A Gonzalez

Publications (17)58.37 Total impact

• Article: HDAC5 is required for maintenance of pericentric heterochromatin, and controls cell-cycle progression and survival of human cancer cells.

  P Peixoto, V Castronovo, N Matheus, C Polese, O Peulen, A Gonzalez, M Boxus, E Verdin, M Thiry, F Dequiedt, D Mottet
  [show abstract] [hide abstract]
  ABSTRACT: 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.
  Cell death and differentiation 02/2012; 19(7):1239-52. · 8.24 Impact Factor
• Article: Deep sequencing of GDF5 reveals the absence of rare variants at this important osteoarthritis susceptibility locus.

  A W Dodd, C Rodriguez-Fontenla, M Calaza, A Carr, J J Gomez-Reino, A Tsezou, L N Reynard, A Gonzalez, J Loughlin
  [show abstract] [hide abstract]
  ABSTRACT: The common single nucleotide polymorphism (SNP) rs143383 in the 5' untranslated region (5'UTR) of growth and differentiation factor 5 (GDF5) is strongly associated with osteoarthritis (OA) and influences GDF5 allelic expression in vitro and in the joint tissues of OA patients. This effect is modulated in cis by another common SNP, also located within the 5'UTR, whilst a common SNP in the 3'UTR influences allelic expression independent of rs143383. DNA variants can be common, rare or extremely rare/unique. To therefore enhance our understanding of the allelic architecture of this very important OA susceptibility locus we sequenced the gene for potentially functional and novel rare variants. Using the Sanger method we sequenced GDF5 in 992 OA patients and 944 controls, with DNA changes identified by sequencing software. We encompassed the protein-coding region of the two GDF5 exons, both untranslated regions and approximately 100 bp of the proximal promoter of the gene. We detected 13 variants. Six were extremely rare with minor allele frequencies (MAFs) of ≤ 0.0006. One is in a predicted transcription factor binding site in the GDF5 promoter whilst two substitute conserved amino acids. The remaining seven variants were common and are previously known variants, with MAFs ranging from 0.025 to 0.39. There was a complete absence of variants with frequencies in-between the extremely rare (n=6) and the common (n=7). This is the first report of the deep sequencing of an OA susceptibility locus. The absence of rare variants informs us that within the regions of the gene that we have sequenced GDF5 does not harbour any novel variants that are able to contribute, at a population level, to the OA association signal mediated by rs143383 nor does it harbour, at a population level, any novel variants that can influence OA susceptibility independent of rs143383.
  Osteoarthritis and Cartilage 01/2011; 19(4):430-4. · 3.90 Impact Factor
• Source

  Available from: Kalliope Panoutsopoulou

  Article: Insights into the genetic architecture of osteoarthritis from stage 1 of the arcOGEN study.

  K Panoutsopoulou, L Southam, K S Elliott, N Wrayner, G Zhai, C Beazley, G Thorleifsson, N K Arden, A Carr, K Chapman, [......], A Tsezou, A G Uitterlinden, J B J van Meurs, B Watkins, M Wheeler, S Mitchell, Y Zhu, J M Zmuda, E Zeggini, J Loughlin
  [show abstract] [hide abstract]
  ABSTRACT: The genetic aetiology of osteoarthritis has not yet been elucidated. To enable a well-powered genome-wide association study (GWAS) for osteoarthritis, the authors have formed the arcOGEN Consortium, a UK-wide collaborative effort aiming to scan genome-wide over 7500 osteoarthritis cases in a two-stage genome-wide association scan. Here the authors report the findings of the stage 1 interim analysis. The authors have performed a genome-wide association scan for knee and hip osteoarthritis in 3177 cases and 4894 population-based controls from the UK. Replication of promising signals was carried out in silico in five further scans (44,449 individuals), and de novo in 14 534 independent samples, all of European descent. None of the association signals the authors identified reach genome-wide levels of statistical significance, therefore stressing the need for corroboration in sample sets of a larger size. Application of analytical approaches to examine the allelic architecture of disease to the stage 1 genome-wide association scan data suggests that osteoarthritis is a highly polygenic disease with multiple risk variants conferring small effects. Identifying loci conferring susceptibility to osteoarthritis will require large-scale sample sizes and well-defined phenotypes to minimise heterogeneity.
  Annals of the rheumatic diseases 12/2010; 70(5):864-7. · 8.11 Impact Factor
• Source

  Available from: Sotelo

  Conference Proceeding: Automatic information recognition of traffic panels using SIFT descriptors and HMMs

