scholarly journals Inheritance of Repressed Chromatin Domains during S-phase Requires the Histone Chaperone NPM1

2021 ◽  
Author(s):  
Thelma M. Escobar ◽  
Jia-Ray Yu ◽  
Sanxiong Liu ◽  
Kimberly Lucero ◽  
Nikita Vasilyev ◽  
...  
Keyword(s):  
Dna Replication ◽  
Expression Profiles ◽  
Histone H3 ◽  
Gene Expression Profiles ◽  
Epigenetic Inheritance ◽  
S Phase ◽  
Facultative Heterochromatin ◽  
Chromatin Domains ◽  
Epigenetic Process ◽  
Integral Component

AbstractThe epigenetic process safeguards cell identity during cell division through the inheritance of appropriate gene expression profiles. We demonstrated previously that parental nucleosomes are inherited by the same chromatin domains during DNA replication only in the case of repressed chromatin. We now show that this specificity is conveyed by NPM1, a histone H3/H4 chaperone. Proteomic analyses of late S-phase chromatin revealed NPM1 in association with both H3K27me3, an integral component of facultative heterochromatin and MCM2, an integral component of the DNA replication machinery; moreover NPM1 interacts directly with PRC2 and with MCM2. Given that NPM1 is essential, the inheritance of repressed chromatin domains was examined anew using mESCs expressing an auxin-degradable version of endogenous NPM1. Upon NPM1 degradation, cells accumulated in S-phase of the cell-cycle and parental nucleosome inheritance from repressed chromatin domains was markedly compromised. Appropriate inheritance required the NPM1 acidic patches that function in chaperone activity, pointing to NPM1 being integral to the epigenetic process.One-Sentence SummaryThe histone H3/H4 chaperone, NPM1, fosters epigenetic inheritance from parental repressed chromatin during DNA replication.

scholarly journals Histone H3 lysine 56 acetylation by Rtt109 is crucial for chromosome positioning

2008 ◽  
Vol 183 (4) ◽  
pp. 641-651 ◽  
Author(s):  
Shin-ichiro Hiraga ◽  
Sotirios Botsios ◽  
Anne D. Donaldson
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Dna Replication ◽  
Histone Acetyltransferase ◽  
Nuclear Periphery ◽  
Histone H3 ◽  
Epigenetic Inheritance ◽  
S Phase ◽  
Chromosome Localization ◽  
Chromosome Domains ◽  
H3k56 Acetylation

Correct intranuclear organization of chromosomes is crucial for many genome functions, but the mechanisms that position chromatin are not well understood. We used a layered screen to identify Saccharomyces cerevisiae mutants defective in telomere localization to the nuclear periphery. We find that events in S phase are crucial for correct telomere localization. In particular, the histone chaperone Asf1 functions in telomere peripheral positioning. Asf1 stimulates acetylation of histone H3 lysine 56 (H3K56) by the histone acetyltransferase Rtt109. Analysis of rtt109Δ and H3K56 mutants suggests that the acetylation/deacetylation cycle of the H3K56 residue is required for proper telomere localization. The function of H3K56 acetylation in localizing chromosome domains is not confined to telomeres because deletion of RTT109 also prevents the correct peripheral localization of a newly identified S. cerevisiae “chromosome-organizing clamp” locus. Because chromosome positioning is subject to epigenetic inheritance, H3K56 acetylation may mediate correct chromosome localization by facilitating accurate transmission of chromatin status during DNA replication.

scholarly journals Profiling of Epigenetic Features in Clinical Samples Reveals Novel Widespread Changes in Cancer

Cancers ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 723 ◽  
Author(s):  
Roberta Noberini ◽  
Camilla Restellini ◽  
Evelyn Oliva Savoia ◽  
Francesco Raimondi ◽  
Lavinia Ghiani ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Expression Profiles ◽  
Histone H3 ◽  
Gene Expression Profiles ◽  
Culture Conditions ◽  
Clinical Samples ◽  
Post Translational Modifications ◽  
A Cell ◽  
Cancer Types ◽  
Histone Modifying Enzymes

