scholarly journals Epigenetic evidence of an Ac/Dc axis by VPA and SAHA

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Sebastian Lunke ◽  
Scott Maxwell ◽  
Ishant Khurana ◽  
Harikrishnan K.N. ◽  
Jun Okabe ◽  
...  
Keyword(s):  
Gene Expression ◽  
Histone Acetylation ◽  
Histone Modifications ◽  
Target Genes ◽  
Hdac Inhibitors ◽  
Histone Deacetylation ◽  
Lysine Methylation ◽  
Blocking Voltage ◽  
Lysine Residues ◽  
Voltage Gated Ion Channels

Abstract Background Valproic acid (VPA) is one of the most commonly used anti-epileptic drugs with pharmacological actions on GABA and blocking voltage-gated ion channels. VPA also inhibits histone deacetylase (HDAC) activity. Suberoylanilide hydroxamic acid is also a member of a larger class of compounds that inhibit HDACs. At the time of this article, there are 123 active international clinical trials for VPA (also known as valproate, convulex, divalproex, and depakote) and SAHA (vorinostat, zolinza). While it is well known that VPA and SAHA influence the accumulation of acetylated lysine residues on histones, their true epigenetic complexity remains poorly understood. Results Primary human cells were exposed to VPA and SAHA to understand the extent of histone acetylation (H3K9/14ac) using chromatin immunoprecipitation followed by sequencing (ChIP-seq). Because histone acetylation is often associated with modification of lysine methylation, we also examined H3K4me3 and H3K9me3. To assess the influence of the HDAC inhibitors on gene expression, we used RNA sequencing (RNA-seq). ChIP-seq reveals a distribution of histone modifications that is robust and more broadly regulated than previously anticipated by VPA and SAHA. Histone acetylation is a characteristic of the pharmacological inhibitors that influenced gene expression. Surprisingly, we observed histone deacetylation by VPA stimulation is a predominant signature following SAHA exposure and thus defines an acetylation/deacetylation (Ac/Dc) axis. ChIP-seq reveals regionalisation of histone acetylation by VPA and broader deacetylation by SAHA. Independent experiments confirm H3K9/14 deacetylation of NFκB target genes by SAHA. Conclusions The results provide an important framework for understanding the Ac/Dc axis by highlighting a broader complexity of histone modifications by the most established and efficacious anti-epileptic medication in this class, VPA and comparison with the broad spectrum HDAC inhibitor, SAHA.

scholarly journals POWERDRESS and HDA9 interact and promote histone H3 deacetylation at specific genomic sites inArabidopsis

2016 ◽  
Vol 113 (51) ◽  
pp. 14858-14863 ◽  
Author(s):  
Yun Ju Kim ◽  
Ruozhong Wang ◽  
Lei Gao ◽  
Dongming Li ◽  
Chi Xu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Histone Acetylation ◽  
Histone Deacetylases ◽  
Target Genes ◽  
Specific Binding ◽  
Expression Profiles ◽  
Histone H3 ◽  
Gene Expression Profiles ◽  
Large Gene ◽  
Lysine Residues

Histone acetylation is a major epigenetic control mechanism that is tightly linked to the promotion of gene expression. Histone acetylation levels are balanced through the opposing activities of histone acetyltransferases (HATs) and histone deacetylases (HDACs).ArabidopsisHDAC genes (AtHDACs) compose a large gene family, and distinct phenotypes amongAtHDACmutants reflect the functional specificity of individualAtHDACs. However, the mechanisms underlying this functional diversity are largely unknown. Here, we show that POWERDRESS (PWR), a SANT (SWI3/DAD2/N-CoR/TFIII-B) domain protein, interacts with HDA9 and promotes histone H3 deacetylation, possibly by facilitating HDA9 function at target regions. The developmental phenotypes ofpwrandhda9mutants were highly similar. Three lysine residues (K9, K14, and K27) of H3 retained hyperacetylation status in bothpwrandhda9mutants. Genome-wide H3K9 and H3K14 acetylation profiling revealed elevated acetylation at largely overlapping sets of target genes in the two mutants. Highly similar gene-expression profiles in the two mutants correlated with the histone H3 acetylation status in thepwrandhda9mutants. In addition,PWRandHDA9modulated flowering time by repressingAGAMOUS-LIKE 19expression through histone H3 deacetylation in the same genetic pathway. Finally, PWR was shown to physically interact with HDA9, and its SANT2 domain, which is homologous to that of subunits in animal HDAC complexes, showed specific binding affinity to acetylated histone H3. We therefore propose that PWR acts as a subunit in a complex with HDA9 to result in lysine deacetylation of histone H3 at specific genomic targets.