  A. Gonzalez, L.M. Bergasa, J.J. Yebes, M.A. Sotelo
  [show abstract] [hide abstract]
  ABSTRACT: This paper presents an algorithm to detect and recognize the information contained in road panels. The aim of this work is to complement the functionality of a traffic signposting inspection system based on computer vision, which is able to collect data related to the maintenance state of traffic signs and panels automatically. In this context, not only a good visibility of the panels is vital for a safe use by road users, but also the suitability of the information contained in the traffic panels. The algorithm presented here, which is based on SIFT descriptors to recognize single characters and also on HMMs to recognize whole words, will be able to make an inventory of the information contained in traffic panels with the aim to check its reliability and brevity automatically. Experimental results and conclusions obtained after analysing a diverse set of real images show the effectiveness of the proposed method.
  Intelligent Transportation Systems (ITSC), 2010 13th International IEEE Conference on; 10/2010
• Article: Practical normalization of mRNA expression in quantitative PCR for cartilage research.

  M Pombo-Suarez, M Calaza, J J Gomez-Reino, A Gonzalez
  Osteoarthritis and Cartilage 12/2008; 17(6):818-9. · 3.90 Impact Factor
• Article: Association of a nsSNP in ADAMTS14 to some osteoarthritis phenotypes.

  J Rodriguez-Lopez, M Pombo-Suarez, J Loughlin, A Tsezou, F J Blanco, I Meulenbelt, P E Slagboom, A M Valdes, T D Spector, J J Gomez-Reino, A Gonzalez
  [show abstract] [hide abstract]
  ABSTRACT: To investigate the effect in OA (Osteoarthritis) susceptibility of putative damaging changes in ADAM (A Disintegrin And Metalloprotease) and ADAMTS (ADAM with ThromboSpondin motif) proteases. Non-synonymous single nucleotide polymorphisms (nsSNP) in 18 ADAMTS and 31 ADAM genes were analyzed with two software applications for prediction of functional damage. Four putative damaging nsSNP were found in ADAMTS2, ADAMTS14, ADAMTS16 and ADAM12, respectively. These nsSNPs were analyzed in case-control sample collections with a variety of phenotypes totalling 3217 OA patients and 2214 healthy controls, all of them Caucasians. No statistically significant differences were found in ADAMTS2, ADAMTS16 and ADAM12 nsSNPs. Conversely, the rare allele of the rs4747096 nsSNP in ADAMTS14 was overrepresented in women requiring joint replacement because of knee OA (O.R.(M-H) (odds ratio. Mantel-Haenszel)=1.41, 95% C.I.=1.1-1.8; P=0.002) and in patients with symptomatic hand OA (O.R.=1.37, 95% C.I.=1.0-1.9; P=0.047). A non significant increase in the frequency of the same allele was also found in patients with hip OA requiring prosthesis (O.R.(M-H)=1.14, 95% C.I.=1.0-1.3; P=0.08). No association was found with other OA phenotypes. Our findings implicate ADAMTS14 in OA, specifically in knee OA requiring joint replacement in women and, possibly, in hand OA. Independent association of ADAMTS14 genetic variation to knee OA in women has been communicated. ADAMTS14 involvement, if confirmed, will open a new area of interest in OA pathogenesis because of its role in the maturation of collagen fibers.
  Osteoarthritis and Cartilage 10/2008; 17(3):321-7. · 3.90 Impact Factor
• Article: Analysis of the functional relevance of a putative regulatory SNP of PDCD1, PD1.3, associated with systemic lupus erythematosus.

  M Suarez-Gestal, I Ferreiros-Vidal, J A Ortiz, J J Gomez-Reino, A Gonzalez
  [show abstract] [hide abstract]
  ABSTRACT: This study aimed to test the functional effects of the PD1.3 single nucleotide polymorphism (SNP) (rs11568821), which were proposed based on its association to systemic lupus erythematosus (SLE) susceptibility and in electrophoretic mobility shift assays (EMSA) results. We analysed transcriptional effects of the PD1.3 locus by enhancer reporter assays. Results were against the hypothesis that the PD1.3 locus acts as enhancer in transcriptional regulation of PDCD1. In addition, they excluded a differential effect of the PD1.3 alleles. EMSA results confirmed that oligonucleotides with the PD1.3 G allele bind RUNX1 but not those with the A allele. However, binding to PD1.3 G oligonucleotides was much lower than binding to positive control oligonucleotides. Criss-cross experiments showed that this was due to flanking nucleotides in the PD1.3 sequence that negatively affect RUNX1 binding. These results cast doubts on the functional relevance of the PD1.3 SNP and, together with the lack of association in several studies, put into question its role as an SLE susceptibility factor. Investigation of other PDCD1 polymorphisms is needed to uncover the possible effect of this gene on SLE susceptibility.
  Genes and immunity 07/2008; 9(4):309-15. · 4.22 Impact Factor
• Article: Further evidence of the role of frizzled-related protein gene polymorphisms in osteoarthritis.

