scholarly journals Restricted epigenetic inheritance of H3K9 methylation

Science ◽  
2015 ◽  
Vol 348 (6230) ◽  
pp. 132-135 ◽  
Author(s):  
Pauline N. C. B. Audergon ◽  
Sandra Catania ◽  
Alexander Kagansky ◽  
Pin Tong ◽  
Manu Shukla ◽  
...  
Keyword(s):  
Dna Sequences ◽  
Histone H3 ◽  
Epigenetic Inheritance ◽  
Histone Demethylase ◽  
Epigenetic Mark ◽  
H3k9 Methylation ◽  
Silent Chromatin ◽  
Wild Type ◽  
Heterochromatin Formation ◽  
Posttranslational Histone Modifications

Posttranslational histone modifications are believed to allow the epigenetic transmission of distinct chromatin states, independently of associated DNA sequences. Histone H3 lysine 9 (H3K9) methylation is essential for heterochromatin formation; however, a demonstration of its epigenetic heritability is lacking. Fission yeast has a single H3K9 methyltransferase, Clr4, that directs all H3K9 methylation and heterochromatin. Using releasable tethered Clr4 reveals that an active process rapidly erases H3K9 methylation from tethering sites in wild-type cells. However, inactivation of the putative histone demethylase Epe1 allows H3K9 methylation and silent chromatin maintenance at the tethering site through many mitotic divisions, and transgenerationally through meiosis, after release of tethered Clr4. Thus, H3K9 methylation is a heritable epigenetic mark whose transmission is usually countered by its active removal, which prevents the unauthorized inheritance of heterochromatin.

scholarly journals SUV39 SET domains mediate crosstalk of heterochromatic histone marks

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Alessandro Stirpe ◽  
Nora Guidotti ◽  
Sarah J Northall ◽  
Sinan Kilic ◽  
Alexandre Hainard ◽  
...  
Keyword(s):  
Structure Function ◽  
Fission Yeast ◽  
Catalytic Domain ◽  
Constitutive Heterochromatin ◽  
Histone H3 ◽  
H3k9 Methylation ◽  
Set Domain ◽  
Heterochromatin Formation ◽  
Heterochromatin Silencing ◽  
Genomic Regions

The SUV39 class of methyltransferase enzymes deposits histone H3 lysine 9 di- and trimethylation (H3K9me2/3), the hallmark of constitutive heterochromatin. How these enzymes are regulated to mark specific genomic regions as heterochromatic is poorly understood. Clr4 is the sole H3K9me2/3 methyltransferase in the fission yeast Schizosaccharomyces pombe, and recent evidence suggests that ubiquitination of lysine 14 on histone H3 (H3K14ub) plays a key role in H3K9 methylation. However, the molecular mechanism of this regulation and its role in heterochromatin formation remain to be determined. Our structure-function approach shows that the H3K14ub substrate binds specifically and tightly to the catalytic domain of Clr4, and thereby stimulates the enzyme by over 250-fold. Mutations that disrupt this mechanism lead to a loss of H3K9me2/3 and abolish heterochromatin silencing similar to clr4 deletion. Comparison with mammalian SET domain proteins suggests that the Clr4 SET domain harbors a conserved sensor for H3K14ub, which mediates licensing of heterochromatin formation.

scholarly journals LSD1 prevents aberrant heterochromatin formation in Neurospora crassa

2020 ◽  
Vol 48 (18) ◽  
pp. 10199-10210
Author(s):  
William K Storck ◽  
Vincent T Bicocca ◽  
Michael R Rountree ◽  
Shinji Honda ◽  
Tereza Ormsby ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Neurospora Crassa ◽  
Constitutive Heterochromatin ◽  
Histone H3 ◽  
Feedback Mechanism ◽  
Histone Demethylase ◽  
Histone Deacetylation ◽  
Heterochromatin Formation ◽  
Lysine Specific Demethylase ◽  
Specialized Form

Abstract Heterochromatin is a specialized form of chromatin that restricts access to DNA and inhibits genetic processes, including transcription and recombination. In Neurospora crassa, constitutive heterochromatin is characterized by trimethylation of lysine 9 on histone H3, hypoacetylation of histones, and DNA methylation. We explored whether the conserved histone demethylase, lysine-specific demethylase 1 (LSD1), regulates heterochromatin in Neurospora, and if so, how. Though LSD1 is implicated in heterochromatin regulation, its function is inconsistent across different systems; orthologs of LSD1 have been shown to either promote or antagonize heterochromatin expansion by removing H3K4me or H3K9me respectively. We identify three members of the Neurospora LSD complex (LSDC): LSD1, PHF1, and BDP-1. Strains deficient for any of these proteins exhibit variable spreading of heterochromatin and establishment of new heterochromatin domains throughout the genome. Although establishment of H3K9me3 is typically independent of DNA methylation in Neurospora, instances of DNA methylation-dependent H3K9me3 have been found outside regions of canonical heterochromatin. Consistent with this, the hyper-H3K9me3 phenotype of Δlsd1 strains is dependent on the presence of DNA methylation, as well as HCHC-mediated histone deacetylation, suggesting that spreading is dependent on some feedback mechanism. Altogether, our results suggest LSD1 works in opposition to HCHC to maintain proper heterochromatin boundaries.

