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 SUV39 SET domains mediate crosstalk of heterochromatic histone marks

2020 ◽  
Author(s):  
Alessandro Stirpe ◽  
Nora Guidotti ◽  
Sarah Northall ◽  
Sinan Kilic ◽  
Alexandre Hainard ◽  
...  
Keyword(s):  
Catalytic Domain ◽  
Constitutive Heterochromatin ◽  
H3k9 Methylation ◽  
Set Domain ◽  
Heterochromatin Formation ◽  
Histone Lysine ◽  
Heterochromatin Silencing ◽  
Central Recruitment ◽  
Genomic Regions ◽  
In Cis

AbstractThe SUV39 class of methyltransferase enzymes deposits histone lysine 9 di- and trimethylation (H3K9me2/3), the epigenetic hallmark of constitutive heterochromatin, which serves as the central recruitment platform for the heterochromatic silencing machinery. How these enzymes are regulated to mark specific genomic regions as heterochromatic is not well understood. Clr4 is the sole H3K9me2/3 methyltransferase in the fission yeast S.pombe and recent evidence suggests that ubiquitination of lysine 14 on H3 tail (H3K14) plays a key role in H3K9 methylation. However, the molecular mechanism of this regulation and its role in heterochromatin formation remains to be determined. Here we present a structure-function approach to understanding how the H3K14ub mark stimulates Clr4 activity in cis. These results show that the H3K14ub substrate binds specifically and tightly to the catalytic domain of Clr4, and thereby activates the enzyme by 250-fold. Mutations that disrupt this mechanism lead to a loss of H3K9me2/3 and abolish heterochromatin silencing similar to a clr4 deletion. Our work reveals a sensor for H3K14 ubiquitylation in the SET domain of Clr4, which mediates the licensing of heterochromatin formation by an epigenetic cross-talk. This sensor is also active in the human SUV39H2 enzyme.

scholarly journals The fission yeast heterochromatin protein Rik1 is required for telomere clustering during meiosis

2004 ◽  
Vol 165 (6) ◽  
pp. 759-765 ◽  
Author(s):  
Creighton T. Tuzon ◽  
Britta Borgstrom ◽  
Dietmar Weilguny ◽  
Richard Egel ◽  
Julia Promisel Cooper ◽  
...  
Keyword(s):  
Fission Yeast ◽  
Mating Type ◽  
Sexual Differentiation ◽  
Histone H3 ◽  
Heterochromatin Protein ◽  
Type Locus ◽  
Heterochromatin Formation ◽  
Mating Type Locus ◽  
Telomere Protein ◽  
Chromosome Movements

Telomeres share the ability to silence nearby transcription with heterochromatin, but the requirement of heterochromatin proteins for most telomere functions is unknown. The fission yeast Rik1 protein is required for heterochromatin formation at centromeres and the mating-type locus, as it recruits the Clr4 histone methyltransferase, whose modification of histone H3 triggers binding by Swi6, a conserved protein involved in spreading of heterochromatin. Here, we demonstrate that Rik1 and Clr4, but not Swi6, are required along with the telomere protein Taz1 for crucial chromosome movements during meiosis. However, Rik1 is dispensable for the protective roles of telomeres in preventing chromosome end-fusion. Thus, a Swi6-independent heterochromatin function distinct from that at centromeres and the mating-type locus operates at telomeres during sexual differentiation.

Swi6/HP1 binding to RNA-DNA hybrids initiates heterochromatin assembly

2020 ◽  
Author(s):  
Jagmohan Singh ◽  
Jyotsna Kumar ◽  
Swati Haldar ◽  
Neelima Gupta ◽  
Viney Kumar ◽  
...  
Keyword(s):  
Fission Yeast ◽  
Rnai Pathway ◽  
Affinity Binding ◽  
Heterochromatin Formation ◽  
Independent Mechanism ◽  
Alternate Model ◽  
Self Association ◽  
Heterochromatin Silencing ◽  
Heterochromatin Structure ◽  
Heterochromatin Assembly

Abstract Heterochromatin formation in fission yeast and metazoans involves di/trimethylation of histone H3 at lysine 9 position (me2/me3-K9-H3) by the histone methyltransferase (HMT) Suv39/Clr4, followed by binding of Swi6/HP1 to me2/me3-K9-H3 via its chromodomain1. Subsequent self-association of Swi6/HP1 on adjacent nucleosomes leads to folded heterochromatin structure1-3. An alternate model suggests a concerted participation of Clr4 and Swi6/HP12,3. HP1 binding to RNA has been invoked for heterochromatin silencing in metazoans4,5. Swi6/HP1 also binds and channels RNA to exosome pathway in fission yeast6. Recruitment of Swi6/HP1 to centromere is also dependent on the RNAi pathway7. Here we show that Swi6/HP1 exhibits binding to RNAs, ranging from promiscuous, low-affinity binding to mRNAs, to moderate-affinity binding to the RNAi-generated siRNAs corresponding to the repeats present in heterochromatin regions7, to high affinity binding to the RNA-DNA hybrids cognate to the repeats. Together with sensitivity of Swi6 localization and silencing to RNaseH, our results suggest a dynamic distribution of Swi6/HP1 among the heterochromatin and euchromatic transcripts and binding to RNA-DNA hybrid as an RNAi-dependent and Me2/me3-K9-H3-independent mechanism of recruitment, leading to heterochromatin formation and silencing.

