Epigenetic Approaches and Methods in Developmental Toxicology: Role of HDAC Inhibition in Teratogenic Events

2012 ◽  
pp. 373-383 ◽  
Author(s):  
Elena Menegola ◽  
Graziella Cappelletti ◽  
Francesca Di Renzo
Keyword(s):  
Hdac Inhibition ◽  
Developmental Toxicology

scholarly journals HDAC stimulates gene expression through BRD4 availability in response to IFN and in interferonopathies

2018 ◽  
Vol 215 (12) ◽  
pp. 3194-3212 ◽  
Author(s):  
Isabelle J. Marié ◽  
Hao-Ming Chang ◽  
David E. Levy
Keyword(s):  
Autoimmune Diseases ◽  
Histone Deacetylases ◽  
Elongation Factor ◽  
Positive Function ◽  
Transcriptional Elongation ◽  
Hdac Inhibition ◽  
Transcriptional Initiation ◽  
Inducible Promoters ◽  
The Common

In contrast to the common role of histone deacetylases (HDACs) for gene repression, HDAC activity provides a required positive function for IFN-stimulated gene (ISG) expression. Here, we show that HDAC1/2 as components of the Sin3A complex are required for ISG transcriptional elongation but not for recruitment of RNA polymerase or transcriptional initiation. Transcriptional arrest by HDAC inhibition coincides with failure to recruit the epigenetic reader Brd4 and elongation factor P-TEFb due to sequestration of Brd4 on hyperacetylated chromatin. Brd4 availability is regulated by an equilibrium cycle between opposed acetyltransferase and deacetylase activities that maintains a steady-state pool of free Brd4 available for recruitment to inducible promoters. An ISG expression signature is a hallmark of interferonopathies and other autoimmune diseases. Combined inhibition of HDAC1/2 and Brd4 resolved the aberrant ISG expression detected in cells derived from patients with two inherited interferonopathies, ISG15 and USP18 deficiencies, defining a novel therapeutic approach to ISG-associated autoimmune diseases.

Anti-fibrotic effects of valproic acid: role of HDAC inhibition and associated mechanisms

Epigenomics ◽  
2016 ◽  
Vol 8 (8) ◽  
pp. 1087-1101 ◽  
Author(s):  
Sabbir Khan ◽  
Kailash Ahirwar ◽  
Gopabandhu Jena
Keyword(s):  
Valproic Acid ◽  
Hdac Inhibition

mTOR Pathway Links Suppressed Autophagy to HDAC Inhibitor-Induced Apoptosis in Myeloid Leukemia,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3614-3614
Author(s):  
Metodi V. Stankov ◽  
Kirsten Heitmann ◽  
Zhe Li ◽  
Basant Kumar Thakur ◽  
Diana Panayotova-Dimitrova ◽  
...  
Keyword(s):  
Cell Lines ◽  
Myeloid Leukemia ◽  
Control Cell ◽  
Hdac Inhibitors ◽  
Fold Increase ◽  
Hdac Inhibition ◽  
Specific Vulnerability ◽  
Induced Apoptosis ◽  
Dose Dependent

