scholarly journals Properties of the yeast nuclear histone deacetylase

1994 ◽  
Vol 303 (3) ◽  
pp. 723-729 ◽  
Author(s):  
M M Sanchez del Pino ◽  
G Lopez-Rodas ◽  
R Sendra ◽  
V Tordera
Keyword(s):  
Molecular Mass ◽  
Histone Deacetylase ◽  
Trichostatin A ◽  
High Mobility ◽  
Inhibitory Effect ◽  
High Molecular Mass ◽  
Core Histones ◽  
Nuclear Histone

A nuclear histone deacetylase from yeast was partially purified and some of its characteristics were studied. Histone deacetylase activity was stimulated in vitro by high-mobility-group nonhistone chromatin proteins 1 and 2 and ubiquitin and inhibited by spermine and spermidine, whereas n-butyrate had no significant inhibitory effect. Like the mammalian enzyme, partially purified histone deacetylase from yeast was strongly inhibited by trichostatin A. However, in crude extract preparations the yeast enzyme was not inhibited and treatment with trichostatin in vivo did not show any effect, either on the histone acetylation level or on cell viability. At low ionic strength, the enzyme can be isolated as a complex of high molecular mass that is much less inhibited by trichostatin A than is partially purified histone deacetylase activity. Furthermore, radiolabelled oligonucleosomes were more efficiently deacetylated by the complex than by the low-molecular-mass form of the enzyme. The histone deacetylase activity was separated from a polyamine deacetylase activity and its specificity studied. Using h.p.l.c.-purified core histone species as substrate, histone deacetylase from yeast is able to deacetylate all core histones with a slight preference for H3. Our results support the idea that the yeast histone deacetylase may act as a high-molecular-mass complex in vivo.

Downregulation of Graft-Versus-Host-Disease (GVHD) by Treatment with Histone Deacetylase (HDAC) Inhibitors Involves Modulation of the JAK/STAT Signaling Pathway.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3050-3050
Author(s):  
Corinna Leng ◽  
Margathe Gries ◽  
Suzanne Lentzsch ◽  
Simone Lusatis ◽  
Paolo Mascagni ◽  
...  
Keyword(s):  
T Cell ◽  
Histone Deacetylase ◽  
Graft Versus Host Disease ◽  
Hdac Inhibitors ◽  
Inhibitory Effect ◽  
Graft Versus Host ◽  
Stat Signaling ◽  
Stat Pathway

Abstract Graft-versus-host disease (GVHD) mediated by alloreactive donor T cells is the most dreaded complication after allogeneic bone marrow transplantation (BMT). Conditioning therapy in the context of BMT creates a proinflammatory milieu, which is thought to be central to the development of GVHD. Interfering with the conditioning-induced inflammatory response could be an approach to prevent GVHD without compromising the graft-versus-malignancy reaction. Histone deacetylase (HDAC) inhibitors belong to a new family of anti-cancer drugs with potent anti-inflammatory properties and have recently been shown to reduce the development of GVHD. The aim of this study was understand the mechanisms underlying the downregulation of GVHD after treatment with the HDAC inhibitor suberonylanilide hydroxamic acid (SAHA). Using the fully MHC-mismatched strain combination B6 to BALB/c, treatment with SAHA resulted in a significantly reduced GVHD mortality. Thus, at days +10 or +37 post-BMT survival for vehicle-treated or SAHA-treated mice was 33 % versus 86 % and 8 % versus 57 % respectively (Chi2 test, p = 0,027 and p = 0,02, respectively). This was associated with a significant reduction in IFN-g and IL-5 serum levels of SAHA-treated animals. As we could not detect any effect of SAHA treatment on T cell activation or T cell expansion in vitro and in vivo, we hypothesized that the inhibitory effect of SAHA treatment on the development of GVHD might be primarily due to an interference in the early events of the inflammatory cascade occurring after conditioning and initial alloactivation. Therefore, we performed gene expression profiling studies in classical GVHD target organs of animals treated with SAHA or vehicle to further understand the mechanisms underlying this effect. SAHA treated animals revealed a significant upregulation of the mRNA expression of the Protein inhibitor of activated stat 1 (PIAS1) gene in the liver compared to vehicle-treated animals. To further strengthen the hypothesis that SAHA might exert its action by interfering with inflammatory reaction and subsequent signaling through the JAK/STAT pathway, we analyzed the effects of SAHA on STAT-1, 3, and 5 activation and expression of SOCS-1 and SOCS-3 in vitro and in vivo. Thus, BALB/c responder splenocytes were incubated with or without irradiated B6 stimulators in the presence or absence of LPS in order to allow for the separate analysis of LPS and alloactivation-induced JAK/STAT activation. Treatment for 24 hours with SAHA completely inhibited phosphorylation of STAT-1 and STAT-3 in response to LPS and alloactivation using western blot analysis. Furthermore, analysis of liver tissue from GVHD animals showed a sustained expression of SOCS-1 protein in SAHA treated animals whereas SOCS-1 was downregulated in the absence of SAHA. In conclusion our data suggest that the inhibitory effect of SAHA on the development of GVHD is associated with an inhibition of the JAK/STAT signaling pathway. Further studies are warranted to understand the precise mechanisms how SAHA interferes with JAK/STAT signaling and how this leads to inhibition of GVHD. However, it is conceivable that interfering with inflammatory signaling pathways using pharmacological inhibitors of the JAK/STAT pathway might provide a highly attractive treatment strategy for the prevention of GVHD.

