-SMA but not with beta-actin. HDAC8 silencing through RNA interference strongly reduced the capacity of HSMCs to contract collagen lattices. Mock transfections had no effect on HSMC contractily, and transfections with small interfering RNAs (siRNAs) specific for HDAC6, a cytosolic HDAC that functions as an alpha-tubulin deacetylase, resulted in a weak contraction inhibition. Although mock- and HDAC6 siRNA-transfected HSMCs showed no noticeable morphological changes, HDAC8 siRNA-transfected HSMCs displayed a size reduction with diminished cell spreading after replating. Altogether, our findings indicate that HDAC8 associates with the smooth muscle actin cytoskeleton and may regulate the contractile capacity of smooth muscle cells. [less ▲]

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See detailHistone deacetylase HDAC8 associates with smooth muscle alpha–actin and is essential for smooth muscle cell contractility
Glénisson, Wendy; Waltregny, David ULg; Tran, Syv Li et al

Conference (2005)

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See detailScreening of histone deacetylases (HDAC) expression in human prostate cancer reveals distinct class IHDAC profiles between epithelial and stromal cells
Waltregny, David ULg; North, Brian; Van Mellaert, Frank et al

in European Journal of Histochemistry (2004), 48(3, Jul-Sep), 273-290

Histone deacetylases (HDACs) represent a large family of enzymes identified as key regulators of nucleosomal histone acetylation, a major epigenetic event that controls eukaryotic gene transcription ... [more ▼]

Histone deacetylases (HDACs) represent a large family of enzymes identified as key regulators of nucleosomal histone acetylation, a major epigenetic event that controls eukaryotic gene transcription. Inappropriate deacetylation mediated by HDACs has been associated with profound alterations in cellular biology. We have thus hypothesized that an altered HDAC expression may favor cancer development/progression. To test this possibility, we have sought to screen the expression profiles of several class I and class 11 HDACs (HDAC1-8) in DU-145, PC-3 and LNCaP human prostate cancer cell lines as well as in matched malignant and nonmalignant prostate tissues by use of real time RT-PCR, immunoblot and immunohistochemistry. All HDAC transcripts tested were detected at various levels in all prostate cancer cell lines and tissue samples analyzed. In prostate tissues, the abundance of HDAC1 protein, which was exclusively expressed in the cell nucleus, was similar in normal and malignant epithelial cells, but was usually lower in stromal cells. Unexpectedly, HDAC8, another class I HDAC, was not detected in epithelial cells but was uniquely expressed in the cytoplasm of stromal cells, HDAC5, a class II HDAC involved in myogenesis, was not detected in the tissues. Altogether, our findings indicate that epithelial and stromal cells exhibit distinct class I HDAC expression profiles, and the abundance of HDAC1 is not altered in human prostate cancer. In addition, our observations are the first to demonstrate the prominently cytosolic distribution of a class I HDAC, HDAC8. [less ▲]

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See detailLa déacétylase d’histones HDAC8 est un nouveau marqueur de différenciation des cellules musculaires lisses
Glénisson, Wendy; de Leval, Laurence ULg; Tran, Syv Li et al

Conference (2004)

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See detailMeasurement of mammalian histone deacetylase activity.
Verdin, Eric; Dequiedt, Franck ULg; Fischle, Wolfgang et al

in Methods in Enzymology (2004), 377

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See detailHDAC7, a thymus-specific class II histone deacetylase, regulates Nur77 transcription and TCR-mediated apoptosis.
Dequiedt, Franck ULg; Kasler, Herbert; Fischle, Wolfgang et al

in Immunity (2003), 18(5), 687-98

We report that HDAC7, a class II histone deacetylase, is highly expressed in CD4(+)CD8(+) double-positive thymocytes. HDAC7 inhibits the expression of Nur77, an orphan receptor involved in apoptosis and ... [more ▼]

We report that HDAC7, a class II histone deacetylase, is highly expressed in CD4(+)CD8(+) double-positive thymocytes. HDAC7 inhibits the expression of Nur77, an orphan receptor involved in apoptosis and negative selection, via the transcription factor MEF2D. HDAC7 is exported from the nucleus during T cell receptor activation, leading to Nur77 expression. A triple HDAC7 mutant (S155A, S318A, S448A) is not exported from the nucleus in response to TCR activation and suppresses TCR-mediated apoptosis. Conversely, a fusion of HDAC7 to the transcriptional activator VP16 activates Nur77 expression. Inhibition of HDAC7 expression by RNA interference causes increased apoptosis in response to TCR activation. These observations define HDAC7 as a regulator of Nur77 and apoptosis in developing thymocytes. [less ▲]

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See detailScreening of histone deacetylase (HDAC) expression profiles in prostate cancer tissues leads to the identification of HDAC8 as a novel marker of smooth muscle differentiation
Waltregny, David ULg; Glénisson, Wendy; Tran, Syv Li et al

Conference (2003)