Vorinostat exhibits anticancer effects in triple-negative breast cancer cells by preventing nitric oxide-driven histone deacetylation

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Marianne B. Palczewski ◽  
Hannah Petraitis Kuschman ◽  
Rhea Bovee ◽  
Jason R. Hickok ◽  
Douglas D. Thomas
Keyword(s):  
Nitric Oxide ◽  
Histone Acetylation ◽  
Triple Negative ◽  
Soluble Guanylyl Cyclase ◽  
Prognostic Indicator ◽  
Histone Deacetylation ◽  
Breast Cancers ◽  
Cellular Iron ◽  
Lysine Residues ◽  
Pathway Interaction

Abstract Triple-negative breast cancers (TNBC) that produce nitric oxide (NO) are more aggressive, and the expression of the inducible form of nitric oxide synthase (NOS2) is a negative prognostic indicator. In these studies, we set out to investigate potential therapeutic strategies to counter the tumor-permissive properties of NO. We found that exposure to NO increased proliferation of TNBC cells and that treatment with the histone deacetylase inhibitor Vorinostat (SAHA) prevented this proliferation. When histone acetylation was measured in response to NO and/or SAHA, NO significantly decreased acetylation on histone 3 lysine 9 (H3K9ac) and SAHA increased H3K9ac. If NO and SAHA were sequentially administered to cells (in either order), an increase in acetylation was observed in all cases. Mechanistic studies suggest that the “deacetylase” activity of NO does not involve S-nitrosothiols or soluble guanylyl cyclase activation. The observed decrease in histone acetylation by NO required the interaction of NO with cellular iron pools and may be an overriding effect of NO-mediated increases in histone methylation at the same lysine residues. Our data revealed a novel pathway interaction of Vorinostat and provides new insight in therapeutic strategy for aggressive TNBCs.

scholarly journals Food Bioactive HDAC Inhibitors in the Epigenetic Regulation of Heart Failure

Nutrients ◽  
2018 ◽  
Vol 10 (8) ◽  
pp. 1120 ◽  
Author(s):  
Levi Evans ◽  
Bradley Ferguson
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
Signaling Pathways ◽  
Intracellular Signaling ◽  
Histone Deacetylases ◽  
Regulation Of Gene Expression ◽  
Hdac Inhibitors ◽  
Drug Efficacy ◽  
Histone Deacetylation ◽  
Epigenetic Modifiers

Approximately 5.7 million U.S. adults have been diagnosed with heart failure (HF). More concerning is that one in nine U.S. deaths included HF as a contributing cause. Current HF drugs (e.g., β-blockers, ACEi) target intracellular signaling cascades downstream of cell surface receptors to prevent cardiac pump dysfunction. However, these drugs fail to target other redundant intracellular signaling pathways and, therefore, limit drug efficacy. As such, it has been postulated that compounds designed to target shared downstream mediators of these signaling pathways would be more efficacious for the treatment of HF. Histone deacetylation has been linked as a key pathogenetic element for the development of HF. Lysine residues undergo diverse and reversible post-translational modifications that include acetylation and have historically been studied as epigenetic modifiers of histone tails within chromatin that provide an important mechanism for regulating gene expression. Of recent, bioactive compounds within our diet have been linked to the regulation of gene expression, in part, through regulation of the epi-genome. It has been reported that food bioactives regulate histone acetylation via direct regulation of writer (histone acetyl transferases, HATs) and eraser (histone deacetylases, HDACs) proteins. Therefore, bioactive food compounds offer unique therapeutic strategies as epigenetic modifiers of heart failure. This review will highlight food bio-actives as modifiers of histone deacetylase activity in the heart.