scholarly journals snRNA and Heterochromatin Formation Are Involved in DNA Excision during Macronuclear Development in Stichotrichous Ciliates

2005 ◽  
Vol 4 (11) ◽  
pp. 1934-1941 ◽  
Author(s):  
Stefan A. Juranek ◽  
Sina Rupprecht ◽  
Jan Postberg ◽  
Hans J. Lipps
Keyword(s):  
Dna Sequences ◽  
Chromatin Immunoprecipitation ◽  
De Novo ◽  
Histone H3 ◽  
Heterochromatin Formation ◽  
Macronuclear Development ◽  
Dna Elimination ◽  
Histone H3 Variant ◽  
Specific Sequences

ABSTRACT Several models for specific excision of micronucleus-specific DNA sequences during macronuclear development in ciliates exist. While the template-guided recombination model suggests recombination events resulting in specific DNA excision and reordering of macronucleus-destined sequences (MDS) guided by a template, there is evidence that an RNA interference-related mechanism is involved in DNA elimination in holotrichous ciliates. We describe that in the stichotrichous ciliate Stylonychia, snRNAs homologous to micronucleus-specific sequences are synthesized during macronuclear differentiation. Western and in situ analyses demonstrate that histone H3 becomes methylated at K9 de novo during macronuclear differentiation, and chromatin immunoprecipitation revealed that micronucleus-specific sequences are associated with methylated H3. To link both observations, expression of a PIWI homolog, member of the RNA-induced silencing complex, was silenced. In these cells, the methylated micronucleus-specific histone H3 variant “X” is still present in macronuclear anlagen and no K9 methylation of histone H3 is observed. We suggest that snRNA recruits chromatin-modifying enzymes to sequences to be excised. Based on our and earlier observations, we believe that this mechanism is not sufficient for specific excision of sequences and reordering of MDS in the developing macronucleus and propose a model for internal eliminated sequence excision and MDS reordering in stichotrichous ciliates.

scholarly journals Osmotic stress induces phosphorylation of histone H3 at threonine 3 in pericentromeric regions of Arabidopsis thaliana

2015 ◽  
Vol 112 (27) ◽  
pp. 8487-8492 ◽  
Author(s):  
Zhen Wang ◽  
Juan Armando Casas-Mollano ◽  
Jianping Xu ◽  
Jean-Jack M. Riethoven ◽  
Chi Zhang ◽  
...  
Keyword(s):  
Osmotic Stress ◽  
Protein Kinases ◽  
Double Mutant ◽  
Histone H3 ◽  
Epigenetic Mark ◽  
Wild Type ◽  
Protein Coding ◽  
Transcriptional Reprogramming ◽  
Genome Wide ◽  
In The Wild

Histone phosphorylation plays key roles in stress-induced transcriptional reprogramming in metazoans but its function(s) in land plants has remained relatively unexplored. Here we report that an Arabidopsis mutant defective in At3g03940 and At5g18190, encoding closely related Ser/Thr protein kinases, shows pleiotropic phenotypes including dwarfism and hypersensitivity to osmotic/salt stress. The double mutant has reduced global levels of phosphorylated histone H3 threonine 3 (H3T3ph), which are not enhanced, unlike the response in the wild type, by drought-like treatments. Genome-wide analyses revealed increased H3T3ph, slight enhancement in trimethylated histone H3 lysine 4 (H3K4me3), and a modest decrease in histone H3 occupancy in pericentromeric/knob regions of wild-type plants under osmotic stress. However, despite these changes in heterochromatin, transposons and repeats remained transcriptionally repressed. In contrast, this reorganization of heterochromatin was mostly absent in the double mutant, which exhibited lower H3T3ph levels in pericentromeric regions even under normal environmental conditions. Interestingly, within actively transcribed protein-coding genes, H3T3ph density was minimal in 5′ genic regions, coincidental with a peak of H3K4me3 accumulation. This pattern was not affected in the double mutant, implying the existence of additional H3T3 protein kinases in Arabidopsis. Our results suggest that At3g03940 and At5g18190 are involved in the phosphorylation of H3T3 in pericentromeric/knob regions and that this repressive epigenetic mark may be important for maintaining proper heterochromatic organization and, possibly, chromosome function(s).