Sox9-dependent transcriptional regulation of the proprotein convertase furin

2007 ◽  
Vol 293 (1) ◽  
pp. C172-C183 ◽  
Author(s):  
Philippe Guimont ◽  
Francine Grondin ◽  
Claire M. Dubois
Keyword(s):  
High Mobility ◽  
Inhibitory Effect ◽  
Nodule Formation ◽  
Mrna Levels ◽  
Paracrine Factor ◽  
Proprotein Convertase ◽  
Hmg Box ◽  
Repressive Effect

The proprotein convertase furin participates in the maturation/bioactivation of a variety of proproteins involved in chondrogenesis events. These include parathyroid hormone-related peptide (PTHrP), an autocrine/paracrine factor that is crucial to both normal cartilage development and cartilage-related pathological processes. Despite the known importance of furin activity in the bioactivation of the polypeptides, the mechanisms that control furin regulation in chondrogenesis remain unknown. To gain insight into the molecular regulation of furin, we used the mouse prechondrogenic ATDC5 cell line, an established in vitro model of cartilage differentiation. Peak expression of both furin mRNA and furin PTHrP maturation was observed during chondrocyte nodule formation stage, an event that correlated with increased mRNA levels of Sox9, a potent high-mobility-group (HMG) box-containing transcription factor required for cartilage formation. Inhibition of furin activity led to a diminution in maturation of PTHrP, suggesting a relationship between Sox9-induced regulation of furin and chondrogenesis events. Transient transfection of Sox9 in nonchondrogenic cells resulted in a marked increase in furin mRNA and in the transactivation of the furin P1A promoter. Direct Sox9 action on the P1A promoter was narrowed down to a critical paired site with Sox9 binding capability in vitro and in vivo. Sox9 transactivation effect was inhibited by L-Sox5 and Sox-6, two Sox9 homologs also expressed in ATDC5 cells. Sox6 inhibitory effect was reduced when using Sox6-HMG-box mutants, indicating a repressive effect through direct HMG-box/DNA binding. Our work suggests a mechanism by which furin is regulated during chondrogenesis. It also adds to the complexity of Sox molecule interaction during gene regulation.

scholarly journals Nicotinamide Clearance by Pnc1 Directly Regulates Sir2-Mediated Silencing and Longevity

2004 ◽  
Vol 24 (3) ◽  
pp. 1301-1312 ◽  
Author(s):  
Christopher M. Gallo ◽  
Daniel L. Smith ◽  
Jeffrey S. Smith
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Nicotinic Acid ◽  
Life Span ◽  
Histone Deacetylase ◽  
Transcriptional Repression ◽  
Transcriptional Silencing ◽  
Inhibitory Effect ◽  
Salvage Pathway