  J Rodriguez-Lopez, M Pombo-Suarez, M Liz, J J Gomez-Reino, A Gonzalez
  [show abstract] [hide abstract]
  ABSTRACT: To replicate the association of frizzled-related protein (FRZB) non-synonymous polymorphisms with osteoarthritis (OA) susceptibility. Three groups of Spanish patients with OA were included: with total joint replacement due to primary OA in the hip (n = 310), or the knee (n = 277), or with hand OA (n = 242). Controls were more than 55 years old and did not show OA (n = 294). SNPs rs288326 (R200W) and rs7775 (R324G) were genotyped. There were no significant differences in allele frequencies between controls and each of the three groups of OA patients. However, allele G of the R324G SNP showed a trend to be more frequent in patients with a clinical OA syndrome at multiple joints (p = 0.07), specifically in women of the total hip replacement group (8.3% in patients without other affected joints, 13.1% with one, 15.9% with two and 24.1% with more than two additional joints, p for trend = 0.008). No direct replication of previous OA association findings was obtained but the results suggest that the R324G SNP of the FRZB gene may have an effect in OA development in multiple joints, with a specific severe involvement of the hip in women. This phenotype could reconcile previous studies that showed association either with generalised OA or with hip OA in women.
  Annals of the Rheumatic Diseases 09/2007; 66(8):1052-5. · 8.73 Impact Factor
• Source

  Available from: InTech

  Chapter: Mechanical and Kinematics Design Methodology of a New Wheelchair with Additional Capabilities

  R. Morales, A. Gonzalez, V. Feliu
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  ABSTRACT: A new approach has been presented for designing and building a climbing-wheelchair. Its main features are: a) automatic adaptation to steps with different heights, b) easy maintenance of the verticality of the wheelchair, c) the climbing of stairs requires less effort from the actuators (only a subset of the actuated degrees of freedom is needed when the trajectory slope of the chair frame is the same as the slope of the racks or the slope of the wheels, depending on the configuration), d) weight and energy consumption are reduced and e) wheelchair stability is guaranteed during every moment because its weight is always transferred to horizontal surfaces and the support polygon is always greater than or equal to the support polygon of the conventional powered wheelchairs. The mechanical design methodology decomposes the original mechanical problem into two different subproblems which have been implemented with separate mechanical devices. On the one hand the climbing mechanism solves the problem to overcome a single step and on the other hand, the positioning mechanism ensures the stability and the verticality of the seat in environments with different height axles. Then, the synthesis process depicts the final dimensions of both mechanical devices. The final solution found has some advantages: very high payload capacity, light weight and low cost. The kinematics design methodology allows full motion of the degrees of freedom of the whole system, and it has been adapted to continuous smooth profiles and profiles composed of flat floor and staircases (this profile admits analytical solutions). The inverse kinematics model of our wheelchair prototype makes it possible to determine the real time trajectories for the articulated degrees of freedom of the wheelchair. This is important since a comfortable motion of the wheelchair requires an individual motion of the degrees of freedom in order to maintain a desired motion of the whole system. The kinematics model and the climbing strategies have been applied together to the wheelchair prototype to illustrate the good environment adaptation of our design as it moves in a staircase composed by two steps while the verticality of the seat and the trajectory of the centre of mass are maintained. All the experiments have been prepared in such a way the passenger comfort has to be guaranteed. The control trajectory is easier, as it relies basically on the motion of only one of the actuators which compose the positioning system (responsible for angle 1) while the second actuator (responsible for angle 2) remains constant throughout the trajectory. Moreover, the planned trajectories are consistent and agree with the experimental results. The reported experimental results show small deviations from the verticality, and demonstrate that our mechanical design allows our chair to climb stairs with the proposed open loop control strategy, with minimum sensors requirements, and guaranteeing the stability and the comfort of the passenger.
  09/2007; , ISBN: 978-3-902613-15-8
• Article: Opposed independent effects and epistasis in the complex association of IRF5 to SLE.

