scholarly journals Simultaneous Mutation of Methylated Lysine Residues in Histone H3 Causes Enhanced Gene Silencing, Cell Cycle Defects, and Cell Lethality in Saccharomyces cerevisiae

2007 ◽  
Vol 27 (19) ◽  
pp. 6832-6841 ◽  
Author(s):  
Yi Jin ◽  
Amy M. Rodriguez ◽  
Julie D. Stanton ◽  
Ana A. Kitazono ◽  
John J. Wyrick
Keyword(s):  
Cell Cycle ◽  
Histone H3 ◽  
Mitotic Cell ◽  
Histone Methyltransferase ◽  
Lethal Phenotype ◽  
Genome Wide ◽  
Lysine Residues ◽  
Sir Complex ◽  
Genomic Regions ◽  
Methylated Lysine

ABSTRACT The methylation of specific lysine residues in histone H3 is integral to transcription regulation; however, little is known about how combinations of methylated lysine residues act in concert to regulate genome-wide transcription. We have systematically mutated methylated histone lysine residues in yeast and found that the triple mutation of H3K4, H3K36, and H3K79 to arginine (H3 K4,36,79R) is lethal. The histone H3 K4,36,79R mutant causes a mitotic cell cycle delay and a progressive transcription defect that initiates in telomere regions and then spreads into the chromosome. This effect is mediated by the silent information regulator (SIR) silencing complex, as we observe increased binding of the SIR complex to genomic regions adjacent to yeast telomeres in the H3 K4,36,79R mutant and deletion of SIR2, SIR3, or SIR4 rescues the lethal phenotype. Curiously, a yeast strain in which the histone methyltransferase genes are simultaneously deleted is viable. Indeed, deletion of the histone methyltransferase genes can suppress the H3 K4,36,79R lethal phenotype. These and other data suggest that the cause of lethality may in part be due to the association of histone methyltransferase enzymes with a histone substrate that cannot be methylated.

scholarly journals Time makes histone H3 modifications drift

2021 ◽  
Author(s):  
Roman Hillje ◽  
Lucilla Luzi ◽  
Stefano Amatori ◽  
Mirco Fanelli ◽  
Pier Giuseppe Pelicci ◽  
...  
Keyword(s):  
Caloric Restriction ◽  
Histone Modifications ◽  
Histone H3 ◽  
Transcription Start ◽  
Transcription Start Sites ◽  
Genome Wide ◽  
Restriction Diet ◽  
Intergenic Regions ◽  
Genomic Regions ◽  
Methylated Lysine

Abstract To disclose the epigenetic drift of time passing, we determined the genome-wide distributions of mono- and tri-methylated lysine 4 and acetylated and tri-methylated lysine 27 of histone H3 in the livers of healthy 3, 6 and 12 months old C57BL/6 mice. The comparison of different age profiles of histone H3 marks revealed global redistribution of histone H3 modifications with time, in particular in intergenic regions and near transcription start sites, as well as altered correlation between the profiles of different histone modifications. Moreover, feeding mice with caloric restriction diet, a treatment known to retard aging, preserved younger state of histone H3 in these genomic regions.

scholarly journals Pathway-Wide Genetic Risks in Chlamydial Infections Overlap between Tissue Tropisms: A Genome-Wide Association Scan

2018 ◽  
Vol 2018 ◽  
pp. 1-9
Author(s):  
Chrissy H. Roberts ◽  
Sander Ouburg ◽  
Mark D. Preston ◽  
Henry J. C. de Vries ◽  
Martin J. Holland ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Chlamydia Trachomatis ◽  
Mitotic Cell ◽  
Genome Wide Association ◽  
Serological Response ◽  
Transmitted Infection ◽  
Genome Wide ◽  
A Genome ◽  
Tissue Tropisms ◽  
Chlamydial Infections

Chlamydia trachomatis is the most commonly diagnosed bacterial sexually transmitted infection and can lead to tubal factor infertility, a disease characterised by fibrosis of the fallopian tubes. Genetic polymorphisms in molecular pathways involving G protein-coupled receptor signalling, the Akt/PI3K cascade, the mitotic cell cycle, and immune response have been identified in association with the development of trachomatous scarring, an ocular form of chlamydia-related fibrotic pathology. In this case-control study, we performed genome-wide association and pathways-based analysis in a sample of 71 Dutch women who attended an STI clinic who were seropositive for Chlamydia trachomatis antibodies and 169 high-risk Dutch women who sought similar health services but who were seronegative. We identified two regions of within-gene SNP association with Chlamydia trachomatis serological response and found that GPCR signalling and cell cycle pathways were also associated with the trait. These pathway-level associations appear to be common to immunological sequelae of chlamydial infections in both ocular and urogenital tropisms. These pathways may be central mediators of human refractoriness to chlamydial diseases.

