The Experts below are selected from a list of 291 Experts worldwide ranked by ideXlab platform

Eric Verdin - One of the best experts on this subject based on the ideXlab platform.

  • Histone Deacetylase 7 mediates tissue-specific autoimmunity via control of innate effector function in invariant Natural Killer T Cells
    eLife, 2018
    Co-Authors: Herbert G. Kasler, Eric Verdin
    Abstract:

    To protect us, our immune system must walk a narrow line: while it eliminates all external threats, it also has to refrain from attacking the healthy tissues of our body. When such misdirected attacks do take place, they can result in life-threatening autoimmune diseases. T cells are a highly diverse population of immune cells that can recognize and orchestrate the body’s response against infected or ‘abnormal’ cells. Early in the development of most types of T cells, the body normally weeds out the ones that target healthy tissues. A gene known as Histone Deacetylase 7 (HDAC7) regulates this process. However, when HDAC7 carries a specific mutation called HDAC7-ΔP, dangerous T cells that can attack healthy tissues ‘escape’ this selection. The HDAC7-ΔP mutation allows T cells that react to many different tissues to survive. However, in mice with this genetic change, only the liver, the digestive system and the pancreas are actually damaged by the immune system and show signs of autoimmune diseases. Why are these organs affected, and not the others? Here, Kasler, Lee et al. find that HDAC7 also helps another type of T cell to develop. Known as invariant natural killer T – or iNKT – cells, these cells specialize in defending the gut, liver and pancreas against bacteria. Mice with the HDAC7-ΔP mutation can no longer produce iNKT cells. Remarkably, restoring normal levels of these cells in the HDAC7-ΔP animals reduces the symptoms of their autoimmune diseases, even though the mice are still carrying the T cells that have escaped selection and can attack healthy tissues. Taken together, these results explain why a mutation in HDAC7 can create problems only for specific organs in the body. However, it is still not clear exactly why losing iNKT cells increases autoimmune attacks of the tissues they normally occupy. One possibility is that these cells limit access to the organs by other immune cells that could cause damage. Another option is that, when iNKT cells are absent, gut bacteria can attack and create an inflammation. This recruits T cells to the site, including the ones that can attack healthy organs. In humans, mutations in HDAC7, as well as in other genes that regulate it, are also associated with autoimmune disorders of the digestive tract and liver. These include inflammatory bowel diseases such as ulcerative colitis or Crohn’s disease. Ultimately the findings presented by Kasler, Lee et al. could be a starting point for finding new treatments for these illnesses.

  • Histone Deacetylase 7 Mediates Tissue-Specific Autoimmunity via Control of Innate Effector Function in Invariant Natural Killer T-Cells
    bioRxiv, 2017
    Co-Authors: Herbert G. Kasler, Eric Verdin
    Abstract:

    We report that Histone Deacetylase 7 (HDAC7) controls the thymic effector programming of Natural Killer T (NKT) cells, and that interference with this function contributes to tissue-specific autoimmunity. Gain of HDAC7 function in thymocytes blocks both negative selection and NKT development, diverting these cells into a Tconv-like lineage. Conversely, HDAC7 deletion promotes thymocyte apoptosis and causes aberrant expansion of innate-effector cells. Investigating the mechanisms involved, we found that HDAC7 binds PLZF and modulates PLZF-dependent transcription. Moreover, HDAC7 and many of its transcriptional targets are human risk loci for IBD and PSC, autoimmune diseases that strikingly resemble the disease we observe in HDAC7 gain-of-function in mice. Importantly, reconstitution of iNKT cells in these mice abrogated their disease, suggesting that interaction between the defects in negative selection and iNKT cells caused by altered HDAC7 function can cause tissue-restricted autoimmunity, a finding that may explain the association between HDAC7 and hepatobiliary autoimmunity.

  • nuclear export of Histone Deacetylase 7 during thymic selection is required for immune self tolerance
    The EMBO Journal, 2012
    Co-Authors: Herbert G. Kasler, D Mottet, Amy M Collins, Eric Verdin
    Abstract:

    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-ΔP) in thymocytes. We find that HDAC7-ΔP 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.

  • Angiopoietin-1 and Vascular Endothelial Growth Factor Regulation of Leukocyte Adhesion to Endothelial Cells Role of Nuclear Receptor-77
    Arteriosclerosis Thrombosis and Vascular Biology, 2012
    Co-Authors: Hodan Ismail, Eric Verdin, Mahroo Mofarrahi, Raquel Echavarria, Sharon Harel, Huiyan Zeng, Sabah N. A. Hussain
    Abstract:

    Objective— Vascular endothelial growth factor (VEGF) promotes leukocyte adhesion to endothelial cells (ECs). Angiopoietin-1 (Ang-1) inhibits this response. Nuclear receptor-77 (Nur77) is a proangiogenic nuclear receptor. In the present study, we assessed the influence of Ang-1 and VEGF on Nur77 expression in ECs, and evaluated its role in Ang-1/VEGF-mediated leukocyte adhesion. Methods and Results— Expression of Nur77 was evaluated with real-time polymerase chain reaction and immunoblotting. Adhesion of leukocytes to ECs was monitored with inverted microscopy. Nur77 expression or activity was inhibited using adenoviruses expressing dominant-negative form of Nur77, retroviruses expressing Nur77 in the antisense direction, and small interfering RNA oligos. Both Ang-1 and VEGF induce Nur77 expression, by >5- and 30-fold, respectively. When combined, Ang-1 potentiates VEGF-induced Nur77 expression. Ang-1 induces Nur77 through the phosphoinositide 3-kinase and extracellular signal-regulated protein kinase 1/2 pathways. VEGF induces Nur77 expression through the protein kinase D/Histone Deacetylase 7/myocyte enhancer factor 2 and extracellular signal-regulated protein kinase 1/2 pathways. VEGF induces nuclear factor-kappaB transcription factor, vascular cell adhesion molecule-1, and E-selectin expressions, and promotes leukocyte adhesion to ECs. Ang-1 inhibits these responses. This inhibitory effect of Ang-1 disappears when Nur77 expression is disrupted, restoring the inductive effects of VEGF on adhesion molecule expression, and increased leukocyte adhesion to ECs. Conclusion— Nur77 promotes anti-inflammatory effects of Ang-1, and functions as a negative feedback inhibitor of VEGF-induced EC activation.

  • Histone Deacetylase 7 regulates cell survival and tcr signaling in cd4 cd8 double positive thymocytes
    Journal of Immunology, 2011
    Co-Authors: Herbert G. Kasler, Eric N Olson, Bryan Young, D Mottet, Amy M Collins, Eric Verdin
    Abstract:

    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 Jα 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.

Junyao Yang - One of the best experts on this subject based on the ideXlab platform.

  • a Histone Deacetylase 7 derived peptide promotes vascular regeneration via facilitating 14 3 3γ phosphorylation
    Stem Cells, 2020
    Co-Authors: Junyao Yang, Ana Moraga, Jing Xu, Yue Zhao, Andriana Margariti, Qiang Zhao, Wei Ding, Gang Wang, Min Zhang
    Abstract:

    : Histone Deacetylase 7 (HDAC7) plays a pivotal role in the maintenance of the endothelium integrity. In this study, we demonstrated that the intron-containing Hdac7 mRNA existed in the cytosol and that ribosomes bound to a short open reading frame (sORF) within the 5' terminal non-coding area of this Hdac7 mRNA in response to vascular endothelial growth factor (VEGF) stimulation in the isolated stem cell antigen-1 positive (Sca1+ ) vascular progenitor cells (VPCs). A 7-amino acid (7A) peptide has been demonstrated to be translated from the sORF in Sca1+ -VPCs in vitro and in vivo. The 7A peptide was shown to receive phosphate group from the activated mitogen-activated protein kinase MEKK1 and transfer it to 14-3-3 gamma protein, forming an MEKK1-7A-14-3-3γ signal pathway downstream VEGF. The exogenous synthetic 7A peptide could increase Sca1+ -VPCs cell migration, reendothelialization in the femoral artery injury and angiogenesis in hindlimb ischemia. An Hd7-7sFLAG transgenic mice line was generated as the loss-of-function model, in which the 7A peptide was replaced by a FLAG-tagged scrabbled peptide. Loss of the endogenous 7A impaired Sca1+ -VPCs cell migration, reendothelialization of the injured femoral artery and angiogenesis in ischemic tissues, which could be partially rescued by the addition of the exogenous 7A/7Ap peptide. This study provides evidence that sORFs can be alternatively translated and the derived peptides may play an important role in physiological processes including vascular remodeling. © AlphaMed Press 2019 SIGNIFICANCE STATEMENT: Histone Deacetylase 7 (HDAC7) plays a pivotal role in the maintenance of the endothelial integrity. Short open reading frames (sORFs) exist within the 5' terminal non-coding area of Hdac7 mRNA. It remains unclear whether these sORFs contribute to HADC7 functions. In this study, we demonstrated that a 7-amino acid peptide could be translated from a sORF. This peptide could act as phosphate group carrier, forming a novel signal transduction pathway, the MEKK1-7A-14-3-3? pathway, downstream VEGF. The novel signal pathway may be involved in vessel wall resident stem/progenitor cell activation and vascular remodeling.

