scholarly journals HDAC3 controls male fertility through enzyme-independent transcriptional regulation at the meiotic exit of spermatogenesis

2021 ◽  
Author(s):  
Huiqi Yin ◽  
Zhenlong Kang ◽  
Yingwen Zhang ◽  
Yingyun Gong ◽  
Mengrou Liu ◽  
...  
Keyword(s):  
Histone Acetylation ◽  
Histone Deacetylases ◽  
Early Stage ◽  
Missense Mutations ◽  
Rna Seq ◽  
Motif Analysis ◽  
Independent Manner ◽  
Spatiotemporal Expression ◽  
Histone Hyperacetylation ◽  
Genomic Recruitment

Abstract The transition from meiotic spermatocytes to postmeiotic haploid germ cells constitutes an essential step in spermatogenesis. The epigenomic regulatory mechanisms underlying this transition remain unclear. Here, we find a prominent transcriptomic switch from the late spermatocytes to the early round spermatids during the meiotic-to-postmeiotic transition, which is associated with robust histone acetylation changes across the genome. Among histone deacetylases (HDACs) and acetyltransferases, we find that HDAC3 is selectively expressed in the late meiotic and early haploid stages. Three independent mouse lines with the testis-specific knockout of HDAC3 show infertility and defects in meiotic exit with an arrest at the late stage of meiosis or early stage of round spermatids. Stage-specific RNA-seq and histone acetylation ChIP-seq analyses reveal that HDAC3 represses meiotic/spermatogonial genes and activates postmeiotic haploid gene programs during meiotic exit, with associated histone acetylation alterations. Unexpectedly, abolishing HDAC3 catalytic activity by missense mutations in the nuclear receptor corepressor (NCOR or SMRT) does not cause infertility, despite causing histone hyperacetylation as HDAC3 knockout, demonstrating that HDAC3 enzyme activity is not required for spermatogenesis. Motif analysis of the HDAC3 cistrome in the testes identified SOX30, which has a similar spatiotemporal expression pattern as HDAC3 during spermatogenesis. Depletion of SOX30 in the testes abolishes the genomic recruitment of the HDAC3 to the binding sites. Collectively, these results establish the SOX30/HDAC3 signaling as a key regulator of the transcriptional program in a deacetylase-independent manner during the meiotic-to-postmeiotic transition in spermatogenesis.

scholarly journals Effect of the HDAC Inhibitor on Histone Acetylation and Methyltransferases in A2780 Ovarian Cancer Cells

Medicina ◽  
2021 ◽  
Vol 57 (5) ◽  
pp. 456
Author(s):  
Umamaheswari Natarajan ◽  
Thiagarajan Venkatesan ◽  
Appu Rathinavelu
Keyword(s):  
Ovarian Cancer ◽  
Histone Acetylation ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Histone Deacetylases ◽  
Dna Methyltransferase ◽  
Positive Impact ◽  
3D Cell Culture ◽  
Ovarian Cancer Cells ◽  
Histone Hyperacetylation

Background andObjective: Epigenetic modifications are believed to play a significant role in the development of cancer progression, growth, differentiation, and cell death. One of the most popular histone deacetylases inhibitors (HDACIs), suberoylanilide hydroxamic acid (SAHA), also known as Vorinostat, can directly activate p21WAF1/CIP1 gene transcription through hyperacetylation of histones by a p53 independent mechanism. In the present investigation, we evaluated the correlation between histone modifications and DNA methyltransferase enzyme levels following SAHA treatments in A2780 ovarian cancer cells. Materials and Methods: Acetylation of histones and methyltransferases levels were analyzed using RT2 profiler PCR array, immunoblotting, and immunofluorescence methods in 2D and 3D cell culture systems. Results: The inhibition of histone deacetylases (HDAC) activities by SAHA can reduce DNA methyl transferases / histone methyl transferases (DNMTs/HMTs) levels through induction of hyperacetylation of histones. Immunofluorescence analysis of cells growing in monolayers and spheroids revealed significant up-regulation of histone acetylation preceding the above-described changes. Conclusions: Our results depict an interesting interplay between histone hyperacetylation and a decrease in methyltransferase levels in ovarian cancer cells, which may have a positive impact on the overall outcomes of cancer treatment.