Aberrations in histone post-translational modifications (PTMs), as well as in the histone modifying enzymes (HMEs) that catalyze their deposition and removal, have been reported in many tumors and many epigenetic inhibitors are currently under investigation for cancer treatment. Therefore, profiling epigenetic features in cancer could have important implications for the discovery of both biomarkers for patient stratification and novel epigenetic targets. In this study, we employed mass spectrometry-based approaches to comprehensively profile histone H3 PTMs in a panel of normal and tumoral tissues for different cancer types, identifying various changes, some of which appear to be a consequence of the increased proliferation rate of tumors, while others are cell-cycle independent. Histone PTM changes found in tumors partially correlate with alterations of the gene expression profiles of HMEs obtained from publicly available data and are generally lost in culture conditions. Through this analysis, we identified tumor- and subtype-specific histone PTM changes, but also widespread changes in the levels of histone H3 K9me3 and K14ac marks. In particular, H3K14ac showed a cell-cycle independent decrease in all the seven tumor/tumor subtype models tested and could represent a novel epigenetic hallmark of cancer.

scholarly journals Arsenic Trioxide Promotes Histone H3 Phosphoacetylation at the Chromatin ofCASPASE-10in Acute Promyelocytic Leukemia Cells

2002 ◽  
Vol 277 (51) ◽  
pp. 49504-49510 ◽  
Author(s):  
Ji Li ◽  
Peili Chen ◽  
Natasha Sinogeeva ◽  
Myriam Gorospe ◽  
Robert P. Wersto ◽  
...  
Keyword(s):  
Arsenic Trioxide ◽  
Acute Promyelocytic Leukemia ◽  
Molecular Mechanisms ◽  
Expression Profiles ◽  
Histone H3 ◽  
Gene Expression Profiles ◽  
Promyelocytic Leukemia ◽  
Therapeutic Effects ◽  
Acid Therapy ◽  
Nb4 Cells

Arsenic trioxide (As2O3) is highly effective for the treatment of acute promyelocytic leukemia, even in patients who are unresponsive to all-trans-retinoic acid therapy. As2O3is believed to function primarily by promoting apoptosis, but the underlying molecular mechanisms remain largely unknown. In this report, using cDNA arrays, we have examined the changes in gene expression profiles triggered by clinically achievable doses of As2O3in acute promyelocytic leukemia NB4 cells.CASPASE-10expression was found to be potently induced by As2O3. Accordingly, caspase-10 activity also substantially increased in response to As2O3treatment. A selective inhibitor of caspase-10, Z-AEVD-FMK, effectively blocked caspase-3 activation and significantly attenuated As2O3-triggered apoptosis. Interestingly, the treatment of NB4 cells with As2O3markedly increased histone H3 phosphorylation at serine 10, an event that is associated with acetylation of the lysine 14 residue. Chromatin immunoprecipitation assays revealed that As2O3potently enhances histone H3 phosphoacetylation at theCASPASE-10locus. These results suggest that the effect of As2O3on histone H3 phosphoacetylation at theCASPASE-10gene may play an important role in the induction of apoptosis and thus contribute to its therapeutic effects on acute promyelocytic leukemia.

scholarly journals Genome duplication in Leishmania major relies on persistent subtelomeric DNA replication

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Jeziel Dener Damasceno ◽  
Catarina A Marques ◽  
Dario Beraldi ◽  
Kathryn Crouch ◽  
Craig Lapsley ◽  
...  
Keyword(s):  
Cell Division ◽  
Dna Replication ◽  
Leishmania Major ◽  
Genome Duplication ◽  
Histone H3 ◽  
S Phase ◽  
Replication Initiation ◽  
G1 Phase ◽  
Dna Replication Initiation ◽  
Single Region