  • A Histone Deacetylase 7‐derived peptide promotes vascular regeneration via facilitating 14‐3‐3γ phosphorylation
    Stem Cells, 2020
    Co-Authors: Junyao Yang, Ana Moraga, Jing Xu, Yue Zhao, Andriana Margariti, Qiang Zhao, Wei Ding, Gang Wang
    Abstract:

    : Histone Deacetylase 7 (HDAC7) plays a pivotal role in the maintenance of the endothelium integrity. In this study, we demonstrated that the intron-containing Hdac7 mRNA existed in the cytosol and that ribosomes bound to a short open reading frame (sORF) within the 5' terminal non-coding area of this Hdac7 mRNA in response to vascular endothelial growth factor (VEGF) stimulation in the isolated stem cell antigen-1 positive (Sca1+ ) vascular progenitor cells (VPCs). A 7-amino acid (7A) peptide has been demonstrated to be translated from the sORF in Sca1+ -VPCs in vitro and in vivo. The 7A peptide was shown to receive phosphate group from the activated mitogen-activated protein kinase MEKK1 and transfer it to 14-3-3 gamma protein, forming an MEKK1-7A-14-3-3γ signal pathway downstream VEGF. The exogenous synthetic 7A peptide could increase Sca1+ -VPCs cell migration, reendothelialization in the femoral artery injury and angiogenesis in hindlimb ischemia. An Hd7-7sFLAG transgenic mice line was generated as the loss-of-function model, in which the 7A peptide was replaced by a FLAG-tagged scrabbled peptide. Loss of the endogenous 7A impaired Sca1+ -VPCs cell migration, reendothelialization of the injured femoral artery and angiogenesis in ischemic tissues, which could be partially rescued by the addition of the exogenous 7A/7Ap peptide. This study provides evidence that sORFs can be alternatively translated and the derived peptides may play an important role in physiological processes including vascular remodeling. © AlphaMed Press 2019 SIGNIFICANCE STATEMENT: Histone Deacetylase 7 (HDAC7) plays a pivotal role in the maintenance of the endothelial integrity. Short open reading frames (sORFs) exist within the 5' terminal non-coding area of Hdac7 mRNA. It remains unclear whether these sORFs contribute to HADC7 functions. In this study, we demonstrated that a 7-amino acid peptide could be translated from a sORF. This peptide could act as phosphate group carrier, forming a novel signal transduction pathway, the MEKK1-7A-14-3-3? pathway, downstream VEGF. The novel signal pathway may be involved in vessel wall resident stem/progenitor cell activation and vascular remodeling.

  • Histone Deacetylase 7 derived peptides play a vital role in vascular repair and regeneration
    Advanced Science, 2018
    Co-Authors: Junyao Yang, Ana Moraga, He Wang, Rongkuan Jiao, Zhongyi Zhang, Yanhua Hu, Deling Kong, Qingbo Xu, Lingfang Zeng, Qiang Zhao
    Abstract:

    : Cardiovascular disease is a leading cause of morbidity and mortality globally. Accumulating evidence indicates that local resident stem/progenitor cells play an important role in vascular regeneration. Recently, it is demonstrated that a Histone Deacetylase 7-derived 7-amino acid peptide (7A, MHSPGAD) is critical in modulating the mobilization and orientated differentiation of these stem/progenitor cells. Here, its therapeutic efficacy in vascular repair and regeneration is evaluated. In vitro functional analyses reveal that the 7A peptide, in particular phosphorylated 7A (7Ap, MH[pSer]PGAD), could increase stem cell antigen-1 positive (Sca1+) vascular progenitor cell (VPC) migration and differentiation toward an endothelial cell lineage. Furthermore, local delivery of 7A as well as 7Ap could enhance angiogenesis and ameliorate vascular injury in ischaemic tissues; these findings are confirmed in a femoral artery injury model and a hindlimb ischaemia model, respectively. Importantly, sustained delivery of 7A, especially 7Ap, from tissue-engineered vascular grafts could attract Sca1+-VPC cells into the grafts, contributing to endothelialization and intima/media formation in the vascular graft. These results suggest that this novel type of peptides has great translational potential in vascular regenerative medicine.

  • a Histone Deacetylase 7 derived 7 amino acid peptide acts as a phosphorylation carrier
    Heart, 2016
    Co-Authors: Junyao Yang, Lingfang Zeng
    Abstract:

    Histone Deacetylase 7 (HDAC7) belongs to class II HDAC family, playing a pivotal role in the maintenance of endothelium integrity. There are 8 splicing variants in mouse HDAC7 mRNAs. Within the 5’ terminal non-coding area of some variants, there exist some short open reading frames (sORFs). Whether these sORFs can be translated and their potential roles in cellular physiology remain unclear. In this study, we demonstrated that one sORF encoding a 7 amino acids (aa)-peptide could be translated in vascular progenitor cells (VPCs) in response to vascular endothelial cell growth factor (VEGF). The 7aa-peptide (7A) could be phosphorylated at serine residue via MEKK1. Importantly, the phosphorylated 7A (7Ap) could transfer the phosphorylation group to the Threonine residue of the 14–3–3I³ protein in a cell free in-gel buffer system. The in vitro functional analyses revealed that 7A enhanced VEGF-induced VPC migration and differentiation toward endothelial cell (EC) lineage, in which MEKK1 and 14–3–3I³ served as the upstream kinase and the downstream effector respectively. Knockdown of either MEKK1 or 14–3–3I³ attenuated VEGF-induced VPC migration and differentiation. Exogenous 7Ap could rescue the effect of VEGF on the MEKK1 siRNA-transfected but not on the 14–3–3I³ siRNA-transfected VPCs. The in vivo studies showed that 7A especially 7Ap induced capillary vessel formation within Matrigel plug assays, increased re-endothelialization and suppressed neointima formation in the femoral artery injury model, and promoted the foot blood perfusion recovery in the hindlimb ischemia model via increasing Sca1+ cell niche formation. These results indicate that the sORFs within the non-coding area can be translated under some circumstances and that the 7aa-peptide may play an important role in cellular processes like migration and differentiation via acting as a phosphorylation carrier.

