Role of histone acetylation in the control of gene expression

2005 ◽  
Vol 83 (3) ◽  
pp. 344-353 ◽  
Author(s):  
Loredana Verdone ◽  
Micaela Caserta ◽  
Ernesto Di Mauro
Keyword(s):  
Gene Expression ◽  
Histone Acetylation ◽  
Dna Sequences ◽  
Control Of Gene Expression ◽  
Functional Roles ◽  
Lysine Residues ◽  
Human Disorders ◽  
Covalent Modifications ◽  
The Stability ◽  
Nuclear Processes

Histone proteins play structural and functional roles in all nuclear processes. They undergo different types of covalent modifications, defined in their ensemble as epigenetic because changes in DNA sequences are not involved. Histone acetylation emerges as a central switch that allows interconversion between permissive and repressive chromatin domains in terms of transcriptional competence. The mechanisms underlying the histone acetylation-dependent control of gene expression include a direct effect on the stability of nucleosomal arrays and the creation of docking sites for the binding of regulatory proteins. Histone acetyltransferases and deacetylases are, respectively, the enzymes devoted to the addition and removal of acetyl groups from lysine residues on the histone N-terminal tails. The enzymes exert fundamental roles in developmental processes and their deregulation has been linked to the progression of diverse human disorders, including cancer.Key words: gene expression, transcription, HATs, HDACs, nucleosome.

scholarly journals Role of polycomb repressive complex 2 in regulation of human transcription factor gene expression

2021 ◽  
Author(s):  
Jay Brown
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Rna Polymerase ◽  
Rna Polymerase Ii ◽  
Dna Sequences ◽  
Binding Sites ◽  
Regulatory Control ◽  
Polycomb Repressive Complex ◽  
Control Of Gene Expression ◽  
Polycomb Repressive Complex 2

Control of gene expression is now recognized as a central issue in the field of molecular biology. We now know the sequences of many genomes including that of the human genome, and we know the nature of many pathways involved in control of gene expression. It remains difficult, however, to look at the DNA sequences surrounding a particular gene and tell which methods of regulatory control are in use. I have been pursuing the idea that progress might be made by comparing the regulatory regions of paired gene populations in which one population is strongly expressed and the other weakly. Here I report the results obtained with human genes encoding transcription factors (TF). In this population, broadly expressed genes are strongly expressed while tissue targeted TF expression is suppressed in most tissues. The results demonstrated that the promoter region of broadly expressed TF genes is enriched in binding sites for POLR2A, a component of RNA polymerase II while promoters of tissue targeted genes are enriched in EZH2, a subunit of polycomb repressive complex 2 (PRC2). It was rare to observe promoters with binding sites for both POLR2A and EZH2. The findings are interpreted to indicate that strong expression of broadly expressed TF genes is due to the presence of RNA polymerase II at the promoter while weak expression of tissue targeted promoters results from the presence of PRC2. Finally, transcription factor families were compared in the proportion of broadly expressed and tissue targeted genes they contain. The results demonstrated that most families possess both broadly expressed and tissue targeted members. For instance, this was the case with 16 of 20 TF families examined. The results are interpreted to indicate that while individual TFs such as EZH2 may be specific for broadly expressed or tissue targeted genes, this is not a property of most TF families.

Involvement of transcription factor C/EBP-beta in stimulation of PEPCK gene expression during exercise

1996 ◽  
Vol 270 (5) ◽  
pp. R1005-R1012 ◽  
Author(s):  
S. E. Nizielski ◽  
C. Arizmendi ◽  
A. R. Shteyngarts ◽  
C. J. Farrell ◽  
J. E. Friedman
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Gene Transcription ◽  
Dna Sequences ◽  
Prolonged Exercise ◽  
Nuclear Proteins ◽  
Control Of Gene Expression ◽  
Total Binding ◽  
Factor C ◽  
Stimulation Of