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 Rbm10 facilitates heterochromatin assembly via the Clr6 HDAC complex

2019 ◽  
Author(s):  
Martina Weigt ◽  
Qingsong Gao ◽  
Hyoju Ban ◽  
Haijin He ◽  
Guido Mastrobuoni ◽  
...  
Keyword(s):  
Fission Yeast ◽  
Intron Retention ◽  
Splicing Factors ◽  
Minor Effect ◽  
Sequencing Data ◽  
Chromatin Remodelers ◽  
Heterochromatin Formation ◽  
Proteomic Data ◽  
Heterochromatin Silencing ◽  
And Function

Splicing factors have recently been shown to be involved in heterochromatin formation, but their role in controlling heterochromatin structure and function remains poorly understood. In this study, we identified a fission yeast homologue of human splicing factor RBM10, which has been linked to TARP syndrome. Overexpression of Rbm10 in fission yeast leads to strong global intron retention. Rbm10 also interacts with splicing factors in a pattern resembling that of human RBM10, suggesting that the function of Rbm10 as a splicing regulator is conserved. Surprisingly, our deep-sequencing data showed that deletion of Rbm10 caused only minor effect on genome-wide gene expression and splicing. However, the mutant displays severe heterochromatin defects. Further analyses indicated that the heterochromatin defects in the mutant did not result from mis-splicing of heterochromatin factors. Our proteomic data revealed that Rbm10 associates with the histone deacetylase Clr6 complex and chromatin remodelers known to be important for heterochromatin silencing. Deletion of Rbm10 results in significant reduction of Clr6 in heterochromatin. Our work together with previous findings further suggests that different splicing subunits may play distinct roles in heterochromatin regulation.

scholarly journals Structure-Function Analysis of SUV39H1 Reveals a Dominant Role in Heterochromatin Organization, Chromosome Segregation, and Mitotic Progression

2000 ◽  
Vol 20 (10) ◽  
pp. 3728-3741 ◽  
Author(s):  
Martin Melcher ◽  
Manfred Schmid ◽  
Louise Aagaard ◽  
Philipp Selenko ◽  
Götz Laible ◽  
...  
Keyword(s):  
Amino Acids ◽  
Structure Function ◽  
Chromosome Segregation ◽  
Function Analysis ◽  
Dominant Role ◽  
Position Effect ◽  
Histone H3 ◽  
Full Length ◽  
Mitotic Progression ◽  
Set Domain

ABSTRACT SUV39H1, a human homologue of theDrosophila position effect variegation modifierSu(var)3-9 and of theSchizosaccharomyces pombe silencing factorclr4, encodes a novel heterochromatic protein that transiently accumulates at centromeric positions during mitosis. Using a detailed structure-function analysis of SUV39H1 mutant proteins in transfected cells, we now show that deregulated SUV39H1 interferes at multiple levels with mammalian higher-order chromatin organization. First, forced expression of full-length SUV39H1 (412 amino acids) redistributes endogenous M31 (HP1β) and induces abundant associations with inter- and metaphase chromatin. These properties depend on the C-terminal SET domain, although the major portion of the SUV39H1 protein (amino acids 89 to 412) does not display affinity for nuclear chromatin. By contrast, the M31 interaction surface, which was mapped to the first 44 N-terminal amino acids, together with the immediately adjacent chromo domain, directs specific accumulation at heterochromatin. Second, cells overexpressing full-length SUV39H1 display severe defects in mitotic progression and chromosome segregation. Surprisingly, whereas localization of centromere proteins is unaltered, the focal, G2-specific distribution of phosphorylated histone H3 at serine 10 (phosH3) is dispersed in these cells. This phosH3 shift is not observed with C-terminally truncated mutant SUV39H1 proteins or with deregulated M31. Together, our data reveal a dominant role(s) for the SET domain of SUV39H1 in the distribution of prominent heterochromatic proteins and suggest a possible link between a chromosomal SU(VAR) protein and histone H3.

scholarly journals MET-2, a SETDB1 family methyltransferase, coordinates embryo events through distinct histone H3 methylation states