  • analysis of Histone Deacetylase 7 hdac7 alternative splicing and its role in embryonic stem cell differentiation toward smooth muscle lineage
    Methods of Molecular Biology, 2016
    Co-Authors: Junyao Yang, Andriana Margariti, Lingfang Zeng
    Abstract:

    : Histone Deacetylases (HDACs) have a central role in the regulation of gene expression, which undergoes alternative splicing during embryonic stem cell (ES) cell differentiation. Alternative splicing gives rise to vast diversity over gene information, arousing public concerns in the last decade. In this chapter, we describe a strategy to detect HDAC7 alternative splicing and analyze its function on ES cell differentiation.

Andriana Margariti - One of the best experts on this subject based on the ideXlab platform.

  • a Histone Deacetylase 7 derived peptide promotes vascular regeneration via facilitating 14 3 3γ phosphorylation
    Stem Cells, 2020
    Co-Authors: Junyao Yang, Ana Moraga, Jing Xu, Yue Zhao, Andriana Margariti, Qiang Zhao, Wei Ding, Gang Wang, Min Zhang
    Abstract:

    : Histone Deacetylase 7 (HDAC7) plays a pivotal role in the maintenance of the endothelium integrity. In this study, we demonstrated that the intron-containing Hdac7 mRNA existed in the cytosol and that ribosomes bound to a short open reading frame (sORF) within the 5' terminal non-coding area of this Hdac7 mRNA in response to vascular endothelial growth factor (VEGF) stimulation in the isolated stem cell antigen-1 positive (Sca1+ ) vascular progenitor cells (VPCs). A 7-amino acid (7A) peptide has been demonstrated to be translated from the sORF in Sca1+ -VPCs in vitro and in vivo. The 7A peptide was shown to receive phosphate group from the activated mitogen-activated protein kinase MEKK1 and transfer it to 14-3-3 gamma protein, forming an MEKK1-7A-14-3-3γ signal pathway downstream VEGF. The exogenous synthetic 7A peptide could increase Sca1+ -VPCs cell migration, reendothelialization in the femoral artery injury and angiogenesis in hindlimb ischemia. An Hd7-7sFLAG transgenic mice line was generated as the loss-of-function model, in which the 7A peptide was replaced by a FLAG-tagged scrabbled peptide. Loss of the endogenous 7A impaired Sca1+ -VPCs cell migration, reendothelialization of the injured femoral artery and angiogenesis in ischemic tissues, which could be partially rescued by the addition of the exogenous 7A/7Ap peptide. This study provides evidence that sORFs can be alternatively translated and the derived peptides may play an important role in physiological processes including vascular remodeling. © AlphaMed Press 2019 SIGNIFICANCE STATEMENT: Histone Deacetylase 7 (HDAC7) plays a pivotal role in the maintenance of the endothelial integrity. Short open reading frames (sORFs) exist within the 5' terminal non-coding area of Hdac7 mRNA. It remains unclear whether these sORFs contribute to HADC7 functions. In this study, we demonstrated that a 7-amino acid peptide could be translated from a sORF. This peptide could act as phosphate group carrier, forming a novel signal transduction pathway, the MEKK1-7A-14-3-3? pathway, downstream VEGF. The novel signal pathway may be involved in vessel wall resident stem/progenitor cell activation and vascular remodeling.

  • A Histone Deacetylase 7‐derived peptide promotes vascular regeneration via facilitating 14‐3‐3γ phosphorylation
    Stem Cells, 2020
    Co-Authors: Junyao Yang, Ana Moraga, Jing Xu, Yue Zhao, Andriana Margariti, Qiang Zhao, Wei Ding, Gang Wang
    Abstract:

    : Histone Deacetylase 7 (HDAC7) plays a pivotal role in the maintenance of the endothelium integrity. In this study, we demonstrated that the intron-containing Hdac7 mRNA existed in the cytosol and that ribosomes bound to a short open reading frame (sORF) within the 5' terminal non-coding area of this Hdac7 mRNA in response to vascular endothelial growth factor (VEGF) stimulation in the isolated stem cell antigen-1 positive (Sca1+ ) vascular progenitor cells (VPCs). A 7-amino acid (7A) peptide has been demonstrated to be translated from the sORF in Sca1+ -VPCs in vitro and in vivo. The 7A peptide was shown to receive phosphate group from the activated mitogen-activated protein kinase MEKK1 and transfer it to 14-3-3 gamma protein, forming an MEKK1-7A-14-3-3γ signal pathway downstream VEGF. The exogenous synthetic 7A peptide could increase Sca1+ -VPCs cell migration, reendothelialization in the femoral artery injury and angiogenesis in hindlimb ischemia. An Hd7-7sFLAG transgenic mice line was generated as the loss-of-function model, in which the 7A peptide was replaced by a FLAG-tagged scrabbled peptide. Loss of the endogenous 7A impaired Sca1+ -VPCs cell migration, reendothelialization of the injured femoral artery and angiogenesis in ischemic tissues, which could be partially rescued by the addition of the exogenous 7A/7Ap peptide. This study provides evidence that sORFs can be alternatively translated and the derived peptides may play an important role in physiological processes including vascular remodeling. © AlphaMed Press 2019 SIGNIFICANCE STATEMENT: Histone Deacetylase 7 (HDAC7) plays a pivotal role in the maintenance of the endothelial integrity. Short open reading frames (sORFs) exist within the 5' terminal non-coding area of Hdac7 mRNA. It remains unclear whether these sORFs contribute to HADC7 functions. In this study, we demonstrated that a 7-amino acid peptide could be translated from a sORF. This peptide could act as phosphate group carrier, forming a novel signal transduction pathway, the MEKK1-7A-14-3-3? pathway, downstream VEGF. The novel signal pathway may be involved in vessel wall resident stem/progenitor cell activation and vascular remodeling.

  • analysis of Histone Deacetylase 7 hdac7 alternative splicing and its role in embryonic stem cell differentiation toward smooth muscle lineage
    Methods of Molecular Biology, 2016
    Co-Authors: Junyao Yang, Andriana Margariti, Lingfang Zeng
    Abstract:

    : Histone Deacetylases (HDACs) have a central role in the regulation of gene expression, which undergoes alternative splicing during embryonic stem cell (ES) cell differentiation. Alternative splicing gives rise to vast diversity over gene information, arousing public concerns in the last decade. In this chapter, we describe a strategy to detect HDAC7 alternative splicing and analyze its function on ES cell differentiation.

  • splicing of Histone Deacetylase 7 modulates smooth muscle cell proliferation and neointima formation through nuclear β catenin translocation
    Arteriosclerosis Thrombosis and Vascular Biology, 2011
    Co-Authors: Boda Zhou, Andriana Margariti, Gang Wang, Yanhua Hu, Lingfang Zeng, Ouassila Habi, Qingzhong Xiao, Daniel Martin, Xian Wang, Qingbo Xu
    Abstract:

    Objective— Vascular smooth muscle cell (SMC) proliferation has an indispensable role in the pathogenesis of vascular disease, but the mechanism is not fully elucidated. The epigenetic enzyme Histone Deacetylase 7 (HDAC7) is involved in endothelial homeostasis and SMC differentiation and could have a role in SMC proliferation. In this study, we sought to examine the effect of 2 HDAC7 isoforms on SMC proliferation and neointima formation. Methods and Results— We demonstrated that overexpression of unspliced HDAC7 (HDAC7u) could suppress SMC proliferation through downregulation of cyclin D1 and cell cycle arrest, whereas spliced HDAC7 (HDAC7s) could not. Small interfering RNA (siRNA)–mediated knockdown of HDAC7 increased SMC proliferation and induced nuclear translocation of β-catenin. Additional experiments showed that only HDAC7u could bind to β-catenin and retain it in the cytoplasm. Reporter gene assay and reverse transcription polymerase chain reaction revealed a reduction of β-catenin activity in cells overexpressing HDAC7u but not HDAC7s. Deletion studies indicated that the C-terminal region of HDAC7u is responsible for the interaction with β-catenin. However, the addition of amino acids to the N terminus of HDAC7u disrupted the binding, further strengthening our hypothesis that HDAC7s does not interact with β-catenin. The growth factor platelet-derived growth factor-BB increased the splicing of HDAC7 while simultaneously decreasing the expression of HDAC7u. Importantly, in an animal model of femoral artery wire injury, we demonstrated that knockdown of HDAC7 by siRNA aggravates neointima formation in comparison with control siRNA. Conclusion— Our findings demonstrate that splicing of HDAC7 modulates SMC proliferation and neointima formation through β-catenin nuclear translocation, which provides a potential therapeutic target in vascular disease.