Prolonged exercise increases gluconeogenesis and activates transcription of the hepatic phosphoenol pyruvate carboxykinase (PEPCK) gene. The mechanisms that regulate the transcriptional control of gene expression depend on the interaction of nuclear proteins with distinct DNA sequences. To determine the involvement with the liver-enriched transcription factor CCAAT/enhancer binding protein beta (C/EMP-beta) in the induction of PEPCK gene transcription during prolonged exercise or adenosine 3',5'-cyclic monophosphate (cAMP) treatment, we examined C/EBP-beta mRNA and nuclear protein concentrations, as well as C/EBP-beta binding to the PEPCK promoter at the cAMP response element (CRE)(-87/-74) and P3I (-248/-230) binding sites. The requirement of these DNA elements for exercise-induced stimulation of PEPCK gene expression was established in transgenic mice carrying -460 +/- 73 of the PEPCK promoter with a mutation in either the CRE or P3I binding domain linked to a bovine growth hormone (bGH) reporter gene. In mice carrying the intact promoter, prolonged exercise increased the concentration of liver bGH mRNA by 510% compared with an increase of only 270% in mice with a mutation in either the CRE or P3I site. Exercise or cAMP injection induced a 7.5- and 13-fold increase in nuclear C/EBP-beta protein, respectively. In electrophoretic mobility shift assays (EMSA), the total quantity of nuclear proteins bound to either oligomer was not altered by treatment. However, addition of C/EBP-beta antisera in the EMSA in a supershift assay indicated that liver nuclear extracts from exercised or cAMP-treated mice demonstrated significantly greater DNA binding due to C/EBP-beta (CRE: control 44.4 +/- 2.3%, exercise 56.7% +/- 2.2%, cAMP 54.5 +/- 3.6% of total binding, P < 0.001; P3I: control 35.8 +/- 2.5%, exercise 64.9 +/- 1.9%, cAMP 57.3 +/- 2.5% of total binding, P < 0.001). Taken together, these results suggest that exercise and cAMP treatment induce a transient increase in C/EBP-beta that may contribute to the molecular mechanism for signaling PEPCK gene transcription and increasing gluconeogenesis during exercise.

Abstract 508: Nuclear Lamins At Enhancers: A New Hypothesis for Laminopathies

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Kohta Ikegami ◽  
Stefano Secchia ◽  
Omar Almakki ◽  
Alexis V Stutzman ◽  
Sachie Ikegami ◽  
...  
Keyword(s):  
Gene Expression ◽  
Histone Acetylation ◽  
Binding Sites ◽  
Nuclear Periphery ◽  
Nuclear Lamina ◽  
Lamin A ◽  
New Paradigm ◽  
Control Of Gene Expression ◽  
Nuclear Lamins ◽  
Nuclear Interior

The segregation of heterochromatin domains (LADs) at the nuclear periphery by the nuclear lamina, composed by polymerized nuclear Lamin A/C, provides a longstanding paradigm for the control of gene expression and for the mechanisms underlying Lamin-A/C-associated disorders, including progeria and cardiomyopathy. Here, we provide evidence supporting a novel paradigm that Lamin A/C functions as a transcription factor in the nuclear interior. We discovered that Ser22-phosphorylated Lamin A/C (pS22-Lamin A/C), required for lamin depolymerization during mitosis, populated the nuclear interior throughout the cell cycle. pS22-Lamin A/C ChIP-deq demonstrated localization at a large subset of putative active enhancers, not LADs. pS22-Lamin A/C-binding sites were co-occupied by the transcriptional activator c-Jun. In progeria patient-derived fibroblasts, a subset of pS22-Lamin A/C-binding sites were lost whereas new pS22-Lamin A/C-binding sites emerged. New pS22-Lamin A/C binding was accompanied by increased histone acetylation and increased c-Jun binding, whereas loss of pS22-Lamin A/C-binding was accompanied by loss of histone acetylation and c-Jun binding. New pS22-Lamin A/C enhancer binding in progeria was associated with upregulated expression of genes implicated in progeria pathophysiology, including cardiovascular disease. In contrast, alteration of LADs in progeria-patient cells could not explain the observed gene expression changes. These results suggest that Lamin A/C regulates gene expression by enhancer binding in the nuclear interior, independent of its function at the nuclear lamina, providing a new paradigm for the pathogenesis of lamin-associated disorders. pS22-Lamin A/C was also present in the nuclear interior of adult mouse cardiomyocytes. Cardiomyocyte-specific deletion of Lmna encoding Lamin A/C in adult mice caused extensive transcriptional changes in the heart and dilated cardiomyopathy, without apparent reduction of nuclear peripheral Lamin A/C. Disruption of the gene regulatory rather than LAD tethering function of Lamin A/C may underlie the pathogenesis of disorders caused by LMNA mutations, including cardiomyopathy.