DNA replication is needed to duplicate a cell’s genome in S phase and segregate it during cell division. Previous work in Leishmania detected DNA replication initiation at just a single region in each chromosome, an organisation predicted to be insufficient for complete genome duplication within S phase. Here, we show that acetylated histone H3 (AcH3), base J and a kinetochore factor co-localise in each chromosome at only a single locus, which corresponds with previously mapped DNA replication initiation regions and is demarcated by localised G/T skew and G4 patterns. In addition, we describe previously undetected subtelomeric DNA replication in G2/M and G1-phase-enriched cells. Finally, we show that subtelomeric DNA replication, unlike chromosome-internal DNA replication, is sensitive to hydroxyurea and dependent on 9-1-1 activity. These findings indicate that Leishmania’s genome duplication programme employs subtelomeric DNA replication initiation, possibly extending beyond S phase, to support predominantly chromosome-internal DNA replication initiation within S phase.

The Dynamics of Chromatin Modification during RA Induced Promyelocyte Differentiation.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4191-4191
Author(s):  
Robert G. Harris ◽  
Diane S. Krause
Keyword(s):  
Expression Profiles ◽  
Chromatin Modification ◽  
Histone H3 ◽  
Gene Expression Profiles ◽  
Sharp Decrease ◽  
Promyelocytic Leukemia ◽  
Mrna Levels ◽  
Nb4 Cells ◽  
Highly Active ◽  
Methylated Lysine

Abstract Epigenetic histone modifications have recently been shown to be important in gene regulation and to be correlated with gene expression profiles. In particular, particular modifications at Lysine 4 and Lysine 9 of Histone H3 may be highly indicative of both active and silenced chromatin. Promoters of highly active genes are generally tri-methylated at Lysine 4 and acetylated at Lysine 9 whereas silenced chromatin is unmethylated or mono methylated at Lysine 4 and di or tri-methylated at Lysine 9. NB4 is a human acute promyelocytic leukemia (t15:17) cell line that can be differentiated down the neutrophil lineage by induction with supraphysiological levels of retinoic acid (RA). We have examined post-translational modifications at Lysine 4 and Lysine 9 of Histone H3 at specific promoters using chromatin immunoprecipitation (ChIP) during differentiation of NB4 cells. We have performed quantitative (q) RT-PCR for the Myeloperoxidase (MPO) and Defensin-alpha (Def-a) genes after 0,12, 24, 48 and 72 hours of RA induction of NB4 cells. Concurrently we performed ChIP followed by qPCR for Di- and Tri-methylated Lysine 4 of Histone H3 and acetyl- and di-methylated Lysine 9 of Histone H3 at the promoters of these genes. MPO mRNA is expressed at time 0, and decreases progressively starting at 24 hours such that by 48 hours mRNA levels are negligible. This correlates nicely with a sharp decrease in tri-methyl Lysine 4 and acetyl Lysine 9 levels by 12 hours, with a smaller decrease again at 24 hours on the MPO promoter. By 72 hours a concurrent increase in dimethyl Lysine 9 levels is seen, indicating chromatin silencing. Conversely, def-a is initially not expressed in NB4 cells. After 24 hours of induction with RA, an increase in mRNA levels is seen. This correlates well with a sharp increase of acetyl Lysine 9 in the promoter and a concurrent decrease in dimethyl lysine 9 levels. In conclusion we have shown that during RA induced differentiation of promyelocytic leukemia cells, chromatin modifications slightly precede changes in mRNA expression levels and recapitulate other studies linking Lysine 4 methylation with active transcription and Lysine 9 methylation with gene silencing.

scholarly journals Changes in Epigenetic Patterns Related to DNA Replication in Vicia faba Root Meristem Cells under Cadmium-Induced Stress Conditions

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3409
Author(s):  
Aneta Żabka ◽  
Natalia Gocek ◽  
Konrad Winnicki ◽  
Paweł Szczeblewski ◽  
Tomasz Laskowski ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Dna Replication ◽  
Vicia Faba ◽  
Histone Modifications ◽  
Root Meristem ◽  
Histone H3 ◽  
S Phase ◽  
Stress Conditions ◽  
Induced Stress ◽  
Immunofluorescence Labeling