A Targeted Histone Acetyltransferase Can Create a Sizable Region of Hyperacetylated Chromatin and Counteract the Propagation of Transcriptionally Silent Chromatin

Genetics ◽  
2003 ◽  
Vol 165 (1) ◽  
pp. 115-125 ◽  
Author(s):  
Ya-Hui Chiu ◽  
Qun Yu ◽  
Joseph J Sandmeier ◽  
Xin Bi
Keyword(s):  
Histone Acetylation ◽  
Structural Component ◽  
Histone Deacetylases ◽  
Histone Acetyltransferase ◽  
Transcriptional Silencing ◽  
Silent Chromatin ◽  
Gene Encoding ◽  
Repressive Chromatin ◽  
Histone Hyperacetylation ◽  
Histone Hypoacetylation

Abstract Transcriptionally silent chromatin is associated with reduced histone acetylation and its propagation depends on histone hypoacetylation promoted by histone deacetylases. We show that tethered histone acetyltransferase (HAT) Esa1p or Gcn5p creates a segment of hyperacetylated chromatin that is at least 2.6 kb in size and counteracts transcriptional silencing that emanates from a silencer in yeast. Esa1p and Gcn5p counteract URA3 silencing even when they are targeted 1.7 kb downstream of the promoter and >2.0 kb from the silencer. The anti-silencing effect of a targeted HAT is strengthened by increasing the number of targeting sites, but impaired by events that enhance silencing. A tethered HAT can also counteract telomeric silencing. The anti-silencing effect of Gcn5p is abolished by a mutation that eliminated its HAT activity or by deleting the ADA2 gene encoding a structural component of Gcn5p-containing HAT complexes. These results demonstrate that a tethered HAT complex can create a sizable region of histone hyperacetylation and serve as a barrier to encroaching repressive chromatin.

scholarly journals The histone deacetylase HDA15 interacts with MAC3A and MAC3B to regulate intron retention of ABA-responsive genes

2020 ◽  
Author(s):  
Yi-Tsung Tu ◽  
Chia-Yang Chen ◽  
Yi-Sui Huang ◽  
Ming-Ren Yen ◽  
Jo-Wei Allison Hsieh ◽  
...  
Keyword(s):  
Histone Acetylation ◽  
Histone Deacetylases ◽  
Intron Retention ◽  
Histone Deacetylation ◽  
Rna Seq ◽  
Acetylation Level ◽  
Aba Insensitive ◽  
Genomic Regions ◽  
Retained Introns

AbstractHistone deacetylases (HDAs) play an important role in transcriptional regulation involved in multiple biological processes. In this study, we investigate the function of HDA15 in abscisic acid (ABA) responses. Immunopurification coupled with mass spectrometry-based proteomics was used to identify the HDA15 interacting proteins. We found that HDA15 can interact with the core subunits of MOS4-Associated Complex (MAC), MAC3A and MAC3B. In addition, ABA enhances the interaction of HDA15 with MAC3B. hda15 and mac3a/mac3b mutants are ABA-insensitive in seed germination and hyposensitive to salinity. RNA sequencing (RNA-seq) analysis demonstrate that HDA15 and MAC3A/MAC3B not only affect the expression of ABA-related genes, but also regulate ABA-responsive intron retention (IR). Furthermore, HDA15 and MAC3A/MAC3B reduce the histone acetylation level of the genomic regions near ABA-responsive IRs. Our studies uncovered the role of histone deacetylation in ABA-mediated splicing regulation and identified that HDA15-MAC3A/MAC3B acts as an important regulation module to mediate splicing of introns in ABA responses.One Sentence SummaryHDA15 and MAC3A/MAC3B coregulate intron retention and reduce the histone acetylation level of the genomic regions near ABA-responsive retained introns.

scholarly journals Sphingosine Kinase 2 and S1P in the Nucleus Regulate Histone Acetylation by Inhibition of Histone Deacetylases

2010 ◽  
Vol 24 (S1) ◽  
Author(s):  
Nitai Chand Hait ◽  
Jeremy Allegood ◽  
Michael Maceyka ◽  
Graham M Strub ◽  
Kuzhuvelil B Harikumar ◽  
...  
Keyword(s):  
Histone Acetylation ◽  
Histone Deacetylases ◽  
Sphingosine Kinase ◽  
Sphingosine Kinase 2

scholarly journals Epigenetic Metabolite Acetate Inhibits Class I/II Histone Deacetylases, Promotes Histone Acetylation, and Increases HIV-1 Integration in CD4+ T Cells

2017 ◽  
Vol 91 (16) ◽  
Author(s):  
Jean-François Bolduc ◽  
Laurent Hany ◽  
Corinne Barat ◽  
Michel Ouellet ◽  
Michel J. Tremblay
Keyword(s):  
T Cells ◽  
Histone Acetylation ◽  
Disease Progression ◽  
Histone Deacetylase ◽  
Histone Deacetylases ◽  
Short Chain Fatty Acids ◽  
Short Chain ◽  
Class I ◽  
Hdac Activity ◽  
Hiv 1