ABSTRACT The Saccharomyces cerevisiae Sir2 protein is an NAD+-dependent histone deacetylase (HDAC) that functions in transcriptional silencing and longevity. The NAD+ salvage pathway protein, Npt1, regulates Sir2-mediated processes by maintaining a sufficiently high intracellular NAD+ concentration. However, another NAD+ salvage pathway component, Pnc1, modulates silencing independently of the NAD+ concentration. Nicotinamide (NAM) is a by-product of the Sir2 deacetylase reaction and is a natural Sir2 inhibitor. Pnc1 is a nicotinamidase that converts NAM to nicotinic acid. Here we show that recombinant Pnc1 stimulates Sir2 HDAC activity in vitro by preventing the accumulation of NAM produced by Sir2. In vivo, telomeric, rDNA, and HM silencing are differentially sensitive to inhibition by NAM. Furthermore, PNC1 overexpression suppresses the inhibitory effect of exogenously added NAM on silencing, life span, and Hst1-mediated transcriptional repression. Finally, we show that stress suppresses the inhibitory effect of NAM through the induction of PNC1 expression. Pnc1, therefore, positively regulates Sir2-mediated silencing and longevity by preventing the accumulation of intracellular NAM during times of stress.

scholarly journals Improved development of mouse SCNT embryos by chlamydocin analogues, class I and IIa histone deacetylase inhibitors†

2021 ◽  
Author(s):  
Satoshi Kamimura ◽  
Kimiko Inoue ◽  
Eiji Mizutani ◽  
Jin-Moon Kim ◽  
Hiroki Inoue ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitors ◽  
Trichostatin A ◽  
Hdac Inhibitors ◽  
Class I ◽  
Cell Stage ◽  
Inhibitory Spectrum ◽  
Developmental Block

Abstract In mammalian cloning by somatic cell nuclear transfer (SCNT), treatment of reconstructed embryos with histone deacetylase (HDAC) inhibitors improves efficiency. So far, most of those used for SCNT are hydroxamic acid derivatives—such as trichostatin A—characterized by their broad inhibitory spectrum. Here, we examined whether mouse SCNT efficiency could be improved using chlamydocin analogues, a family of newly designed agents that specifically inhibit Class I and IIa HDACs. Development of SCNT-derived embryos in vitro and in vivo revealed that four out of five chlamydocin analogues tested could promote the development of cloned embryos. The highest pup rates (7.1 to 7.2%) were obtained with Ky-9, similar to those achieved with trichostatin A (7.2 to 7.3%). Thus, inhibition of Class I and/or IIa HDACs in SCNT-derived embryos is enough for significant improvements in full-term development. In mouse SCNT, the exposure of reconstructed oocytes to HDAC inhibitors is limited to 8–10 h because longer inhibition with Class I inhibitors causes a 2-cell developmental block. Therefore, we used Ky-29, with higher selectivity for Class IIa than Class I HDACs for longer treatment of SCNT-derived embryos. As expected, 24-h treatment with Ky-29 up to the 2-cell stage did not induce a developmental block, but the pup rate was not improved. This suggests that the 1-cell stage is a critical period for improving SCNT cloning using HDAC inhibitors. Thus, chlamydocin analogues appear promising for understanding and improving the epigenetic status of mammalian SCNT-derived embryos through their specific inhibitory effects on HDACs.

48 TREATMENT OF CLONED BOVINE EMBRYOS WITH HISTONE DEACETYLASE INHIBITORS INCREASES IN VITRO DEVELOPMENT BUT NOT IN VIVO CLONING EFFICIENCY

2009 ◽  
Vol 21 (1) ◽  
pp. 124
Author(s):  
J. E. Oliver ◽  
T. Delaney ◽  
J. N. Oswald ◽  
M. C. Berg ◽  
B. Oback ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Nuclear Transfer ◽  
Histone Deacetylase Inhibitors ◽  
Trichostatin A ◽  
Cloning Efficiency ◽  
In Vitro Development ◽  
Significant Difference ◽  
Vitro Development