  • Sp1-dependent activation of HDAC7 is required for platelet-derived growth factor-BB-induced smooth muscle cell differentiation from stem cells
    Journal of Biological Chemistry, 2010
    Co-Authors: Li Zhang, Andriana Margariti, Gang Wang, Lingfang Zeng, Anna Zampetaki, Shu Ye, Qingzhong Xiao
    Abstract:

    We have previously demonstrated that Histone Deacetylase 7 (HDAC7) expression and splicing play an important role in smooth muscle cell (SMC) differentiation from embryonic stem (ES) cells, but the molecular mechanisms of increased HDAC7 expression during SMC differentiation are currently unknown. In this study, we found that platelet-derived growth factor-BB (PDGF-BB) induced a 3-fold increase in the transcripts of HDAC7 in differentiating ES cells. Importantly, our data also revealed that PDGF-BB regulated HDAC7 expression not through phosphorylation of HDAC7 but through transcriptional activation. By dissecting its promoters with progressive deletion analysis, we identified the sequence between −343 and −292 bp in the 5′-flanking region of the Hdac7 gene promoter as the minimal PDGF-BB-responsive element, which contains one binding site for the transcription factor, specificity protein 1 (Sp1). Mutation of the Sp1 site within this PDGF-BB-responsive element abolished PDGF-BB-induced HDAC7 activity. PDGF-BB treatment enhanced Sp1 binding to the Hdac7 promoter in differentiated SMCs in vivo as demonstrated by the chromatin immunoprecipitation assay. Moreover, we also demonstrated that knockdown of Sp1 abrogated PDGF-BB-induced HDAC7 up-regulation and SMC differentiation gene expression in differentiating ES cells, although enforced expression of Sp1 alone was sufficient to increase the activity of the Hdac7 promoter and expression levels of SMC differentiation genes. Importantly, we further demonstrated that HDAC7 was required for Sp1-induced SMC differentiation of gene expression. Our data suggest that Sp1 plays an important role in the regulation of Hdac7 gene expression in SMC differentiation from ES cells. These findings provide novel molecular insights into the regulation of HDAC7 and enhance our knowledge in SMC differentiation and vessel formation during embryonic development.

Lingfang Zeng - One of the best experts on this subject based on the ideXlab platform.

  • Histone Deacetylase 7 derived peptides play a vital role in vascular repair and regeneration
    Advanced Science, 2018
    Co-Authors: Junyao Yang, Ana Moraga, He Wang, Rongkuan Jiao, Zhongyi Zhang, Yanhua Hu, Deling Kong, Qingbo Xu, Lingfang Zeng, Qiang Zhao
    Abstract:

    : Cardiovascular disease is a leading cause of morbidity and mortality globally. Accumulating evidence indicates that local resident stem/progenitor cells play an important role in vascular regeneration. Recently, it is demonstrated that a Histone Deacetylase 7-derived 7-amino acid peptide (7A, MHSPGAD) is critical in modulating the mobilization and orientated differentiation of these stem/progenitor cells. Here, its therapeutic efficacy in vascular repair and regeneration is evaluated. In vitro functional analyses reveal that the 7A peptide, in particular phosphorylated 7A (7Ap, MH[pSer]PGAD), could increase stem cell antigen-1 positive (Sca1+) vascular progenitor cell (VPC) migration and differentiation toward an endothelial cell lineage. Furthermore, local delivery of 7A as well as 7Ap could enhance angiogenesis and ameliorate vascular injury in ischaemic tissues; these findings are confirmed in a femoral artery injury model and a hindlimb ischaemia model, respectively. Importantly, sustained delivery of 7A, especially 7Ap, from tissue-engineered vascular grafts could attract Sca1+-VPC cells into the grafts, contributing to endothelialization and intima/media formation in the vascular graft. These results suggest that this novel type of peptides has great translational potential in vascular regenerative medicine.

  • a Histone Deacetylase 7 derived 7 amino acid peptide acts as a phosphorylation carrier
    Heart, 2016
    Co-Authors: Junyao Yang, Lingfang Zeng
    Abstract:

    Histone Deacetylase 7 (HDAC7) belongs to class II HDAC family, playing a pivotal role in the maintenance of endothelium integrity. There are 8 splicing variants in mouse HDAC7 mRNAs. Within the 5’ terminal non-coding area of some variants, there exist some short open reading frames (sORFs). Whether these sORFs can be translated and their potential roles in cellular physiology remain unclear. In this study, we demonstrated that one sORF encoding a 7 amino acids (aa)-peptide could be translated in vascular progenitor cells (VPCs) in response to vascular endothelial cell growth factor (VEGF). The 7aa-peptide (7A) could be phosphorylated at serine residue via MEKK1. Importantly, the phosphorylated 7A (7Ap) could transfer the phosphorylation group to the Threonine residue of the 14–3–3I³ protein in a cell free in-gel buffer system. The in vitro functional analyses revealed that 7A enhanced VEGF-induced VPC migration and differentiation toward endothelial cell (EC) lineage, in which MEKK1 and 14–3–3I³ served as the upstream kinase and the downstream effector respectively. Knockdown of either MEKK1 or 14–3–3I³ attenuated VEGF-induced VPC migration and differentiation. Exogenous 7Ap could rescue the effect of VEGF on the MEKK1 siRNA-transfected but not on the 14–3–3I³ siRNA-transfected VPCs. The in vivo studies showed that 7A especially 7Ap induced capillary vessel formation within Matrigel plug assays, increased re-endothelialization and suppressed neointima formation in the femoral artery injury model, and promoted the foot blood perfusion recovery in the hindlimb ischemia model via increasing Sca1+ cell niche formation. These results indicate that the sORFs within the non-coding area can be translated under some circumstances and that the 7aa-peptide may play an important role in cellular processes like migration and differentiation via acting as a phosphorylation carrier.