Changes in Promoter Methylation and Gene Expression in Patients with MDS and MDS-AML Treated with 5-Azacitidine and Sodium Phenylbutyrate.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 469-469 ◽  
Author(s):  
Steven D. Gore ◽  
Stephen B. Baylin ◽  
Tianna Dauses ◽  
Michael R. Grever ◽  
Anchalee Jiemjit ◽  
...  
Keyword(s):  
Gene Expression ◽  
Histone Acetylation ◽  
Real Time ◽  
Promoter Methylation ◽  
Hdac Inhibitors ◽  
Clinical Activity ◽  
Hematologic Toxicity ◽  
Clinical Responses ◽  
The Relationship ◽  
Sodium Phenylbutyrate

Abstract Despite its clinical activity in myelodysplastic syndrome (MDS), the relationship between the inhibition of DNA methyltransferase 1 (DNMT) by 5-azacitidine (5AC) and hematologic improvement has not been well-explored. Optimal in vitro re-expression of genes silenced through promoter methylation requires sequential exposure to a DNMT inhibitor (i) and an histone deacetylase (HDAC)i. In a dose/schedule exploration study, patients with MDS (including MDS-AML) were treated with various regimens of 5AC SQ, followed by a 7 day infusion of the HDACi sodium phenylbutyrate (PB). Patients received 5AC at the following doses: 50 mg/m2/day * 10 doses (cohort A, n = 8), 50 mg/m2/day * 14 doses (cohort B, n = 3), and 25 mg/m2/day * 14 doses (cohort C, n = 5). Patients received a minimum of 4 cycles (q28 days). Clinical responses were graded according to IWG criteria. Changes in promoter methylation of p15INK4B and E-Cadherin (E-CAD), the most commonly methylated genes in MDS and AML, were monitored using a real time-PCR modification of methylation specific-PCR (rtMSP). Changes in gene expression were monitored using real time rtPCR. Dose-limiting hematologic toxicity (myelosuppression > 14 days) occurred in 2/3 patients in cohort B. The other two dose schedules were well-tolerated. Clinical responses developed in 4/8 patients in cohort A (3 CR, 1 PR), 2/3 patients in cohort B (1 hematologic improvement (HI)-P, N, major, 1 HI-P-major), and 3/3 currently evaluable patients in cohort C (2 HI-N-major, 1 HI-P, major). p15 was methylated in 10/10 evaluable samples pre-treatment; E-CAD was methylated in 5/7. Treatment with 5AC decreased p15 methylation in 50% of patients studied. p15 expression increased in patients in whom methylation was decreased; this included 3/4 clinical responders studied. In several cases, reversal of methylation was confirmed by bisulfite sequencing (BSQ) of serial samples. BSQ suggested that 5AC treatment led to gradual demethylation of the clone, rather than replacement of a methylated clone with a normal unmethylated clone. Surprisingly, treatment with 5AC increased global acetylation of histones H3 and/or H4 (Western analysis) in 7/8 patients in cohort A, and 2/2 evaluable patients in cohort B, (cohort C data pending). Acetylation was further increased following PB administration in 4/8 patients in cohort A and 1/2 in cohort B. These data confirm for the first time that clinical administration of 5AC leads to substantial reversal of promoter methylation associated with gene re-expression. Administration of 5AC is also associated with induction of global histone acetylation; the mechanism underlying histone acetylation in response to 5AC is unclear. While administration of 5AC and PB is associated with re-expression of p15, the relative contributions of the DNMT and HDAC inhibitors cannot be determined from the present study. Gene methylation data obtained using rtMSP correlates well with BSQ. The use of this semi-quantitative technique to monitor larger studies of 5AC with and without HDAC inhibitors will facilitate determination of the relationship between reversal of promoter methylation of p15 and other genes and clinical response to DNMTis.

scholarly journals Alterations in epigenetic modifications during oocyte growth in mice