scholarly journals N-Terminus Does Not Govern Protein Turnover of Schizosaccharomyces pombe CENP-A

2020 ◽  
Vol 21 (17) ◽  
pp. 6175
Author(s):  
Hwei Ling Tan ◽  
Yi Bing Zeng ◽  
Ee Sin Chen
Keyword(s):  
Schizosaccharomyces Pombe ◽  
Dna Sequences ◽  
Protein Turnover ◽  
Protein A ◽  
Histone H3 ◽  
Epigenetic Inheritance ◽  
Cell Extract ◽  
Insoluble Fraction ◽  
Independent Manner ◽  
Histone H3 Variant

Centromere integrity underlies an essential framework for precise chromosome segregation and epigenetic inheritance. Although centromeric DNA sequences vary among different organisms, all eukaryotic centromeres comprise a centromere-specific histone H3 variant, centromeric protein A (CENP-A), on which other centromeric proteins assemble into the kinetochore complex. This complex connects chromosomes to mitotic spindle microtubules to ensure accurate partitioning of the genome into daughter cells. Overexpression of CENP-A is associated with many cancers and is correlated with its mistargeting, forming extra-centromeric kinetochore structures. The mislocalization of CENP-A can be counteracted by proteolysis. The amino (N)-terminal domain (NTD) of CENP-A has been implicated in this regulation and shown to be dependent on the proline residues within this domain in Saccharomyces cerevisiae CENP-A, Cse4. We recently identified a proline-rich GRANT motif in the NTD of Schizosaccharomyces pombe CENP-A (SpCENP-A) that regulates the centromeric targeting of CENP-A via binding to the CENP-A chaperone Sim3. Here, we investigated whether the NTD is required to confer SpCENP-A turnover (i.e., counter stability) using various truncation mutants of SpCENP-A. We show that sequential truncation of the NTD did not improve the stability of the protein, indicating that the NTD of SpCENP-A does not drive turnover of the protein. Instead, we reproduced previous observations that heterochromatin integrity is important for SpCENP-A stability, and showed that this occurs in an NTD-independent manner. Cells bearing the null mutant of the histone H3 lysine 9 methyltransferase Clr4 (Δclr4), which have compromised constitutive heterochromatin integrity, showed reductions in the proportion of SpCENP-A in the chromatin-containing insoluble fraction of the cell extract, suggesting that heterochromatin may promote SpCENP-A chromatin incorporation. Thus, a disruption in heterochromatin may result in the delocalization of SpCENP-A from chromatin, thus exposing it to protein turnover. Taken together, we show that the NTD is not required to confer SpCENP-A protein turnover.

scholarly journals The H3K27me3 Demethylase dUTX Is a Suppressor of Notch- and Rb-Dependent Tumors in Drosophila

2010 ◽  
Vol 30 (10) ◽  
pp. 2485-2497 ◽  
Author(s):  
Hans-Martin Herz ◽  
Laurence D. Madden ◽  
Zhihong Chen ◽  
Clare Bolduc ◽  
Eugene Buff ◽  
...  
Keyword(s):  
Drosophila Melanogaster ◽  
Histone H3 ◽  
Epigenetic Mark ◽  
Dependent Manner ◽  
Wild Type ◽  
Independent Manner ◽  
Jmjc Domain ◽  
Mutant Cells ◽  
Excessive Activation

ABSTRACT Trimethylated lysine 27 of histone H3 (H3K27me3) is an epigenetic mark for gene silencing and can be demethylated by the JmjC domain of UTX. Excessive H3K27me3 levels can cause tumorigenesis, but little is known about the mechanisms leading to those cancers. Mutants of the Drosophila H3K27me3 demethylase dUTX display some characteristics of Trithorax group mutants and have increased H3K27me3 levels in vivo. Surprisingly, dUTX mutations also affect H3K4me1 levels in a JmjC-independent manner. We show that a disruption of the JmjC domain of dUTX results in a growth advantage for mutant cells over adjacent wild-type tissue due to increased proliferation. The growth advantage of dUTX mutant tissue is caused, at least in part, by increased Notch activity, demonstrating that dUTX is a Notch antagonist. Furthermore, the inactivation of Retinoblastoma (Rbf in Drosophila) contributes to the growth advantage of dUTX mutant tissue. The excessive activation of Notch in dUTX mutant cells leads to tumor-like growth in an Rbf-dependent manner. In summary, these data suggest that dUTX is a suppressor of Notch- and Rbf-dependent tumors in Drosophila melanogaster and may provide a model for UTX-dependent tumorigenesis in humans.

scholarly journals A conserved RNA degradation complex required for spreading and epigenetic inheritance of heterochromatin