scholarly journals Gcn5-mediated acetylation at MBF-regulated promoters induces the G1/S transcriptional wave

2019 ◽  
Vol 47 (16) ◽  
pp. 8439-8451 ◽  
Author(s):  
Alberto González-Medina ◽  
Elena Hidalgo ◽  
José Ayté
Keyword(s):  
Cell Cycle ◽  
Molecular Mechanisms ◽  
Histone H3 ◽  
Dependent Manner ◽  
Saga Complex ◽  
Lysine Residues ◽  
Physical Barriers ◽  
A Cell ◽  
Cycle Dependent ◽  
Regulated Promoters

Abstract In fission yeast, MBF-dependent transcription is inactivated at the end of S phase through a negative feedback loop that involves the co-repressors, Yox1 and Nrm1. Although this repression system is well known, the molecular mechanisms involved in MBF activation remain largely unknown. Compacted chromatin constitutes a barrier to activators accessing promoters. Here, we show that chromatin regulation plays a key role in activating MBF-dependent transcription. Gcn5, a part of the SAGA complex, binds to MBF-regulated promoters through the MBF co-activator Rep2 in a cell cycle-dependent manner and in a reverse correlation to the binding of the MBF co-repressors, Nrm1 or Yox1. We propose that the co-repressors function as physical barriers to SAGA recruitment onto MBF promoters. We also show that Gcn5 acetylates specific lysine residues on histone H3 in a cell cycle-regulated manner. Furthermore, either in a gcn5 mutant or in a strain in which histone H3 is kept in an unacetylated form, MBF-dependent transcription is downregulated. In summary, Gcn5 is required for the full activation and correct timing of MBF-regulated gene transcription.

scholarly journals Genome-Wide Analysis of the Relationship between Transcriptional Regulation by Rpd3p and the Histone H3 and H4 Amino Termini in Budding Yeast

2004 ◽  
Vol 24 (20) ◽  
pp. 8823-8833 ◽  
Author(s):  
Nevin Sabet ◽  
Sam Volo ◽  
Cailin Yu ◽  
James P. Madigan ◽  
Randall H. Morse
Keyword(s):  
Gene Expression ◽  
Budding Yeast ◽  
Histone H3 ◽  
Global Gene Expression ◽  
Amino Terminus ◽  
Histone H4 ◽  
Histone Tails ◽  
Genome Wide ◽  
Lysine Residues ◽  
The Relationship

ABSTRACT The histone amino termini have emerged as key targets for a variety of modifying enzymes that function as transcriptional coactivators and corepressors. However, an important question that has remained largely unexplored is the extent to which specific histone amino termini are required for the activating and repressive functions of these enzymes, Here we address this issue by focusing on the prototypical histone deacetylase, Rpd3p, in the budding yeast Saccharomyces cerevisiae. We show that targeting Rpd3p to a reporter gene in this yeast can partially repress transcription when either the histone H3 or the histone H4 amino terminus is deleted, indicating that the “tails” are individually dispensable for repression by Rpd3p. In contrast, we find that the effect of rpd3 gene disruption on global gene expression is considerably reduced in either a histone H3Δ1-28 (H3 lacking the amino-terminal 28 amino acids) or a histone H4(K5,8,12,16Q) (H4 with lysine residues 5, 8, 12, and 16 changed to glutamine residues) background compared to the wild-type background, indicating a requirement for one or both of these histone tails in Rpd3p-mediated regulation for many genes. These results suggest that acetylation of either the H3 or the H4 amino terminus could suffice to allow the activation of such genes. We also examine the relationship between H3 tails and H4 tails in global gene expression and find substantial overlap among the gene sets regulated by these histone tails. We also show that the effects on genome-wide expression of deleting the H3 or H4 amino terminus are similar but not identical to the effects of mutating the lysine residues in these same regions. These results indicate that the gene regulatory potential of the H3 and H4 amino termini is substantially but not entirely contained in these modifiable lysine residues.

scholarly journals Transcriptional Repression by the Retinoblastoma Protein through the Recruitment of a Histone Methyltransferase

2001 ◽  
Vol 21 (19) ◽  
pp. 6484-6494 ◽  
Author(s):  
Laurence Vandel ◽  
Estelle Nicolas ◽  
Olivier Vaute ◽  
Roger Ferreira ◽  
Slimane Ait-Si-Ali ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Transcriptional Repression ◽  
Histone Deacetylases ◽  
Histone H3 ◽  
Histone Methyltransferase ◽  
S Phase ◽  
E2f Transcription Factor ◽  
Cycle Dependent