Reproduction ◽  
2007 ◽  
Vol 133 (1) ◽  
pp. 85-94 ◽  
Author(s):  
Shun-ichiro Kageyama ◽  
Honglin Liu ◽  
Naoto Kaneko ◽  
Masatoshi Ooga ◽  
Masao Nagata ◽  
...  
Keyword(s):  
Gene Expression ◽  
Histone Modifications ◽  
Epigenetic Modification ◽  
Germinal Vesicle ◽  
Epigenetic Modifications ◽  
Condensed Chromatin ◽  
Rt Pcr ◽  
Oocyte Growth ◽  
Lysine Residues ◽  
Signal Intensities

During oocyte growth, chromatin structure is altered globally and gene expression is silenced. To investigate the involvement of epigenetic modifications in the regulation of these phenomena, changes in global DNA methylation and in various histone modifications, i.e. acetylation of H3K9, H3K18, H4K5, and H4K12, and methylation of H3K4 and H3K9, were examined during the growth of mouse oocytes. Immunocytochemical analysis revealed that the signal intensities of all these modifications increased during growth and that fully grown, germinal vesicle (GV)-stage oocytes showed the most modifications. Since acetylation of most of the lysine residues on histones and methylation of H3K4 are associated with active gene expression, the increased levels of these modifications do not seem to be associated with gene silencing in GV-stage oocytes. Given that there are two types of GV-stage oocytes with different chromatin configurations and transcriptional activities, the epigenetic modification statuses of these two types were compared. The levels of all the epigenetic modifications examined were higher in the SN(surrounded nucleolus)-type oocytes, in which highly condensed chromatin is concentrated in the area around the nucleolus and gene expression is silenced than in the NSN(not surrounded nucleolus)-type oocytes, in which less-condensed chromatin does not surround the nucleolus and gene expression is active. In addition, the expression levels of various enzymes that catalyze histone modifications were shown by RT-PCR to increase with oocyte growth. Taken together, the results show that all of the epigenetic modifications increased in a concerted manner during oocyte growth, and suggest that these increases are not associated with gene expression.

scholarly journals Effect of Trichostatin A on Histone Deacetylases 1, 2 and 3, p21Cip1/Waf1/Sdi1, p27Kip1, and p57Kip2 Gene Expression in Breast Cancer SK-BR-3 Cell Line

2020 ◽  
Vol 5 (2) ◽  
pp. 57-62
Author(s):  
Masumeh Sanaei ◽  
Fraidoon Kavoosi
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Cell Line ◽  
Cell Apoptosis ◽  
Histone Deacetylases ◽  
Trichostatin A ◽  
Hdac Inhibitors ◽  
Histone Deacetylation ◽  
Relative Expression Level ◽  
Hematological Cancers

Objective: DNA methylation, the covalent addition of a methyl group to cytosine, and histone modification play an important role in the establishment and maintenance of the program of gene expression. The balance of histone acetylation is determined by the activities of two groups of enzymes including histone acetyltransferases (HATs) and histone deacetylases (HDACs). Histone deacetylation is generally associated with silencing gene expression resulting in several solid tumors. HDAC inhibitors (HDACIs) are the new class of potential anticancer compounds for the treatment of the solid and hematological cancers. The current study was designed to evaluate the effect of trichostatin A (TSA) on histone deacetylases 1, 2 and 3, p21Cip1/Waf1/Sdi1 (p21), p27Kip1 (p27), and p57Kip2 (p57) gene expression in breast cancer SK-BR-3 cell line. Materials and Methods: The breast cancer SK-BR-3 line was treated with TSA. To determine cell viability, cell apoptosis, and the relative expression level of the genes, MTT assay, cell apoptosis assay, and qRT-PCR were done respectively. Results: TSA significantly inhibited cell growth, and induced apoptosis. Furthermore, this compound increased p21, p27, and p57 and decreased histone deacetylases 1, 2 and 3 gene expression significantly. Conclusion: The TSA can reactivate the p21, p27, and p57 through down-regulation of histone deacetylases 1, 2 and 3 gene expression.

scholarly journals BAP1 constrains pervasive H2AK119ub1 to control the transcriptional potential of the genome

2020 ◽  
Author(s):  
Nadezda A. Fursova ◽  
Anne H. Turberfield ◽  
Neil P. Blackledge ◽  
Emma L. Findlater ◽  
Anna Lastuvkova ◽  
...  
Keyword(s):  
Gene Expression ◽  
Histone Modifications ◽  
Transcription Initiation ◽  
Target Genes ◽  
Regulatory Elements ◽  
Polycomb Group ◽  
Gene Promoters ◽  
Histone H2a ◽  
Gene Regulatory Elements ◽  
Gene Regulatory