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Gergana Shipkovenska ◽  
Alexander Durango ◽  
Marian Kalocsay ◽  
Steven P Gygi ◽  
Danesh Moazed
Keyword(s):  
Ribosomal Rna ◽  
Rna Processing ◽  
Histone H3 ◽  
Epigenetic Inheritance ◽  
Rna Degradation ◽  
Heterochromatin Formation ◽  
Polynucleotide Kinase ◽  
Ribosomal Rna Processing ◽  
Formation System ◽  
Insight Into

Heterochromatic domains containing histone H3 lysine 9 methylation (H3K9me) can be epigenetically inherited independently of underlying DNA sequence. To gain insight into the mechanisms that mediate epigenetic inheritance, we used a Schizosaccharomyces pombe inducible heterochromatin formation system to perform a genetic screen for mutations that abolish heterochromatin inheritance without affecting its establishment. We identified mutations in several pathways, including the conserved and essential Rix1-associated complex (henceforth the rixosome), which contains RNA endonuclease and polynucleotide kinase activities with known roles in ribosomal RNA processing. We show that the rixosome is required for spreading and epigenetic inheritance of heterochromatin in fission yeast. Viable rixosome mutations that disrupt its association with Swi6/HP1 fail to localize to heterochromatin, lead to accumulation of heterochromatic RNAs, and block spreading of H3K9me and silencing into actively transcribed regions. These findings reveal a new pathway for degradation of heterochromatic RNAs with essential roles in heterochromatin spreading and inheritance.

scholarly journals A non-enzymatic function associated with a putative histone demethylase licenses epigenetic inheritance

2019 ◽  
Author(s):  
Gulzhan Raiymbek ◽  
Sojin An ◽  
Nidhi Khurana ◽  
Saarang Gopinath ◽  
Raymond Trievel ◽  
...  
Keyword(s):  
Histone Deacetylases ◽  
Catalytic Domain ◽  
Epigenetic Inheritance ◽  
Specific Pattern ◽  
Histone Demethylase ◽  
Enzymatic Process ◽  
Heterochromatin Formation ◽  
Enzymatic Function ◽  
Primary Mechanism ◽  
Genome Wide

ABSTRACTH3K9 methylation (H3K9me) specifies the establishment and maintenance of transcriptionally silent epigenetic states or heterochromatin. The enzymatic erasure of histone modifications is widely assumed to be the primary mechanism that resets epigenetic states during and after DNA replication. Here, we demonstrate that a putative histone-demethylase Epe1 in fission yeast, regulates epigenetic inheritance through a non-enzymatic process. Mutations that map to its putative catalytic domain disrupt its interaction with Swi6HP1 and heterochromatin specific pattern of localization without any requirement for enzymatic activity. Epe1 and Swi6HP1 form an inhibitory complex which displaces histone deacetylases from sites of heterochromatin formation. Sequence-specific recruitment of a histone deacetylase, Clr3 renders heterochromatin refractory to the anti-silencing functions of Epe1 and licenses the inheritance of epigenetic states in cis. Epigenetic inheritance solely depends on the read-write activity of the H3K9 methyltransferase Clr4 which competes with genome-wide nucleosome turnover processes in the absence of enzymatic erasure.

scholarly journals An H3K9 methylation-dependent protein interaction regulates the non-enzymatic functions of a putative histone demethylase

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Gulzhan Raiymbek ◽  
Sojin An ◽  
Nidhi Khurana ◽  
Saarang Gopinath ◽  
Ajay Larkin ◽  
...  
Keyword(s):  
Protein Interaction ◽  
Histone Demethylase ◽  
H3k9 Methylation ◽  
Heterochromatin Formation ◽  
Protein Protein Interaction ◽  
Enzymatic Function ◽  
C Terminus ◽  
Jmjc Domain

H3K9 methylation (H3K9me) specifies the establishment and maintenance of transcriptionally silent epigenetic states or heterochromatin. The enzymatic erasure of histone modifications is widely assumed to be the primary mechanism that reverses epigenetic silencing. Here, we reveal an inversion of this paradigm where a putative histone demethylase Epe1 in fission yeast, has a non-enzymatic function that opposes heterochromatin assembly. Mutations within the putative catalytic JmjC domain of Epe1 disrupt its interaction with Swi6HP1 suggesting that this domain might have other functions besides enzymatic activity. The C-terminus of Epe1 directly interacts with Swi6HP1, and H3K9 methylation stimulates this protein-protein interaction in vitro and in vivo. Expressing the Epe1 C-terminus is sufficient to disrupt heterochromatin by outcompeting the histone deacetylase, Clr3 from sites of heterochromatin formation. Our results underscore how histone modifying proteins that resemble enzymes have non-catalytic functions that regulate the assembly of epigenetic complexes in cells.

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