ABSTRACT The E2F transcription factor controls the cell cycle-dependent expression of many S-phase-specific genes. Transcriptional repression of these genes in G0 and at the beginning of G1by the retinoblasma protein Rb is crucial for the proper control of cell proliferation. Rb has been proposed to function, at least in part, through the recruitment of histone deacetylases. However, recent results indicate that other chromatin-modifying enzymes are likely to be involved. Here, we show that Rb also interacts with a histone methyltransferase, which specifically methylates K9 of histone H3. The results of coimmunoprecipitation experiments of endogenous or transfected proteins indicate that this histone methyltransferase is the recently described heterochromatin-associated protein Suv39H1. Interestingly, phosphorylation of Rb in vitro as well as in vivo abolished the Rb-Suv39H1 interaction. We also found that Suv39H1 and Rb cooperate to repress E2F activity and that Suv39H1 could be recruited to E2F1 through its interaction with Rb. Taken together, these data indicate that Suv39H1 is involved in transcriptional repression by Rb and suggest an unexpected link between E2F regulation and heterochromatin.

scholarly journals The budding yeast heterochromatic SIR complex resets upon exit from stationary phase

2019 ◽  
Author(s):  
Hrvoje Galic ◽  
Pauline Vasseur ◽  
Marta Radman-Livaja
Keyword(s):  
Cell Cycle ◽  
Stationary Phase ◽  
De Novo ◽  
Budding Yeast ◽  
Growth Conditions ◽  
Clear Understanding ◽  
Turnover Rates ◽  
Heterochromatin Formation ◽  
Genome Wide ◽  
Sir Complex

AbstractThe budding yeast SIR complex (Silent Information Regulator) is the principal actor in heterochromatin formation, which causes epigenetically regulated gene silencing phenotypes. The maternal chromatin bound SIR complex is disassembled during replication. Consequently, if heterochromatin is to be restored on both daughter strands, the SIR complex has to be reformed on both strands to pre-replication levels. The dynamics of SIR complex maintenance and re-formation during the cell-cycle and in different growth conditions are however not clear. Understanding exchange rates of SIR subunits during the cell cycle and their distribution pattern to daughter chromatids after replication has important implications for how heterochromatic states may be inherited and therefore how epigenetic states are maintained from one cellular generation to the next. We used the tag switch RITE system to measure genome wide turnover rates of the SIR subunit Sir3 before and after exit from stationary phase and show that maternal Sir3 subunits are completely replaced with newly synthesized Sir3 at subtelomeric regions during the first cell cycle after release from stationary phase. The SIR complex is therefore not “inherited” and the silenced state has to be established de novo upon exit from stationary phase. Additionally, our analysis of genome-wide transcription dynamics shows that precise Sir3 dosage is needed for the optimal up-regulation of “growth” genes during the first cell-cycle after release from stationary phase.

scholarly journals Identification of genomic regions required for DNA replication during Drosophila embryogenesis.

Genetics ◽  
1993 ◽  
Vol 135 (3) ◽  
pp. 817-829 ◽  
Author(s):  
A V Smith ◽  
J A King ◽  
T L Orr-Weaver
Keyword(s):  
Cell Cycle ◽  
Dna Replication ◽  
Mitotic Cell ◽  
Complementation Group ◽  
G1 Phase ◽  
Mitotic Cell Cycle ◽  
Drosophila Embryogenesis ◽  
Late Embryogenesis ◽  
Brdu Labeling ◽  
Genomic Regions

Abstract A collection of Drosophila deficiency stocks was examined by bromodeoxyuridine (BrdU) labeling of embryos to analyze the DNA replication patterns in late embryogenesis. This permitted us to screen 34% of the genome for genes that when absent in homozygous deficiencies affect the cell cycle or DNA replication. We found three genomic intervals that when deleted result in cessation of DNA replication in the embryo, 39D2-3;E2-F1, 51E and 75C5-7;F1. Embryos deleted for the 75C5-7;F1 region stop DNA replication at the time in embryogenesis when a G1 phase is added to the mitotic cell cycle and the larval tissues begin to become polytene. Thus, this interval may contain a gene controlling these cell cycle transitions. DNA replication arrests earlier in embryos homozygous for deletions for the other two regions. Analysis of the effects of deletions in the 39D2-3;E2-F1 region on DNA replication showed that the block to DNA replication correlates with deletion of the histone genes. We were able to identify a single, lethal complementation group in 51E, l(2)51Ec, that is responsible for the cessation of replication observed in this interval. Deficiencies that removed one of the Drosophila cdc2 genes and the cyclin A gene had no effect on replication during embryogenesis. Additionally, our analysis identified a gene, pimples, that is required for the proper completion of mitosis in the post-blastoderm divisions of the embryo.

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.

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