Background: Histone deacetylation mediated by histone deacetylases (HDAC) plays a key role in the regulation of gene expression. Inhibition of HDAC activity is associated with profound alterations in ... [more ▼]

Background: Histone deacetylation mediated by histone deacetylases (HDAC) plays a key role in the regulation of gene expression. Inhibition of HDAC activity is associated with profound alterations in cellular biology, such as cell growth arrest, apoptosis and differentiation. It has been hypothesized that altered HDAC expression and/or activity could play a role in cancer development and progression. Objectives: To investigate this possibility, we undertook a study in which we screened HDAC expression profiles in human prostate cancer. In addition, we sought to determine the specific biological effects of selected HDACs. Methods: A variety of techniques, including immunochemistry, Q-RT-PCR, and immunobloting, were used to examine the expression of several class I and class II HDACs in human prostate cancer cell lines and matched malignant and non-malignant prostate tissues. Analysis of the specific biological effects of selected HDACs was performed after knocking down their expression with the use of specific small interfering RNAs (siRNA) and/or after forcing their overexpression by transfection of the cDNAs of interest. Results: Normal prostate epithelial and stromal cells displayed distinct HDAC expression profiles, suggesting specific functions for these enzymes in the prostate. Human prostate cancer cells did not exhibit significant alterations in the abundance of any of the HDAC enzymes analyzed. One of the HDACs tested, herein referred to as HDACX, was specifically expressed, in vivo, by cells showing smooth muscle phenotype, including vascular and prostate smooth muscle cells and myoepithelial cells. HDACX expression co-localized with the expression of the specific smooth muscle marker alpha smooth muscle actin (alpha-SMA) in all human tissues tested. Nucleo-cytoplasmic fractionation experiments showed that HDACX was mainly expressed in the cytosol of human smooth muscle cells (HSMC) obtained from umbilical cord veins. Transfection experiments leading to overexpression of HDACX in mouse fibroblasts indicated that the enzyme was detected both in the cytosol and in the nucleus. By immunocytochemistry, it was observed that HDACX pattern of expression was reminiscent of actin stress fibers, suggesting that this HDAC may be involved in the regulation of the smooth muscle cell cytoskeleton. Trichostatin A (TSA), a specific global HDAC inhibitor, as well as specific HDACX siRNAs, were able to completely prevent the TGFß1-induced differentiation of fibroblasts into myofibroblasts, as assessed by alpha-SMA abundance. Forced downregulation of HDACX by siRNAs in HSMC caused a dramatic reduction in their contraction capacity, as determined with the use of hydrated collagen lattices contraction assays. Conclusions : HDACs diplay distinct expression profiles among normal prostate epithelial and stromal cells. The abundance of the HDACs analyzed in this study is not altered in prostate cancer. Further experiments are required to determine whether the activity of these enzymes is altered in prostate cancer. We have identified for the first time an HDAC that (i) is specifically expressed in cells showing smooth muscle phenotype, (ii) is required for myofibroblastic differentiation, and (iii) is involved in smooth muscle cell contraction. This HDAC may become a target for the therapy of several pathological conditions, including chronic inflammation and cancer, in which myofibroblasts play a major role. [less ▲]

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See detailNonisotopic substrate for assaying both human zinc and NAD+-dependent histone deacetylases.
Heltweg, Birgit; Dequiedt, Franck ULg; Verdin, Eric et al

in Analytical Biochemistry (2003), 319(1), 42-8

Histone deacetylases (HDACs) are involved in the regulation of transcription and their inhibitors are a promising class of new anticancer drugs. We have previously reported Boc(Ac)Lys-AMC, also termed MAL ... [more ▼]

Histone deacetylases (HDACs) are involved in the regulation of transcription and their inhibitors are a promising class of new anticancer drugs. We have previously reported Boc(Ac)Lys-AMC, also termed MAL, as a fluorescent substrate for HDACs. Now we present a modification of MAL called Z-MAL that is characterized by an increased rate of conversion by histone deacetylases of classes I and II and the recently discovered sirtuins (histone deacetylases class III). MAL and Z-MAL are the first nonradioactive substrates for class III enzymes. The new substrate Z-MAL allows for shorter assay times in inhibitor screening and is applicable to diverse sources of deacetylase activity even with completely different catalytic mechanisms. Interestingly, MAL shows some relative preference toward class II, indicating that subtype selectivity in small-molecule HDAC substrates might be obtained. [less ▲]

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See detailClass II histone deacetylases: versatile regulators.
Verdin, Eric; Dequiedt, Franck ULg; Kasler, Herbert G

in Trends in Genetics (2003), 19(5), 286-93

Histone acetylation and deacetylation play essential roles in modifying chromatin structure and regulating gene expression in eukaryotes. Histone deacetylases (HDACs) catalyze the deacetylation of lysine ... [more ▼]