Previous studies in the mouse have shown treatment of somatic cell nuclear transfer (SCNT) embryos with histone deacetylase inhibitors (HDACi) to significantly increase cloning efficiency (Kishigami S et al. 2006 BBRC 340, 183–189; van Thuan N 2007 Asian Reproductive Biology Society 4, 9 abst). Increasing histone acetylation may open donor chromatin allowing better access for oocyte cytoplasmic factors to facilitate reprogramming. Here, we determined the effect of two HDACi, Trichostatin A (TSA), and scriptaid (Sigma-Aldrich, Castle Hill, NSW, Australia), on bovine cloning efficiency. Zona-free SCNT was performed with serum starved fibroblasts fused to enucleated MII-arrested IVM oocytes. After 4 h, reconstructs were activated with 5 μm ionomycin and 2 mm 6-dimethylaminopurine (DMAP) and cultured individually in 5 μL drops of AgResearch synthetic oviduct fluid (SOF) medium. Treatment with HDACi commenced concomitant with the 4 h DMAP incubation and continued in SOF for the remainder of the treatment period; totalling either 18 or 48 h post activation (hpa). TSA concentrations examined were: 0, 5, 50, and 500 nm, with all treatments containing 0.5% DMSO (n = 1121). Following TSA treatment, increased histone (H) acetylation at lysine (K) of H4K5 was confirmed by semi-quantitative immunofluorescence at the eight-cell stage. Scriptaid concentrations examined were: 0, 5, 50, 250, and 1000 nm, with all treatments containing 0.5% DMSO during DMAP and 0.1% DMSO during IVC (n = 1059). In vitro development on Day 7 was expressed in terms of transferable quality embryos as a percentage of reconstructs cultured. Data were analyzed using a generalized linear model with binomial variation and logit link. Embryos from selected treatments were transferred singularly to recipient cows on Day 7 with pregnancy data analyzed using Fisher’s exact test. Day 7 in vitro development was significantly greater with 5 nm TSA treatment for 18 hpa compared to controls (47.1% v. 34.5%; P < 0.02). Treatment of embryos with TSA for 48 hpa had no effect at any concentration tested. In contrast, scriptaid treatment for 18 hpa had no effect in vitro, while exposure for 48 hpa at 1000 nm significantly increased the development of transferable quality embryos compared to 0 nm (44.0% v. 32.4%; P < 0.005). There was no significant difference in embryo survival rates at D150 of gestation between embryos treated with 0 or 5 nm TSA for 18 hpa (8/48 v. 10/48; 16.7% v. 20.8%). However, in vivo development at Day 150 of gestation following treatment of embryos with 1000 nm scriptaid for 48 hpa was significantly lower compared to controls (1/37 v. 6/31; 2.7% v. 19.4%; P < 0.05). Contrary to the mouse, TSA or scriptaid treatment as used in this study did not increase cloning efficiency in cattle. The use of various HDACi either alone or in combination with DNA demethylating agents may still prove beneficial for reprogramming following nuclear transfer. Supported by FRST C10X0303.

Molecular Characterization and Drug-Sensitivity of Pan Histone Deacetylase Inhibitor Resistant Human Acute Myeloid Leukemia Cells.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 807-807 ◽  
Author(s):  
Warren Fiskus ◽  
Rekha Rao ◽  
Pravina Fernandez ◽  
Bryan Herger ◽  
Yonghua Yang ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Drug Sensitivity ◽  
Trichostatin A ◽  
Resistance Index ◽  
Leukemia Cells ◽  
Cell Surface Expression ◽  
In Vivo Model ◽  
Acid Analogue