scholarly journals Defects in lamin B1 expression or processing affect interphase chromosome position and gene expression

2007 ◽  
Vol 176 (5) ◽  
pp. 593-603 ◽  
Author(s):  
Ashraf Malhas ◽  
Chiu Fan Lee ◽  
Rebecca Sanders ◽  
Nigel J. Saunders ◽  
David J. Vaux
Keyword(s):  
Gene Expression ◽  
Nuclear Lamina ◽  
Chromosome Territory ◽  
Full Length ◽  
Interphase Chromosome ◽  
Control Of Gene Expression ◽  
Lamin B1 ◽  
Chromosome Position ◽  
Normal Expression ◽  
The Stability

Radial organization of nuclei with peripheral gene-poor chromosomes and central gene-rich chromosomes is common and could depend on the nuclear boundary as a scaffold or position marker. To test this, we studied the role of the ubiquitous nuclear envelope (NE) component lamin B1 in NE stability, chromosome territory position, and gene expression. The stability of the lamin B1 lamina is dependent on lamin endoproteolysis (by Rce1) but not carboxymethylation (by Icmt), whereas lamin C lamina stability is not affected by the loss of full-length lamin B1 or its processing. Comparison of wild-type murine fibroblasts with fibroblasts lacking full-length lamin B1, or defective in CAAX processing, identified genes that depend on a stable processed lamin B1 lamina for normal expression. We also demonstrate that the position of mouse chromosome 18 but not 19 is dependent on such a stable nuclear lamina. The results implicate processed lamin B1 in the control of gene expression as well as chromosome position.

scholarly journals DNA Methylation and Chromatin: Role(s) of Methyl-CpG-Binding Protein ZBTB38

2018 ◽  
Vol 11 ◽  
pp. 251686571881111 ◽  
Author(s):  
Maud de Dieuleveult ◽  
Benoit Miotto
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Transcription Factors ◽  
Dna Sequences ◽  
Mammalian Cells ◽  
Expression Patterns ◽  
Control Of Gene Expression ◽  
Methylated Dna

DNA methylation plays an essential role in the control of gene expression during early stages of development as well as in disease. Although many transcription factors are sensitive to this modification of the DNA, we still do not clearly understand how it contributes to the establishment of proper gene expression patterns. We discuss here the recent findings regarding the biological and molecular function(s) of the transcription factor ZBTB38 that binds methylated DNA sequences in vitro and in cells. We speculate how these findings may help understand the role of DNA methylation and DNA methylation–sensitive transcription factors in mammalian cells.

DNA methylation and epigenetic inheritance

1990 ◽  
Vol 326 (1235) ◽  
pp. 329-338 ◽  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Dna Sequences ◽  
Mammalian Cells ◽  
Germ Line ◽  
Experimental System ◽  
Epigenetic Inheritance ◽  
Epigenetic Mechanisms ◽  
Control Of Gene Expression ◽  
Developmental Programme

Classical genetics has revealed the mechanisms for the transmission of genes from generation to generation, but the strategy of the genes in unfolding the developmental programme remains obscure. Epigenetics comprises the study of the mechanisms that impart temporal and spatial control on the activities of all those genes required for the development of a complex organism from the zygote to the adult. Epigenetic changes in gene activity can be studied in relation to DNA methylation in cultured mammalian cells and it is also possible to isolate and characterize mutants with altered DNA methylase activity. Although this experimental system is quite far removed from the epigenetic controls acting during development it does provide the means to clarify the rules governing the silencing of genes by specific DNA methylation and their reactivation by demethylation. This in turn will facilitate studies on the control of gene expression in somatic cells of the developing organism or the adult. The general principles of epigenetic mechanisms can be defined. There are extreme contrasts between instability or switches in gene expression, such as those in stem-line cells, and the stable heritability of a specialized pattern of gene activities. In some situations cell lineages are known to be important, whereas in others coordinated changes in groups of cells have been demonstrated. Control of numbers of cell divisions and the size of organisms, or parts of organisms, is also essential. The epigenetic determination of gene expression can be reversed or reprogrammed in the germ line. The extent to which methylation or demethylation of specific DNA sequences can help explain these basic epigenetic mechanisms is briefly reviewed.