Abstract Abstract 3614 Despite well-described anti-cancer effects and promising results in clinical trials, little is known regarding the selectivity of histone deacetylase (HDAC) inhibitors in killing malignant and sparing normal cells. Using Down syndrome associated myeloid leukemia (DS-AMKL) as a model for an exceptionally sensitive form of acute myeloid leukemia (AML), we elucidated a role of HDAC inhibitors in blocking autophagy, which exploits a specific vulnerability of several types of cancer. We could show that HDAC1/2 inhibition efficiently inversed the DS-AMKL gene signature, resulting in p53-independent cell cycle arrest (BrdU incorporation and CFSE assay) and apoptosis (Annexin V/ 7-AAD and Nicoletti staining, caspase 3/7 activity assay) of DS-AMKL cell lines (CMK and CMY) and primary DS-AMKL leukemic blast. In contrast, control cell lines K562 and M07 were resistant to VPA-induced apoptosis. DS-AMKL is characterized by the high activation of the insulin-like growth factor (IGF) signaling cascade, which in turn results in the constitutive activation of mammalian target of rapamycin (mTOR). mTOR has been characterized as a major suppressor of autophagy, a lysosomal degradation process that takes place constitutively at a basal level and protects cells against damaged or unnecessary organelles and protein aggregates. Measuring endogenous LC3-I to LC3-II conversion levels by Western blot, a posttranslational modification during autophagy, we confirmed a lower basal autophagic activity in DS-AMKL cells compared to the control cell lines, K562 and M07 (LC3B-II/actin [RU]: 1.5 CMK, 1.0 CMY, 6.0 K562 and 3.0 M07). Studying the effect of HDAC inhibition on autophagy, we detected an initial, dose-dependent increase in LC3-II band formation, punctae formation and decrease in total LC3-GFP cellular abundance (i.e., autophagy activation) 12h after VPA treatment in all cell lines (CMK, CMY, K562 and M07), indicative for induction of autophagy. However, prolonged exposure to VPA for up to 24h led to a block of autophagic flux, as shown by a gradual accumulation of LC3-GFP (fold increase in LC3-GFP MFI compared to untreated control: 1.3 CMK**, 1.1 CMY*, 2.0 K562** and 2.0 M07** at 2mM VPA; **p<0.01; *p<0.05). Autophagy participates in the removal of damaged mitochondria, which prevents the initiation of intrinsic apoptotic pathway or DNA damage by increased ROS generation. Our results demonstrated a dose-dependent relationship between VPA-associated accumulation of mitochondrial mass and the intrinsic autophagic activity of the respective leukemic cell lines (fold increase in MitoTracker green MFI: 4.7 CMK**, 4.8 CMY**, 1.3 K562 and 1.2 M07 at 10mM VPA; **p<0.01). Likewise, the VPA-mediated mitochondrial mass accumulation correlated with ROS formation (fold increase in CM-H2DCFDA MFI: 3.3 CMK**, 2.7 CMY**, 1.5 K562** and 1.2 M07** at 10mM VPA; **p<0.01) and reflects the sensitivity to VPA induced apoptosis. In addition, we detected DNA-double strand breaks as indicated by an increase of phosphorylated H2AX. The effects of HDAC inhibitors on DS-AMKL cells could be recapitulated by pharmacologic (autophagosome-lysosome fusion using vinblastine and nocodazole; autophagolysosomal degradation using ammonium chloride, chloroquine and hydroxychloroquine) and genetic (shRNA-mediated knockdown of ATG5 or ATG7) inhibition of autophagy, underlining dependency on their low basal level of autophagy. Inversely, induction of autophagy by starvation reversed the effects of HDAC inhibition on cell lines and primary DS-AMKL cells (i.e. induction of apoptosis, accumulation of mitochondria and ROS-production). Thus, our study identified the role of HDAC inhibitors in blocking autophagy, exploiting the specific vulnerability of DS-AMKL cells with suppressed basic autophagy due to high mTOR activation. This was unexpected as previous studies proposed HDAC inhibitors as autophagy activators. VPA treatment of DS-AMKL cell lines and primary cells repressed autophagy below a critical threshold leading to accumulation of mitochondria, production of ROS, DNA-damage and apoptosis, which could be reverted upon autophagy activation. Our findings suggest repression of autophagy by HDAC inhibition as a novel treatment strategy in leukemic cells with highly active mTOR pathway. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Regulation of intestinal serotonin transporter expression via epigenetic mechanisms: role of HDAC2

2013 ◽  
Vol 304 (4) ◽  
pp. C334-C341 ◽  
Author(s):  
Ravinder K. Gill ◽  
Anoop Kumar ◽  
Pooja Malhotra ◽  
Daniel Maher ◽  
Varsha Singh ◽  
...  
Keyword(s):  
Hdac Inhibitors ◽  
In Vivo Model ◽  
Mrna Levels ◽  
Epigenetic Mechanisms ◽  
Hdac Inhibition ◽  
Exon 2 ◽  
Protein Levels ◽  
Histone Hyperacetylation