ABSTRACT In this study, we investigated the effect of acetate, the most concentrated short-chain fatty acid (SCFA) in the gut and bloodstream, on the susceptibility of primary human CD4+ T cells to HIV-1 infection. We report that HIV-1 replication is increased in CD3/CD28-costimulated CD4+ T cells upon acetate treatment. This enhancing effect correlates with increased expression of the early activation marker CD69 and impaired class I/II histone deacetylase (HDAC) activity. In addition, acetate enhances acetylation of histones H3 and H4 and augments HIV-1 integration into the genome of CD4+ T cells. Thus, we propose that upon antigen presentation, acetate influences class I/II HDAC activity that transforms condensed chromatin into a more relaxed structure. This event leads to a higher level of viral integration and enhanced HIV-1 production. In line with previous studies showing reactivation of latent HIV-1 by SCFAs, we provide evidence that acetate can also increase the susceptibility of primary human CD4+ T cells to productive HIV-1 infection. IMPORTANCE Alterations in the fecal microbiota and intestinal epithelial damage involved in the gastrointestinal disorder associated with HIV-1 infection result in microbial translocation that leads to disease progression and virus-related comorbidities. Indeed, notably via production of short-chain fatty acids, bacteria migrating from the lumen to the intestinal mucosa could influence HIV-1 replication by epigenetic regulatory mechanisms, such as histone acetylation. We demonstrate that acetate enhances virus production in primary human CD4+ T cells. Moreover, we report that acetate impairs class I/II histone deacetylase activity and increases integration of HIV-1 DNA into the host genome. Therefore, it can be postulated that bacterial metabolites such as acetate modulate HIV-1-mediated disease progression.

scholarly journals Genome-wide profiling in colorectal cancer identifies PHF19 and TBC1D16 as oncogenic super enhancers

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Qing-Lan Li ◽  
Xiang Lin ◽  
Ya-Li Yu ◽  
Lin Chen ◽  
Qi-Xin Hu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colorectal Cancer Patient ◽  
Nucleotide Polymorphisms ◽  
Rna Seq ◽  
Motif Analysis ◽  
Single Nucleotide ◽  
Super Enhancer ◽  
Genome Wide ◽  
Functional Factors ◽  
Cancer Tissues

AbstractColorectal cancer is one of the most common cancers in the world. Although genomic mutations and single nucleotide polymorphisms have been extensively studied, the epigenomic status in colorectal cancer patient tissues remains elusive. Here, together with genomic and transcriptomic analysis, we use ChIP-Seq to profile active enhancers at the genome wide level in colorectal cancer paired patient tissues (tumor and adjacent tissues from the same patients). In total, we sequence 73 pairs of colorectal cancer tissues and generate 147 H3K27ac ChIP-Seq, 144 RNA-Seq, 147 whole genome sequencing and 86 H3K4me3 ChIP-Seq samples. Our analysis identifies 5590 gain and 1100 lost variant enhancer loci in colorectal cancer, and 334 gain and 121 lost variant super enhancer loci. Multiple key transcription factors in colorectal cancer are predicted with motif analysis and core regulatory circuitry analysis. Further experiments verify the function of the super enhancers governing PHF19 and TBC1D16 in regulating colorectal cancer tumorigenesis, and KLF3 is identified as an oncogenic transcription factor in colorectal cancer. Taken together, our work provides an important epigenomic resource and functional factors for epigenetic studies in colorectal cancer.

scholarly journals Transcriptome of peanut kernel and shell reveals the mechanism of calcium on peanut pod development

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Sha Yang ◽  
Jianguo Wang ◽  
Zhaohui Tang ◽  
Feng Guo ◽  
Ye Zhang ◽  
...  
Keyword(s):  
Early Stage ◽  
Central Element ◽  
Abnormal Development ◽  
Transcriptional Level ◽  
Peanut Kernel ◽  
Rna Seq ◽  
Embryo Abortion ◽  
Genes Encoding ◽  
Pod Development ◽  
The Relationship

Abstract Calcium is not only a nutrient necessary for plant growth but also a ubiquitous central element of different signaling pathways. Ca2+ deficiency in soil may cause embryo abortion, which can eventually lead to abnormal development of peanut pods during the harvest season. To further study the mechanisms by which Ca2+ affects the shells and kernels of peanuts, transcriptome sequencing was used to explore the genes differentially expressed in shells and kernels during the early stage of peanut pod development between Ca2+ sufficient and deficient treatments. In this study, 38,894 expressed genes were detected. RNA-seq based gene expression profiling showed a large number of genes at the transcriptional level that changed significantly in shells and kernels between the Ca2+ sufficient and deficient treatments, respectively. Genes encoding key proteins involved in Ca2+ signal transduction, hormones, development, ion transport, and nutrition absorption changed significantly. Meanwhile, in the early stage of pod development, calcium first promoted nutrient absorption and development of shells, which has less effect on the formation of seed kernels. These results provide useful information for understanding the relationship between Ca2+ absorption and pod development.