  I Ferreiro-Neira, M Calaza, E Alonso-Perez, M Marchini, R Scorza, G D Sebastiani, F J Blanco, I Rego, R Pullmann, C G Kallenberg, [......], T Witte, C Papasteriades, I Kappou-Rigatou, E Endreffy, A Kovacs, J Ordi-Ros, E Balada, P Carreira, J J Gomez-Reino, A Gonzalez
  [show abstract] [hide abstract]
  ABSTRACT: Genetic variation in the interferon regulatory factor 5 (IRF5) gene affects systemic lupus erythematosus (SLE) susceptibility. However, association is complex and incompletely defined. We obtained fourteen European sample collections with a total of 1383 SLE patients and 1614 controls to better define the role of the different IRF5 variants. Eleven polymorphisms were studied, including nine tag single nucleotide polymorphisms (SNPs) and two extra functional polymorphisms. Two tag SNPs showed independent and opposed associations: susceptibility (rs10488631, P<10(-17)) and protection (rs729302, P<10(-6)). Haplotype analyses showed that the susceptibility haplotype, identified by the minor allele of rs10488631, can be due to epistasis between three IRF5 functional polymorphisms. These polymorphisms determine increased mRNA expression, a splice variant with a different exon 1 and a longer proline-rich region in exon 6. This result is striking as none of the three polymorphisms had an independent effect on their own. Protection was independent of these polymorphisms and seemed to reside in the 5' side of the gene. In conclusion, our results help to understand the role of the IRF5 locus in SLE susceptibility by clearly separating protection from susceptibility as caused by independent polymorphisms. In addition, we have found evidence for epistasis between known functional polymorphisms for the susceptibility effect.
  Genes and Immunity 07/2007; 8(5):429-38. · 3.87 Impact Factor
• Article: Bias in association studies of systemic lupus erythematosus susceptibility due to geographical variation in the frequency of a programmed cell death 1 polymorphism across Europe.

  I Ferreiros-Vidal, S D'Alfonso, C Papasteriades, F N Skopouli, M Marchini, R Scorza, S Migliaresi, G D Sebastiani, E Endreffy, M Mavromati, I Kappou-Rigatou, S Ruzickova, C Dostal, R E Schmidt, T Witte, J J Gomez-Reino, A Gonzalez
  [show abstract] [hide abstract]
  ABSTRACT: We obtained eight collections of DNA samples from ethnically matched systemic lupus erythematosus (SLE) patients and controls from five European countries totaling 783 patients and 1210 controls. A highly significant cline in the frequency of the PD1.3 A allele was found among controls but not among SLE patients. The frequency of the PD1.3 A allele increased from the Northeast to the Southwest of Europe. The cline was clearly apparent (P=1.2 x 10(-6)) when data from controls of other five SLE susceptibility studies were included in the analysis. This variation has severely biased SLE association studies owing to the lack of parallel changes in SLE patients. As a consequence, the PD1.3 A allele was more common in SLE patients than in controls in the Northeast and Center of Europe, similar to controls in Southeast Europe, and less frequent than in the controls in the Southwest of the Continent. This dissociation in allele frequencies between SLE patients and controls in different subpopulations indicated that programmed cell death 1 variation and disease susceptibility are not independent but the type of relationship is currently unclear. As allele frequency clines are common in other polymorphisms their impact in genetic epidemiology studies should be carefully considered.
  Genes and Immunity 04/2007; 8(2):138-46. · 3.87 Impact Factor
• Article: Environment adaptation of a new staircase-climbing wheelchair

  R. Morales, A. Gonzalez, V. Feliu, P. Pintado
  [show abstract] [hide abstract]
  ABSTRACT: This paper describes the mechanical devices conforming a novel wheelchair prototype capable of climbing staircases. The key feature of the mechanical design is the use of two decoupled mechanisms in each axle, one to negotiate steps, and the other to position the axle with respect to the chair to accommodate the overall slope. This design simplifies the control task substantially. Kinematic models are necessary to describe the behavior of the system and to control the actuated degrees of freedom of the wheelchair to ensure the passenger’s comfort. The choice of a good climbing strategy simplifies the control and decreases the power consumption of the wheelchair. In particular, we demonstrate that if the movement of the wheelchair has the same slope as the racks or the same slope as the terrain that supports the wheel axles (depending on the configuration mechanism), control is easier and power consumption is less. Experimental results are reported which show the behavior of the prototype as it moves over different situations: (a) ascending a single step of different heights using different climbing strategies; and (b) climbing a staircase using an appropriate climbing strategy that simplifies the control and reduces the power consumption of the wheelchair.
  Autonomous Robots 01/2007; 23(4):275-292. · 1.50 Impact Factor
• Conference Proceeding: Coordinated motion of a new staircase climbing wheelchair with increased passenger comfort