The serotonin (5-HT) transporter (SERT) facilitates clearance of extracellular 5-HT by its uptake and internalization. Decreased expression of SERT and consequent high 5-HT levels have been implicated in various diarrheal disorders. Thus, appropriate regulation of SERT is critical for maintenance of 5-HT homeostasis in health and disease. Previous studies demonstrated that SERT is regulated via posttranslational and transcriptional mechanisms. However, the role of epigenetic mechanisms in SERT regulation is not known. Current studies investigated the effects of histone deacetylase (HDAC) inhibition on SERT expression and delineated the mechanisms. Treatment of Caco-2 cells with the pan-HDAC inhibitors butyrate (5 mM) and trichostatin (TSA, 1 μM) decreased SERT mRNA and protein levels. Butyrate- or TSA-induced decrease in SERT was associated with decreased activity of human SERT (hSERT) promoter 1 (upstream of exon 1a), but not hSERT promoter 2 (upstream of exon 2). Butyrate + TSA did not show an additive effect on SERT expression, indicating that mechanisms involving histone hyperacetylation may be involved. Chromatin immunoprecipitation assays demonstrated enrichment of the hSERT promoter 1 (flanking nt −250/+2) with tetra-acetylated histone H3 or H4, which was increased (∼3-fold) by butyrate. Interestingly, specific inhibition of HDAC2 (but not HDAC1) utilizing small interfering RNA decreased SERT mRNA and protein levels. The decrease in SERT expression by HDAC inhibition was recapitulated in an in vivo model . SERT mRNA levels were decreased in the ileum and colon of mice fed pectin (increased availability of butyrate) compared with controls fed a fiber-free diet (∼50–60%). Our results identify a novel role of HDAC2 as a regulator of SERT gene expression in intestinal epithelial cells.

scholarly journals Dietary Sulforaphane in Cancer Chemoprevention: The Role of Epigenetic Regulation and HDAC Inhibition

2015 ◽  
Vol 22 (16) ◽  
pp. 1382-1424 ◽  
Author(s):  
Stephanie M. Tortorella ◽  
Simon G. Royce ◽  
Paul V. Licciardi ◽  
Tom C. Karagiannis
Keyword(s):  
Epigenetic Regulation ◽  
Cancer Chemoprevention ◽  
Hdac Inhibition

scholarly journals The Role of DNMT and HDACs in the Fetal Programming of Hypertension by Glucocorticoids

2020 ◽  
Vol 2020 ◽  
pp. 1-17 ◽  
Author(s):  
J. Lamothe ◽  
S. Khurana ◽  
S. Tharmalingam ◽  
C. Williamson ◽  
C. J. Byrne ◽  
...  
Keyword(s):  
Gene Expression ◽  
Fetal Programming ◽  
Histone Deacetylases ◽  
In Utero ◽  
Dna Methyltransferases ◽  
In Utero Exposure ◽  
Hdac Inhibition ◽  
Adult Rats ◽  
Genetic And Environmental Factors

The causes of hypertension are complex and involve both genetic and environmental factors. Environment changes during fetal development have been linked to adult diseases including hypertension. Studies show that timed in utero exposure to the synthetic glucocorticoid (GC) dexamethasone (Dex) results in the development of hypertension in adult rats. Evidence suggests that in utero stress can alter patterns of gene expression, possibly a result of alterations in the topology of the genome by epigenetic markers such as DNA methyltransferases (DNMTs) and histone deacetylases (HDACs). The objective of this study was to determine the effects of epigenetic regulators in the fetal programming and the development of adult hypertension. Specifically, this research examined the effects of the HDAC inhibitor valproic acid (VPA) and the DNMT inhibitor 5-aza-2′-deoxycytidine (5aza2DC) on blood pressure (BP) and gene expression in prenatal Dex-programmed rats. Data suggest that both VPA and 5aza2DC attenuated the Dex-mediated development of hypertension and restored BP to control levels. Epigenetic DNMT inhibition (DNMTi) or HDAC inhibition (HDACi) also successfully attenuated elevations in the majority of altered catecholamine (CA) enzyme expression, phenylethanolamine N-methyltransferase (PNMT) protein, and elevated epinephrine (Epi) levels in males. Although females responded to HDACi similar to males, DNMTi drove increased glucocorticoid receptor (GR) and PNMT expression and elevations in circulating Epi in females despite showing normotensive BP.

The role of maternal diet in the developmental toxicology of ethanol

1984 ◽  
Vol 73 (2) ◽  
pp. 256-267 ◽  
Author(s):  
Phillip T. Goad ◽  
Donald E. Hill ◽  
William Slikker ◽  
Carole A. Kimmel ◽  
David W. Gaylor
Keyword(s):  
Maternal Diet ◽  
Developmental Toxicology
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