  • analysis of Histone Deacetylase 7 hdac7 alternative splicing and its role in embryonic stem cell differentiation toward smooth muscle lineage
    Methods of Molecular Biology, 2016
    Co-Authors: Junyao Yang, Andriana Margariti, Lingfang Zeng
    Abstract:

    : Histone Deacetylases (HDACs) have a central role in the regulation of gene expression, which undergoes alternative splicing during embryonic stem cell (ES) cell differentiation. Alternative splicing gives rise to vast diversity over gene information, arousing public concerns in the last decade. In this chapter, we describe a strategy to detect HDAC7 alternative splicing and analyze its function on ES cell differentiation.

  • Abstract 186: Hdac7-derived 7aa Peptide May Function as a Phosphorylation Carrier
    Arteriosclerosis Thrombosis and Vascular Biology, 2016
    Co-Authors: Junyao Yang, Wen Wang, Qian Wang, Lingfang Zeng
    Abstract:

    Background: Histone Deacetylase 7 (HDAC7) belongs to class II HDAC family, playing a pivotal role in the maintenance of endothelium integrity. There are 8 splicing variants in mouse HDAC7 mRNAs. Within the 5’ terminal non-coding area of some variants, there exist some short open reading frames (sORFs). Whether these sORFs can be translated and their potential roles in cellular physiology remain unclear. Method and results: Our previous studies suggested that one mouse HDAC7 produced a 7aa peptide from the non-coding area. In this study, we demonstrated that one sORF encoding a 7 amino acids (aa)-peptide could be translated in response to vascular endothelial cell growth factor (VEGF) in vascular progenitor cells (VPCs). The 7aa-peptide (7A) could be phosphorylated at serine residue via MEKK1. Importantly, the phosphorylated 7aa-peptide (7Ap) could transfer the phosphorylation group to the Thr residue of the 14-3-3γ protein in a cell free in-gel buffer system. The in vitro functional analyses revealed that 7A enhanced VEGF-induced VPC migration and differentiation toward endothelial cell (EC) lineage, in which MEKK1 and 14-3-3γ served as upstream kinase and downstream effector respectively. Knockdown of either MEKK1 or 14-3-3γ attenuated VEGF-induced VPC migration and differentiation. Exogenous 7Ap could rescue VEGF effect in MEKK1 but not in 14-3-3γ knockdown cells. The in vivo studies showed that 7A especially 7Ap induced capillary vessel formation within matrigel plug assays, increased re-endothelialization and suppressed neointima formation in the femoral artery injury model, and promoted the foot blood perfusion recovery in the hindlimb ischemia model. Conclusion: These results indicate that the sORFs within the non-coding area can be translated under some circumstances and that the 7aa-peptide may play an important role in cellular processes like migration and differentiation via acting as a phosphorylation carrier. Significance: As a phosphorylation carrier, 7aa possesses therapeutic potentials in tackling angiogenesis related diseases.

  • splicing of Histone Deacetylase 7 modulates smooth muscle cell proliferation and neointima formation through nuclear β catenin translocation
    Arteriosclerosis Thrombosis and Vascular Biology, 2011
    Co-Authors: Boda Zhou, Andriana Margariti, Gang Wang, Yanhua Hu, Lingfang Zeng, Ouassila Habi, Qingzhong Xiao, Daniel Martin, Xian Wang, Qingbo Xu
    Abstract:

    Objective— Vascular smooth muscle cell (SMC) proliferation has an indispensable role in the pathogenesis of vascular disease, but the mechanism is not fully elucidated. The epigenetic enzyme Histone Deacetylase 7 (HDAC7) is involved in endothelial homeostasis and SMC differentiation and could have a role in SMC proliferation. In this study, we sought to examine the effect of 2 HDAC7 isoforms on SMC proliferation and neointima formation. Methods and Results— We demonstrated that overexpression of unspliced HDAC7 (HDAC7u) could suppress SMC proliferation through downregulation of cyclin D1 and cell cycle arrest, whereas spliced HDAC7 (HDAC7s) could not. Small interfering RNA (siRNA)–mediated knockdown of HDAC7 increased SMC proliferation and induced nuclear translocation of β-catenin. Additional experiments showed that only HDAC7u could bind to β-catenin and retain it in the cytoplasm. Reporter gene assay and reverse transcription polymerase chain reaction revealed a reduction of β-catenin activity in cells overexpressing HDAC7u but not HDAC7s. Deletion studies indicated that the C-terminal region of HDAC7u is responsible for the interaction with β-catenin. However, the addition of amino acids to the N terminus of HDAC7u disrupted the binding, further strengthening our hypothesis that HDAC7s does not interact with β-catenin. The growth factor platelet-derived growth factor-BB increased the splicing of HDAC7 while simultaneously decreasing the expression of HDAC7u. Importantly, in an animal model of femoral artery wire injury, we demonstrated that knockdown of HDAC7 by siRNA aggravates neointima formation in comparison with control siRNA. Conclusion— Our findings demonstrate that splicing of HDAC7 modulates SMC proliferation and neointima formation through β-catenin nuclear translocation, which provides a potential therapeutic target in vascular disease.