Experiments on Vicia faba root meristem cells exposed to 150 µM cadmium chloride (CdCl2) were undertaken to analyse epigenetic changes, mainly with respect to DNA replication stress. Histone modifications examined by means of immunofluorescence labeling included: (1) acetylation of histone H3 on lysine 56 (H3K56Ac), involved in transcription, S phase, and response to DNA damage during DNA biosynthesis; (2) dimethylation of histone H3 on lysine 79 (H3K79Me2), correlated with the replication initiation; (3) phosphorylation of histone H3 on threonine 45 (H3T45Ph), engaged in DNA synthesis and apoptosis. Moreover, immunostaining using specific antibodies against 5-MetC-modified DNA was used to determine the level of DNA methylation. A significant decrease in the level of H3K79Me2, noted in all phases of the CdCl2-treated interphase cell nuclei, was found to correspond with: (1) an increase in the mean number of intranuclear foci of H3K56Ac histones (observed mainly in S-phase), (2) a plethora of nuclear and nucleolar labeling patterns (combined with a general decrease in H3T45Ph), and (3) a decrease in DNA methylation. All these changes correlate well with a general viewpoint that DNA modifications and post-translational histone modifications play an important role in gene expression and plant development under cadmium-induced stress conditions.

scholarly journals A mechanism for preventing asymmetric histone segregation onto replicating DNA strands

Science ◽  
2018 ◽  
Vol 361 (6409) ◽  
pp. 1386-1389 ◽  
Author(s):  
Chuanhe Yu ◽  
Haiyun Gan ◽  
Albert Serra-Cardona ◽  
Lin Zhang ◽  
Songlin Gan ◽  
...  
Keyword(s):  
Dna Replication ◽  
Dna Polymerase ◽  
Histone H3 ◽  
Epigenetic Inheritance ◽  
Yeast Cells ◽  
Replication Forks ◽  
Dna Strands ◽  
Leading Strand ◽  
Lagging Strand

How parental histone (H3-H4)2 tetramers, the primary carriers of epigenetic modifications, are transferred onto leading and lagging strands of DNA replication forks for epigenetic inheritance remains elusive. Here we show that parental (H3-H4)2 tetramers are assembled into nucleosomes onto both leading and lagging strands, with a slight preference for lagging strands. The lagging-strand preference increases markedly in budding yeast cells lacking Dpb3 and Dpb4, two subunits of the leading strand DNA polymerase, Pol ε, owing to the impairment of parental (H3-H4)2 transfer to leading strands. Dpb3-Dpb4 binds H3-H4 in vitro and participates in the inheritance of heterochromatin. These results indicate that different proteins facilitate the transfer of parental (H3-H4)2 onto leading versus lagging strands and that Dbp3-Dpb4 plays an important role in this poorly understood process.

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.

scholarly journals Epigenetic inheritance of circadian period in clonal cells

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Yan Li ◽  
Yongli Shan ◽  
Gokhul Krishna Kilaru ◽  
Stefano Berto ◽  
Guang-Zhong Wang ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Cell Lines ◽  
Gene Networks ◽  
Large Scale ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Epigenetic Inheritance ◽  
Fibroblast Cell ◽  
Circadian Period ◽  
Clonal Cell Lines

Circadian oscillations are generated via transcriptional-translational negative feedback loops. However, individual cells from fibroblast cell lines have heterogeneous rhythms, oscillating independently and with different period lengths. Here we showed that heterogeneity in circadian period is heritable and used a multi-omics approach to investigate underlying mechanisms. By examining large-scale phenotype-associated gene expression profiles in hundreds of mouse clonal cell lines, we identified and validated multiple novel candidate genes involved in circadian period determination in the absence of significant genomic variants. We also discovered differentially co-expressed gene networks that were functionally associated with period length. We further demonstrated that global differential DNA methylation bidirectionally regulated these same gene networks. Interestingly, we found that depletion of DNMT1 and DNMT3A had opposite effects on circadian period, suggesting non-redundant roles in circadian gene regulation. Together, our findings identify novel gene candidates involved in periodicity, and reveal DNA methylation as an important regulator of circadian periodicity.

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