2018 ◽  
Author(s):  
Beste Mutlu ◽  
Huei-Mei Chen ◽  
David H. Hall ◽  
Susan E. Mango
Keyword(s):  
Developmental Plasticity ◽  
Histone H3 ◽  
Cell Counting ◽  
H3k9 Methylation ◽  
Developmental Potential ◽  
Heterochromatin Formation ◽  
Histone H3 Methylation ◽  
Summary Statement ◽  
Genome Activation ◽  
The Relationship

AbstractDuring the first hours of embryogenesis, formation of higher-order heterochromatin coincides with the loss of developmental potential. Here we examine the relationship between these two processes, and we probe the determinants that contribute to their onset. Mutations that disrupt histone H3 lysine 9 (H3K9) methyltransferases reveal that the methyltransferase MET-2 helps terminate developmental plasticity, likely through mono- and di- methylation of H3K9 (me1/me2), and promotes heterochromatin formation, likely through H3K9me3. We examine how MET-2 is regulated and find that methylated H3K9 appears gradually and depends on the accumulated time of embryogenesis. H3K9me is independent of zygotic genome activation or cell counting. These data reveal how central events are synchronized during embryogenesis and distinguish distinct roles for different H3K9 methylation states.Summary StatementDuring early embryogenesis, heterochromatin formation and loss of developmental plasticity are coordinately regulated by distinct Histone H3 Lysine 9 (H3K9) methylation states, by the methyltransferase MET-2.

scholarly journals Rbm10 facilitates heterochromatin assembly via the Clr6 HDAC complex

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Martina Weigt ◽  
Qingsong Gao ◽  
Hyoju Ban ◽  
Haijin He ◽  
Guido Mastrobuoni ◽  
...  
Keyword(s):  
Fission Yeast ◽  
Intron Retention ◽  
Splicing Factors ◽  
Minor Effect ◽  
Sequencing Data ◽  
Chromatin Remodelers ◽  
Heterochromatin Formation ◽  
Proteomic Data ◽  
Heterochromatin Silencing ◽  
And Function

AbstractSplicing factors have recently been shown to be involved in heterochromatin formation, but their role in controlling heterochromatin structure and function remains poorly understood. In this study, we identified a fission yeast homologue of human splicing factor RBM10, which has been linked to TARP syndrome. Overexpression of Rbm10 in fission yeast leads to strong global intron retention. Rbm10 also interacts with splicing factors in a pattern resembling that of human RBM10, suggesting that the function of Rbm10 as a splicing regulator is conserved. Surprisingly, our deep-sequencing data showed that deletion of Rbm10 caused only minor effect on genome-wide gene expression and splicing. However, the mutant displays severe heterochromatin defects. Further analyses indicated that the heterochromatin defects in the mutant did not result from mis-splicing of heterochromatin factors. Our proteomic data revealed that Rbm10 associates with the histone deacetylase Clr6 complex and chromatin remodelers known to be important for heterochromatin silencing. Deletion of Rbm10 results in significant reduction of Clr6 in heterochromatin. Our work together with previous findings further suggests that different splicing subunits may play distinct roles in heterochromatin regulation.

scholarly journals A heterochromatin domain forms gradually at a new telomere and is highly dynamic at stable telomeres

2017 ◽  
Author(s):  
Jinyu Wang ◽  
Jessica R Eisenstatt ◽  
Julien Audry ◽  
Kristen Cornelius ◽  
Matthew Shaughnessy ◽  
...  
Keyword(s):  
Schizosaccharomyces Pombe ◽  
Fission Yeast ◽  
Histone H3 ◽  
Heterochromatic Region ◽  
Strand Break ◽  
Heterochromatin Formation ◽  
Dna Double Strand Break ◽  
Development And Aging ◽  
Organismal Development ◽  
Heterochromatin Domain

AbstractHeterochromatin domains play important roles in chromosome biology, organismal development and aging. In the fission yeast Schizosaccharomyces pombe and metazoans, heterochromatin is marked by histone H3 lysine 9 dimethylation. While factors required for heterochromatin have been identified, the dynamics of heterochromatin formation are poorly understood. Telomeres convert adjacent chromatin into heterochromatin. To form a new heterochromatic region in S. pombe, an inducible DNA double-strand break (DSB) was engineered next to 48 bp of telomere repeats in euchromatin, which caused formation of new telomere and gradual spreading of heterochromatin. However, spreading was highly dynamic even after the telomere had reached its stable length. The system also revealed the presence of repeats located at the boundaries of euchromatin and heterochromatin that are oriented to allow the efficient healing of a euchromatic DSB to cap the chromosome end with a new telomere. Telomere formation in S. pombe therefore reveals novel aspects of heterochromatin dynamics and the presence of failsafe mechanisms to repair subtelomeric breaks, with implications for similar processes in metazoan genomes.

Sign in / Sign up

Export Citation Format

Share Document