Histone acetylation and deacetylation play essential roles in modifying chromatin structure and regulating gene expression in eukaryotes. Histone deacetylases (HDACs) catalyze the deacetylation of lysine residues in the histone N-terminal tails and are found in large multiprotein complexes with transcriptional co-repressors. Human HDACs are grouped into three classes based on their similarity to known yeast factors: class I HDACs are similar to the yeast transcriptional repressor yRPD3, class II HDACs to yHDA1 and class III HDACs to ySIR2. In this review, we focus on the biology of class II HDACs. These newly discovered enzymes have been implicated as global regulators of gene expression during cell differentiation and development. We discuss their emerging biological functions and the molecular mechanisms by which they are regulated. [less ▲]

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See detailHistone deacetylases inhibitors as anti-angiogenic agents altering vascular endothelial growth factor signaling
Deroanne, Christophe ULg; Bonjean, Karine; Servotte, Sandrine et al

in Oncogene (2002), 21(3), 427-436

Angiogenesis is a complex biological process involving the coordinated modulation of many genes. Histone deacetylases (HDAC) are a growing family of enzymes that mediate the availability of chromatin to ... [more ▼]

Angiogenesis is a complex biological process involving the coordinated modulation of many genes. Histone deacetylases (HDAC) are a growing family of enzymes that mediate the availability of chromatin to the transcriptional machinery. Trichostatin-A (TSA) and suberoylanilide hydroxamic acid (SAHA), two HDAC inhibitors known to relieve gene silencing, were evaluated as potential antiangiogenic agents. TSA and SAHA were shown to prevent vascular endothelial growth factor (VEGF)-stimulated human umbilical cord endothelial cells (HUVEC) from invading a type I collagen gel and forming capillary-like structures. SAHA and TSA inhibited the VEGF-induced formation of a CD31-positive capillary-like network in embryoid bodies and inhibited the VEGF-induced angiogenesis in the CAM assay. TSA also prevented, in a dose-response relationship, the sprouting of capillaries from rat aortic rings. TSA inhibited in a dose-dependent and reversible fashion the VEGF-induced expression of VEGF receptors, VEGFR1, VEGFR2, and neuropilin-1. TSA and SAHA upregulated the expression by HUVEC of semaphorin III, a recently described VEGF competitor, at both mRNA and protein levels. This effect was specific to endothelial cells and was not observed in human fibroblasts neither in vascular smooth muscle cells. These observations provide a conspicuous demonstration that HDAC inhibitors are potent anti-angiogenic factors altering VEGF signaling. [less ▲]

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See detailEnzymatic activity associated with class II HDACs is dependent on a multiprotein complex containing HDAC3 and SMRT/N-CoR.
Fischle, Wolfgang; Dequiedt, Franck ULg; Hendzel, Michael J et al

in Molecular Cell (2002), 9(1), 45-57

Histone deacetylases (HDACs) play a key role in regulating eukaryotic gene expression. The HDAC domain, homologous to the yeast repressors RPD3 and HDA1, is considered necessary and sufficient for ... [more ▼]

Histone deacetylases (HDACs) play a key role in regulating eukaryotic gene expression. The HDAC domain, homologous to the yeast repressors RPD3 and HDA1, is considered necessary and sufficient for enzymatic activity. Here, we show that the catalytic domain of HDAC4 interacts with HDAC3 via the transcriptional corepressor N-CoR/SMRT. All experimental conditions leading to the suppression of HDAC4 binding to SMRT/N-CoR and to HDAC3 result in the loss of enzymatic activity associated with HDAC4. In vitro reconstitution experiments indicate that HDAC4 and other class II HDACs are inactive in the context of the SMRT/N-CoR-HDAC3 complex and do not contribute to its enzymatic activity. These observations indicate that class II HDACs regulate transcription by bridging the enzymatically active SMRT/N-CoR-HDAC3 complex and select transcription factors independently of any intrinsic HDAC activity. [less ▲]

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See detailThe emerging role of class II histone deacetylases.
Fischle, Wolfgang; Kiermer, Véronique; Dequiedt, Franck ULg et al

in Biochemistry & Cell Biology (2001), 79(3), 337-48

Histone acetylation and deacetylation play essential roles in modifying chromatin structure and regulating gene expression in all eukaryotes. Several histone acetyltransferases have been identified that ... [more ▼]

Histone acetylation and deacetylation play essential roles in modifying chromatin structure and regulating gene expression in all eukaryotes. Several histone acetyltransferases have been identified that act as transcriptional coactivators. In contrast, histone deacetylases (HDACs) are part of transcriptional corepressor complexes. Based on their similarity to known yeast factors, the human HDACs are grouped into three classes. Class I HDACs are similar to the yeast transcriptional repressor yRPD3, while class II HDACs are related to yHDA1 and class III HDACs to ySIR2. In this review, we focus on the biology of class II HDACs. These newly discovered enzymes have been implicated in cell differentiation and development, and many molecular details are emerging that shed light on class II HDAC function and regulation. We discuss the biological role of these factors in the context of physiological processes. [less ▲]

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