AbstractHistone-modifying systems play fundamental roles in gene regulation and the development of multicellular organisms. Histone modifications that are enriched at gene regulatory elements have been heavily studied, but the function of modifications that are found more broadly throughout the genome remains poorly understood. This is exemplified by histone H2A mono-ubiquitylation (H2AK119ub1) which is enriched at Polycomb-repressed gene promoters, but also covers the genome at lower levels. Here, using inducible genetic perturbations and quantitative genomics, we discover that the BAP1 deubiquitylase plays an essential role in constraining H2AK119ub1 throughout the genome. Removal of BAP1 leads to pervasive accumulation of H2AK119ub1, which causes widespread reductions in gene expression. We show that elevated H2AK119ub1 represses gene expression by counteracting transcription initiation from gene regulatory elements, causing reductions in transcription-associated histone modifications. Furthermore, failure to constrain pervasive H2AK119ub1 compromises Polycomb complex occupancy at a subset of Polycomb target genes leading to their derepression, therefore explaining the original genetic characterisation of BAP1 as a Polycomb group gene. Together, these observations reveal that the transcriptional potential of the genome can be modulated by regulating the levels of a pervasive histone modification, without the need for elaborate gene-specific targeting mechanisms.

Kinetic analysis of histone acetylation turnover and Trichostatin A induced hyper- and hypoacetylation in alfalfa

2002 ◽  
Vol 80 (3) ◽  
pp. 279-293 ◽  
Author(s):  
Jakob H Waterborg ◽  
Tamás Kapros
Keyword(s):  
Gene Expression ◽  
Steady State ◽  
Histone Acetylation ◽  
Histone Deacetylases ◽  
Trichostatin A ◽  
Similar Rate ◽  
Lysine Methylation ◽  
Histone H2a ◽  
Turnover Rates

Dynamic histone acetylation is a characteristic of chromatin transcription. The first estimates for the rate of acetylation turnover of plants are reported, measured in alfalfa cells by pulse, pulse-chase, and steady-state acetylation labeling. Acetylation turnover half-lives of about 0.5 h were observed by all methods used for histones H3, H4, and H2B. This is consistent with the rate at which changes in gene expression occur in plants. Treatment with histone deacetylase inhibitor Trichostatin A (TSA) induced hyperacetylation at a similar rate. Replacement histone variant H3.2, preferentially localized in highly acetylated chromatin, displayed faster acetyl turnover. Histone H2A with a low level of acetylation was not subject to rapid turnover or hyperacetylation. Patterns of acetate labeling revealed fundamental differences between histone H3 versus histones H4 and H2B. In H3, acetylation of all molecules, limited by lysine methylation, had similar rates, independent of the level of lysine acetylation. Acetylation of histones H4 and H2B was seen in only a fraction of all molecules and involved multiacetylation. Acetylation turnover rates increased from mono- to penta- and hexaacetylated forms, respectively. TSA was an effective inhibitor of alfalfa histone deacetylases in vivo and caused a doubling in steady-state acetylation levels by 4–6 h after addition. However, hyperacetylation was transient due to loss of TSA inhibition. TSA-induced overexpression of cellular deacetylase activity produced hypoacetylation by 18 h treatment with enhanced acetate turnover labeling of alfalfa histones. Thus, application of TSA to change gene expression in vivo in plants may have unexpected consequences.

scholarly journals Acetyl-CoA Metabolism and Histone Acetylation in the Regulation of Aging and Lifespan

Antioxidants ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 572
Author(s):  
Patrick C. Bradshaw
Keyword(s):  
Histone Acetylation ◽  
Metabolic Flux ◽  
Target Genes ◽  
Nuclear Translocation ◽  
Hdac Inhibitors ◽  
Creb Binding Protein ◽  
Atp Citrate Lyase ◽  
Acetyl Coa ◽  
Peripheral Tissues ◽  
Hypothalamic Inflammation