scholarly journals A histone-like motif in yellow fever virus contributes to viral replication

2020 ◽  
Author(s):  
Diego Mourão ◽  
Shoudeng Chen ◽  
Uwe Schaefer ◽  
Leonia Bozzacco ◽  
Leticia A. Carneiro ◽  
...  
Keyword(s):  
Gene Expression ◽  
Yellow Fever ◽  
Yellow Fever Virus ◽  
Rna Virus ◽  
Fever Virus ◽  
Host Protein ◽  
Histone H4 ◽  
Host Proteins ◽  
Control Of Gene Expression ◽  
Lysine Residues

The mimicry of host proteins by viruses contributes to their ability to suppress antiviral immunity and hijack host biosynthetic machinery1. Host adaptation to evade this exploitation depends on host protein functional redundancy2. Non-redundant, essential host proteins have limited potential to adapt without severe consequences3. Histones, which are essential for genome architecture and control of gene expression, are among the most evolutionary conserved proteins4. Here we show that the capsid protein of the flavivirus yellow fever virus (YFV), mimics histone H4 and interferes with chromatin gene regulation by BRD4, a bromodomain and extraterminal domain (BET) protein. Two acetyl-lysine residues of YFV capsid are embedded in a histone-like motif that interacts with the BRD4 bromodomain, affecting gene expression and influencing YFV replication. These findings reveal histone mimicry as a strategy employed by an RNA virus that replicates in the cytosol5 and define convergent and distinct molecular determinants for motif recognition of the viral mimic versus histone H4.

scholarly journals The Eaf3 chromodomain acts as a pH sensor for gene expression by altering its binding affinity for histone methylated-lysine residues

2020 ◽  
Vol 40 (2) ◽  
Author(s):  
Masahiko Okuda ◽  
Yoshifumi Nishimura
Keyword(s):  
Gene Expression ◽  
Histone Acetylation ◽  
Binding Affinity ◽  
Histone H3 ◽  
Histidine Residue ◽  
Ph Titration ◽  
Epigenetic Marker ◽  
Aromatic Cage ◽  
Lysine Residues ◽  
Methylated Lysine

Abstract During gene expression, histone acetylation by histone acetyltransferase (HAT) loosens the chromatin structure around the promoter to allow RNA polymerase II (Pol II) to initiate transcription, while de-acetylation by histone deacetylase (HDAC) tightens the structure in the transcribing region to repress false initiation. Histone acetylation is also regulated by intracellular pH (pHi) with global hypoacetylation observed at low pHi, and hyperacetylation, causing proliferation, observed at high pHi. However, the mechanism underlying the pHi-dependent regulation of gene expression remains elusive. Here, we have explored the role of the chromodomain (CD) of budding yeast Eaf3, a common subunit of both HAT and HDAC that is thought to recognize methylated lysine residues on histone H3. We found that Eaf3 CD interacts with histone H3 peptides methylated at Lys4 (H3K4me, a promoter epigenetic marker) and Lys36 (H3K36me, a coding region epigenetic marker), as well as with many dimethyl-lysine peptides and even arginine-asymmetrically dimethylated peptides, but not with unmethylated, phosphorylated or acetylated peptides. The Eaf3 CD structure revealed an unexpected histidine residue in the aromatic cage essential for binding H3K4me and H3K36me. pH titration experiments showed that protonation of the histidine residue around physiological pH controls the charge state of the aromatic cage to regulate binding to H3K4me and H3K36me. Histidine substitution and NMR experiments confirmed the correlation of histidine pKa with binding affinity. Collectively, our findings suggest that Eaf3 CD functions as a pHi sensor and a regulator of gene expression via its pHi-dependent interaction with methylated nucleosomes.

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.

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