Abstract Hydroxamic acid analogue pan-histone deacetylase (HDAC) inhibitors (HA-HDIs), e.g., vorinostat, LAQ824 and LBH589, induce in vitro growth arrest, differentiation and apoptosis of human acute leukemia cells. Continuous and protracted use of HA-HDI, as currently used in the clinic against hematologic malignancies is likely to result in the emergence of HA-HDI resistance in leukemia cells. By continuous in vitro exposure of the AML HL-60 cells to the cinnamic acid analogue HA-HDI LAQ824, we have generated an in vitro and in vivo model of HA-HDI-resistant HL-60/LR cells, which are capable of growth in high concentrations (200 nM) of LAQ824. HL-60/LR versus the parental HL-60 cells have a shorter doubling time (12 versus 24 hours), increased % of cells in the S phase of the cell cycle (62.4 versus 40.0) and exhibit shorter interval to generation of leukemia and survival in NOD/SCID mice. As compared to HL-60, HL-60/LR cells have a resistance index of 100 for LAQ824, and are cross-resistant to other antileukemia agents exhibiting resistance index for LBH589: 50; trichostatin A: 15; vorinostat: 30; sodium butyrate: 10; etoposide: 5.0; Ara-C: 3.3 and TRAIL: 31.3. As compared to HL-60, HL-60/LR cells express higher levels of Bcl-xL and XIAP but lower levels of MCL-1. HL-60/LR versus HL-60 cells also express markedly reduced levels of Bim and Bak but higher levels of Bax. Although expressing higher levels of the death receptors (DR) 4 and 5 and lower levels of c-FLIP, HL-60/LR cells lack expression of caspase-8 and show barely detectable levels of FADD. Additionally, HL-60/LR versus HL-60 cells have markedly higher levels of AKT, c-RAF, and p-STAT5. Although expressing higher levels of HDAC1, HDAC2, and HDAC4, HL-60/LR cells lack detectable expression of HDAC6, with increased expression of hyper-acetylated hsp90 and α-tubulin- two of the substrates deacetylated by HDAC6. As compared to hsp90 in HL-60 cells, hyper-acetylated hsp90 in HL-60/LR cells exhibits less binding to ATP and p23. Utilizing a polyclonal antibody generated against acetylated hsp90α, confocal immunofluorescence microscopy showed higher and mostly cell surface expression of acetylated hsp90α in HL-60/LR versus HL-60 cells. As compared to HL-60, treatment of HL-60/LR cells with LAQ824 failed to induce p21 and hsp70, or increase the levels of hyper-acetylated hsp90 and α-tubulin. Notably, although cross-resistant to several anti-leukemia drugs, HL-60/LR cells are collaterally sensitive to the hsp90-inhibiting geldanamycin analogues 17-allylamino-demothoxy geldanamycin (17-AAG) and 17-DMAG with a four and five-fold increased sensitivity to 17-AAG and 17-DMAG, respectively. This was associated with a lack of both a 17-AAG mediated induction of hsp70 and a lesser decline in the levels of AKT and c-RAF in HL-60/LR versus HL-60 cells. Taken together, these findings elucidate several notable in vitro and in vivo biologic characteristics and drug-sensitivity profile of the first fully-characterized HA-HDI-resistant human AML cells. Our findings clearly demonstrate that in vitro resistance to HA-HDIs is associated with loss of HDAC6 expression, hyperacetylation of hsp90, aggressive leukemia phenotype, but cross-sensitivity to 17-AAG. These findings also suggest that hsp90 inhibitors should be tested for overriding de novo or acquired HA-HDI resistance in AML.

scholarly journals Characterization of Mediator Complexes from HeLa Cell Nuclear Extract

2001 ◽  
Vol 21 (14) ◽  
pp. 4604-4613 ◽  
Author(s):  
Gang Wang ◽  
Greg T. Cantin ◽  
Jennitte L. Stevens ◽  
Arnold J. Berk
Keyword(s):  
Hela Cell ◽  
Molecular Mass ◽  
Rna Polymerase Ii ◽  
Nuclear Extract ◽  
High Molecular Mass ◽  
Multiprotein Complexes ◽  
Hela Cell Nuclear Extract ◽  
Cell Nuclear Extract

ABSTRACT A number of mammalian multiprotein complexes containing homologs ofSaccharomyces cerevisiae Mediator subunits have been described recently. High-molecular-mass complexes (1 to 2 MDa) sharing several subunits but apparently differing in others include the TRAP/SMCC, NAT, DRIP, ARC, and human Mediator complexes. Smaller multiprotein complexes (∼500 to 700 kDa), including the murine Mediator, CRSP, and PC2, have also been described that contain subsets of subunits of the larger complexes. To evaluate whether these different multiprotein complexes exist in vivo in a single form or in multiple different forms, HeLa cell nuclear extract was directly resolved over a Superose 6 gel filtration column. Immunoblotting of column fractions using antisera specific for several Mediator subunits revealed one major size class of high-molecular-mass (∼2-MDa) complexes containing multiple mammalian Mediator subunits. No peak was apparent at ∼500 to 700 kDa, indicating that either the smaller complexes reported are much less abundant than the higher-molecular-mass complexes or they are subcomplexes generated by dissociation of larger complexes during purification. Quantitative immunoblotting indicated that there are about 3 × 105to 6 × 105 molecules of hSur2 Mediator subunit per HeLa cell, i.e., the same order of magnitude as RNA polymerase II and general transcription factors. Immunoprecipitation of the ∼2-MDa fraction with anti-Cdk8 antibody indicated that at least two classes of Mediator complexes occur, one containing CDK8 and cyclin C and one lacking this CDK-cyclin pair. The ∼2-MDa complexes stimulated activated transcription in vitro, whereas a 150-kDa fraction containing a subset of Mediator subunits inhibited activated transcription.