  R. Morales, V. Feliu, A. Gonzalez, P. Pintado
  [show abstract] [hide abstract]
  ABSTRACT: This paper describes the mechanical devices, the movements and the trajectory generation of a novel wheelchair prototype capable of climbing staircases. The key feature of the mechanical design is the use of two decoupled mechanisms for each axle, one used to negotiate steps, and the other to position the axle with respect to the chair to accommodate the overall slope. This decoupling makes many different climbing strategies possible, the overall mechanism becoming extraordinarily versatile from a control point of view. A control system is necessary to synchronize the movements of all the actuators of the wheelchair so that its centre of mass can follow arbitrary spatial trajectories. Different trajectories have been designed in order to keep the seat as erect as possible to guarantee passenger comfort. Experimental results with the real prototype are reported which show the efficiency of our mechanism, the accuracy of the developed kinematic models for control, and the comparison of comfort for two different spatial trajectories
  Robotics and Automation, 2006. ICRA 2006. Proceedings 2006 IEEE International Conference on; 06/2006
• Article: CARD15/NOD2 analysis in rheumatoid arthritis susceptibility.

  I Ferreirós-Vidal, F Barros, J L Pablos, A Carracedo, J J Gómez-Reino, A Gonzalez
  [show abstract] [hide abstract]
  ABSTRACT: To determine if the mutations in the CARD15/NOD2 gene predisposing to Crohn's disease (CD) contribute also to the genetic susceptibility to rheumatoid arthritis (RA). The frequencies of the three commonest mutations of CARD15/NOD2 predisposing to CD (2104C > T, 2722G>C and 3020insC) were determined in 210 RA patients and 227 controls. Allelic frequencies of the CARD15/NOD2 mutations in RA patients (2104C>T, 2.8%; 2722G>C, 0.9%; and 3020insC, 2.4%) did not differ significantly from the controls (2104C>T, 5.3%; 2722G>C, 0.7%; and 3020insC, 1.1%). There was no evidence of association between the commonest CD CARD15/NOD2 mutations and RA susceptibility.
  Rheumatology 11/2003; 42(11):1380-2. · 4.06 Impact Factor
• Article: The three most common CARD15 mutations associated with Crohn's disease and the chromosome 16 susceptibility locus for systemic lupus erythematosus.

  I Ferreiros-Vidal, J Garcia-Meijide, P Carreira, F Barros, A Carracedo, J J Gomez-Reino, A Gonzalez
  [show abstract] [hide abstract]
  ABSTRACT: To test if the three most common mutations contributing to Crohn's disease on the CARD15/NOD2 gene could contribute also to genetic susceptibility to systemic lupus erythematosus (SLE), which has been found to be linked to the region of chromosome 16q13 where the CARD15 gene is located. We obtained DNA samples from the blood of 189 SLE patients (according to the American College of Rheumatology classification criteria) and 194 controls of Spanish ancestry. Genotypes for the three CARD15 mutations (3020insC, 2722G>C and 2104C>T) were determined by hybridization with fluorescence resonance energy transfer probes on a LightCycler real-time polymerase chain reaction system. CARD15 genotypes were similar in SLE patients and in controls from the general population (allelic frequencies for 3020insC 0.013 in SLE patients vs 0.013 in controls; for 2722G > C 0.011 vs 0.008; and for 2104C > T 0.032 vs 0.051). We did not find evidence that the Crohn's disease-associated mutations on CARD15 contributed to SLE susceptibility.
  Rheumatology 04/2003; 42(4):570-4. · 4.06 Impact Factor
• Article: HDAC5 is required for maintenance of pericentric heterochromatin, and controls cell-cycle progression and survival of human cancer cells.

  P Peixoto, V Castronovo, N Matheus, C Polese, Olivier Peulen, A Gonzalez, M Boxus, E Verdin, M Thiry, F Dequiedt, D Mottet
  [show abstract] [hide abstract]
  ABSTRACT: 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.Cell Death and Differentiation advance online publication, 3 February 2012; doi:10.1038/cdd.2012.3.
• Article: HDAC5 is required for maintenance of pericentric heterochromatin, and controls cell-cycle progression and survival of human cancer cells.

  P Peixoto, V Castronovo, N Matheus, C Polese, Olivier Peulen, A Gonzalez, M Boxus, E Verdin, M Thiry, F Dequiedt, D Mottet
  [show abstract] [hide abstract]
  ABSTRACT: 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.Cell Death and Differentiation advance online publication, 3 February 2012; doi:10.1038/cdd.2012.3.