Acetyl-CoA is a metabolite at the crossroads of central metabolism and the substrate of histone acetyltransferases regulating gene expression. In many tissues fasting or lifespan extending calorie restriction (CR) decreases glucose-derived metabolic flux through ATP-citrate lyase (ACLY) to reduce cytoplasmic acetyl-CoA levels to decrease activity of the p300 histone acetyltransferase (HAT) stimulating pro-longevity autophagy. Because of this, compounds that decrease cytoplasmic acetyl-CoA have been described as CR mimetics. But few authors have highlighted the potential longevity promoting roles of nuclear acetyl-CoA. For example, increasing nuclear acetyl-CoA levels increases histone acetylation and administration of class I histone deacetylase (HDAC) inhibitors increases longevity through increased histone acetylation. Therefore, increased nuclear acetyl-CoA likely plays an important role in promoting longevity. Although cytoplasmic acetyl-CoA synthetase 2 (ACSS2) promotes aging by decreasing autophagy in some peripheral tissues, increased glial AMPK activity or neuronal differentiation can stimulate ACSS2 nuclear translocation and chromatin association. ACSS2 nuclear translocation can result in increased activity of CREB binding protein (CBP), p300/CBP-associated factor (PCAF), and other HATs to increase histone acetylation on the promoter of neuroprotective genes including transcription factor EB (TFEB) target genes resulting in increased lysosomal biogenesis and autophagy. Much of what is known regarding acetyl-CoA metabolism and aging has come from pioneering studies with yeast, fruit flies, and nematodes. These studies have identified evolutionary conserved roles for histone acetylation in promoting longevity. Future studies should focus on the role of nuclear acetyl-CoA and histone acetylation in the control of hypothalamic inflammation, an important driver of organismal aging.

scholarly journals A conserved BAH module within mammalian BAHD1 connects H3K27me3 to Polycomb gene silencing

2021 ◽  
Author(s):  
Huitao Fan ◽  
Yiran Guo ◽  
Yi-Hsuan Tsai ◽  
Aaron J. Storey ◽  
Arum Kim ◽  
...  
Keyword(s):  
Gene Silencing ◽  
Histone Acetylation ◽  
Mammalian Cells ◽  
Target Genes ◽  
Direct Interaction ◽  
Histone Deacetylation ◽  
List Type ◽  
Bah Domain ◽  
Organismal Development ◽  
Point Mutagenesis

ABSTRACTTrimethylation of histone H3 lysine 27 (H3K27me3) is important for gene silencing and imprinting, (epi)genome organization and organismal development. In a prevalent model, the functional readout of H3K27me3 in mammalian cells is achieved through the H3K27me3-recognizing chromodomain harbored within the chromobox (CBX) component of canonical Polycomb repressive complex 1 (cPRC1), which induces chromatin compaction and gene repression. Here, we report that binding of H3K27me3 by a Bromo Adjacent Homology (BAH) domain harbored within BAH domain-containing protein 1 (BAHD1) is required for overall BAHD1 targeting to chromatin and for optimal repression of the H3K27me3-demarcated genes in mammalian cells. Disruption of direct interaction between BAHD1BAH and H3K27me3 by point mutagenesis leads to chromatin remodeling, notably, increased histone acetylation, at its Polycomb gene targets. Mice carrying an H3K27me3-interaction-defective mutation of Bahd1BAH causes marked embryonic lethality, showing a requirement of this pathway for normal development. Altogether, this work demonstrates an H3K27me3-initiated signaling cascade that operates through a conserved BAH “reader” module within BAHD1 in mammals.Key PointsBAHD1BAH is a functionally validated mammalian “reader” of H3K27me3, mediating BAHD1 targeting for gene silencing.BAHD1BAH connects H3K27me3 together with histone deacetylation, an integral step of gene silencing.BAHD1BAH-mediated functional readout of H3K27me3 is essential for organismal development.Graphic abstractA mammalian H3K27me3-transduction pathway operates through an H3K27me3-specific ‘reader’ module (BAH) of BAHD1, which assembles a complex with corepressors (HDACs and others) for suppressing histone acetylation and repressing expression at Polycomb target genes.

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