Herbert G. Kasler - One of the best experts on this subject based on the ideXlab platform.

  • Histone Deacetylase 7 mediates tissue-specific autoimmunity via control of innate effector function in invariant Natural Killer T Cells
    eLife, 2018
    Co-Authors: Herbert G. Kasler, Eric Verdin
    Abstract:

    To protect us, our immune system must walk a narrow line: while it eliminates all external threats, it also has to refrain from attacking the healthy tissues of our body. When such misdirected attacks do take place, they can result in life-threatening autoimmune diseases. T cells are a highly diverse population of immune cells that can recognize and orchestrate the body’s response against infected or ‘abnormal’ cells. Early in the development of most types of T cells, the body normally weeds out the ones that target healthy tissues. A gene known as Histone Deacetylase 7 (HDAC7) regulates this process. However, when HDAC7 carries a specific mutation called HDAC7-ΔP, dangerous T cells that can attack healthy tissues ‘escape’ this selection. The HDAC7-ΔP mutation allows T cells that react to many different tissues to survive. However, in mice with this genetic change, only the liver, the digestive system and the pancreas are actually damaged by the immune system and show signs of autoimmune diseases. Why are these organs affected, and not the others? Here, Kasler, Lee et al. find that HDAC7 also helps another type of T cell to develop. Known as invariant natural killer T – or iNKT – cells, these cells specialize in defending the gut, liver and pancreas against bacteria. Mice with the HDAC7-ΔP mutation can no longer produce iNKT cells. Remarkably, restoring normal levels of these cells in the HDAC7-ΔP animals reduces the symptoms of their autoimmune diseases, even though the mice are still carrying the T cells that have escaped selection and can attack healthy tissues. Taken together, these results explain why a mutation in HDAC7 can create problems only for specific organs in the body. However, it is still not clear exactly why losing iNKT cells increases autoimmune attacks of the tissues they normally occupy. One possibility is that these cells limit access to the organs by other immune cells that could cause damage. Another option is that, when iNKT cells are absent, gut bacteria can attack and create an inflammation. This recruits T cells to the site, including the ones that can attack healthy organs. In humans, mutations in HDAC7, as well as in other genes that regulate it, are also associated with autoimmune disorders of the digestive tract and liver. These include inflammatory bowel diseases such as ulcerative colitis or Crohn’s disease. Ultimately the findings presented by Kasler, Lee et al. could be a starting point for finding new treatments for these illnesses.

  • Histone Deacetylase 7 Mediates Tissue-Specific Autoimmunity via Control of Innate Effector Function in Invariant Natural Killer T-Cells
    bioRxiv, 2017
    Co-Authors: Herbert G. Kasler, Eric Verdin
    Abstract:

    We report that Histone Deacetylase 7 (HDAC7) controls the thymic effector programming of Natural Killer T (NKT) cells, and that interference with this function contributes to tissue-specific autoimmunity. Gain of HDAC7 function in thymocytes blocks both negative selection and NKT development, diverting these cells into a Tconv-like lineage. Conversely, HDAC7 deletion promotes thymocyte apoptosis and causes aberrant expansion of innate-effector cells. Investigating the mechanisms involved, we found that HDAC7 binds PLZF and modulates PLZF-dependent transcription. Moreover, HDAC7 and many of its transcriptional targets are human risk loci for IBD and PSC, autoimmune diseases that strikingly resemble the disease we observe in HDAC7 gain-of-function in mice. Importantly, reconstitution of iNKT cells in these mice abrogated their disease, suggesting that interaction between the defects in negative selection and iNKT cells caused by altered HDAC7 function can cause tissue-restricted autoimmunity, a finding that may explain the association between HDAC7 and hepatobiliary autoimmunity.

  • nuclear export of Histone Deacetylase 7 during thymic selection is required for immune self tolerance
    The EMBO Journal, 2012
    Co-Authors: Herbert G. Kasler, D Mottet, Amy M Collins, Eric Verdin
    Abstract:

    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-ΔP) in thymocytes. We find that HDAC7-ΔP 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.

  • Histone Deacetylase 7 regulates cell survival and tcr signaling in cd4 cd8 double positive thymocytes
    Journal of Immunology, 2011
    Co-Authors: Herbert G. Kasler, Eric N Olson, Bryan Young, D Mottet, Amy M Collins, Eric Verdin
    Abstract:

    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 Jα 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.

  • Histone Deacetylase 7 Regulates Cell Survival and TCR Signaling in CD4/CD8 Double-Positive Thymocytes
    Journal of Immunology, 2011
    Co-Authors: Herbert G. Kasler, Eric N Olson, Amy M Collins, Denis Mottet, Bryan D. Young, Eric Verdin
    Abstract:

    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 Jα 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.