scholarly journals AGL15 Controls the Embryogenic Reprogramming of Somatic Cells in Arabidopsis through the Histone Acetylation-Mediated Repression of the miRNA Biogenesis Genes

2020 ◽  
Vol 21 (18) ◽  
pp. 6733
Author(s):  
Katarzyna Nowak ◽  
Joanna Morończyk ◽  
Anna Wójcik ◽  
Małgorzata D. Gaj
Keyword(s):  
Histone Acetylation ◽  
Histone Deacetylases ◽  
Trichostatin A ◽  
Somatic Cells ◽  
Regulatory Function ◽  
Mirna Biogenesis ◽  
Embryogenic Culture ◽  
Cell Transcriptome ◽  
The Impact ◽  
Embryogenic Transition

The embryogenic transition of somatic cells requires an extensive reprogramming of the cell transcriptome. Relevantly, the extensive modulation of the genes that have a regulatory function, in particular the genes encoding the transcription factors (TFs) and miRNAs, have been indicated as controlling somatic embryogenesis (SE) that is induced in vitro in the somatic cells of plants. Identifying the regulatory relationships between the TFs and miRNAs during SE induction is of central importance for understanding the complex regulatory interplay that fine-tunes a cell transcriptome during the embryogenic transition. Hence, here, we analysed the regulatory relationships between AGL15 (AGAMOUS-LIKE 15) TF and miR156 in an embryogenic culture of Arabidopsis. Both AGL15 and miR156 control SE induction and AGL15 has been reported to target the MIR156 genes in planta. The results showed that AGL15 contributes to the regulation of miR156 in an embryogenic culture at two levels that involve the activation of the MIR156 transcription and the containment of the abundance of mature miR156 by repressing the miRNA biogenesis genes DCL1 (DICER-LIKE1), SERRATE and HEN1 (HUA-ENHANCER1). To repress the miRNA biogenesis genes AGL15 seems to co-operate with the TOPLESS co-repressors (TPL and TPR1-4), which are components of the SIN3/HDAC silencing complex. The impact of TSA (trichostatin A), an inhibitor of the HDAC histone deacetylases, on the expression of the miRNA biogenesis genes together with the ChIP results implies that histone deacetylation is involved in the AGL15-mediated repression of miRNA processing. The results indicate that HDAC6 and HDAC19 histone deacetylases might co-operate with AGL15 in silencing the complex that controls the abundance of miR156 during embryogenic induction. This study provides new evidence about the histone acetylation-mediated control of the miRNA pathways during the embryogenic reprogramming of plant somatic cells and the essential role of AGL15 in this regulatory mechanism.

Marfan Syndrome

2005 ◽  
Vol 44 (04) ◽  
pp. 487-497 ◽  
Author(s):  
G. Mátyás ◽  
B. Steinmann ◽  
D. Baumgartner ◽  
C. Baumgartner
Keyword(s):  
Medical Treatment ◽  
Marfan Syndrome ◽  
Clinical Symptoms ◽  
Early Stage ◽  
Molecular Genetic ◽  
Clinical Manifestations ◽  
Hierarchical Cluster ◽  
Molecular Genetic Analysis ◽  
Missense Mutations ◽  
Surgical Interventions

Summary Objectives: Marfan syndrome (MFS) is an autosomal dominant inherited connective tissue disorder caused by mutations in the fibrillin-1 (FBN1) gene with variable clinical manifestations in the cardiovascular, musculoskeletal and ocular systems. Methods: Data of molecular genetic analysis and a catalogue of clinical manifestations including aortic elastic parameters were mined in order to (i) assess aortic abnormality before and during medical treatment, and to (ii) identify novel correlations between the genotype and phenotype of the disease using hierarchical cluster analysis and logistic regression analysis. A score measure describing the similarity between a patient’s clinical symptoms and a characteristic phenotype class was introduced. Results: A probabilistic model for monitoring the loss of aortic elasticity was built on merely aortic parameters of 34 patients with classic MFS and 43 control subjects showing a sensitivity of 82% and a specificity of 96%. The clinical phenotypes of 100 individuals with classical or suspected MFS were clustered yielding four different phenotypic expressions. The highest correlation was found between FBN1 missense mutations, which manifested as ectopia lentis, skeletal major and skin minor criteria, and two out of four clustered phenotypes. The probability of the presence of a missense mutation in both phenotype classes is approximately 70%. Conclusions: Monitoring of aortic elastic properties during medical treatment may serve as additional criterion to indicate elective surgical interventions. Genotype-phenotype correlation may contribute to anticipate the clinical consequences of specific FBN1 mutations more comprehensively and may be helpful to identify MFS patients at risk at an early stage of disease.

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