H1 and HMGB1: modulators of chromatin structure

2012 ◽  
Vol 40 (2) ◽  
pp. 341-346 ◽  
Author(s):  
Jean O. Thomas ◽  
Katherine Stott
Keyword(s):  
Chromatin Structure ◽  
High Mobility ◽  
Stable Structure ◽  
Dynamic Nature ◽  
High Mobility Group Protein ◽  
Chromosomal Proteins ◽  
Core Histones ◽  
Group Protein

Histone H1 and HMGB1 (high-mobility group protein B1) are the most abundant chromosomal proteins apart from the core histones (on average, one copy per nucleosome and per ten nucleosomes respectively). They are both highly mobile in the cell nucleus, with high on/off rates for binding. In vivo and in vitro evidence shows that both are able to organize chromatin structure, with H1 binding resulting in a more stable structure and HMGB1 binding in a less stable structure. The binding sites for H1 and HMGB1 in chromatin are partially overlapping, and replacement of H1 by HMGB1 through the highly dynamic nature of their binding, possibly facilitated by interaction between them, could result in switching of chromatin states. Binding of HMGB1 to DNA or chromatin is regulated by its long and highly acidic tail, which is also involved in H1 binding. The present article focuses mainly on HMGB1 and its interaction with chromatin and H1, as well as its chaperone role in the binding of certain transcription factors (e.g. p53) to their cognate DNA.

Histone Deacetylases Are Essential for Chromatin Condensation and Enucleation in Mammalian Erythroblasts

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1375-1375
Author(s):  
Peng Ji ◽  
Francisco J Sánchez-Rivera ◽  
Harvey F. Lodish
Keyword(s):  
Histone Deacetylases ◽  
Trichostatin A ◽  
Chromatin Condensation ◽  
Hemoglobin Concentration ◽  
Kinetic Studies ◽  
Inhibitory Effect ◽  
Evolution Of Mammals ◽  
Oxygen Carrying Capacity

Abstract In the last steps of differentiation mammalian erythroid cells undergo chromatin condensation and enucleation; the latter process does not occur in other vertebrates. Enucleation was critical for the evolution of mammals, as it permits an enhanced hemoglobin concentration – and thus oxygen- carrying capacity – in mammalian red blood cells. We previously reported that Rac GTPases and their downstream forming target mDia2 are required for mouse fetal erythroblast enucleation. We also found that the nucleus undergoes a gradual ~10- fold decrease in volume during erythropoiesis. Since histone deacetylases (HDACs) play important roles in chromatin condensation, we hypothesized that HDACs are involved in mammalian erythroblast enucleation. To test this hypothesis, we purified E13.5 mouse fetal TER119 negative erythroblasts and cultured them in fibronectin-coated plates. Cells were then treated with Trichostatin A (TSA), a pan-HDAC inhibitor, at different times during erythropoiesis. TSA completely blocked enucleation and kinetic studies showed this inhibitory effect occurred earlier than the step catalyzed by the Rac-mDia2 pathway. This indicates that chromatin condensation is required for the final extrusion of the nucleus. We further investigated the activity ofHDAC6 specifically, since HDAC6 is known to interact with mDia2. We found that mDia2is acetylated in vitro and in vivo and that HDAC6 interacts with and deacetylates mDia2. Treatment of purified TER119 negative mouse fetal erythroblasts with a specific HDAC6inhibitor partially blocked enucleation. We conclude that histone deacetylase activities are essential for mammalian erythroblasts to undergo enucleation and that HDACs act both on chromatin condensation and mDia2 deacetylation to promote enucleation.

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