Publications by authors named "Shiv I Grewal"

Heterochromatin can be epigenetically inherited in cis, leading to stable gene silencing. However, the mechanisms underlying heterochromatin inheritance remain unclear. Here, we identify Fft3, a fission yeast homolog of the mammalian SMARCAD1 SNF2 chromatin remodeler, as a factor uniquely required for heterochromatin inheritance, rather than for de novo assembly.

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Uniparental disomy (UPD), in which an individual contains a pair of homologous chromosomes originating from only one parent, is a frequent phenomenon that is linked to congenital disorders and various cancers. UPD is thought to result mostly from pre- or post-zygotic chromosome missegregation. However, the factors that drive UPD remain unknown.

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Cotranscriptional RNA processing and surveillance factors mediate heterochromatin formation in diverse eukaryotes. In fission yeast, RNAi machinery and RNA elimination factors including the Mtl1-Red1 core and the exosome are involved in facultative heterochromatin assembly; however, the exact mechanisms remain unclear. Here we show that RNA elimination factors cooperate with the conserved exoribonuclease Dhp1/Rat1/Xrn2, which couples pre-mRNA 3'-end processing to transcription termination, to promote premature termination and facultative heterochromatin formation at meiotic genes.

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Transposable elements (TEs) constitute a substantial fraction of the eukaryotic genome and, as a result, have a complex relationship with their host that is both adversarial and dependent. To minimize damage to cellular genes, TEs possess mechanisms that target integration to sequences of low importance. However, the retrotransposon Tf1 of Schizosaccharomyces pombe integrates with a surprising bias for promoter sequences of stress-response genes.

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Advanced techniques including the chromosome conformation capture (3C) methodology and its derivatives are complementing microscopy approaches to study genome organization, and are revealing new details of three-dimensional (3D) genome architecture at increasing resolution. The fission yeast Schizosaccharomyces pombe (S. pombe) comprises a small genome featuring organizational elements of more complex eukaryotic systems, including conserved heterochromatin assembly machinery.

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Chromatin regulatory proteins affect diverse developmental and environmental response pathways via their influence on nuclear processes such as the regulation of gene expression. Through a genome-wide genetic screen, we implicate a novel protein called X-chromosome-associated protein 5 (Xap5) in chromatin regulation. We show that Xap5 is a chromatin-associated protein acting in a similar manner as the histone variant H2A.

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The regulation of protein-coding and noncoding RNAs is linked to nuclear processes, including chromatin modifications and gene silencing. However, the mechanisms that distinguish RNAs and mediate their functions are poorly understood. We describe a nuclear RNA-processing network in fission yeast with a core module comprising the Mtr4-like protein, Mtl1, and the zinc-finger protein, Red1.

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Understanding how complex networks of genes integrate to produce dividing cells is an important goal that is limited by the difficulty in defining the function of individual genes. Current resources for the systematic identification of gene function such as siRNA libraries and collections of deletion strains are costly and organism specific. We describe here integration profiling, a novel approach to identify the function of eukaryotic genes based upon dense maps of transposon integration.

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Heterochromatin causes epigenetic repression that can be transmitted through multiple cell divisions. However, the mechanisms underlying silencing and stability of heterochromatin are not fully understood. We show that heterochromatin differs from euchromatin in histone turnover and identify histone deacetylase (HDAC) Clr3 as a factor required for inhibiting histone turnover across heterochromatin domains in Schizosaccharomyces pombe.

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Article Synopsis
  • * In the fission yeast Schizosaccharomyces pombe, RNAi works alongside heterochromatin factors to silence various genes, including those involved in sexual differentiation and retrotransposons, with the exosome RNA degradation machinery also playing a key role.
  • * The creation of siRNAs and heterochromatin formation is triggered by the poly(A) polymerase Pla1 and is influenced by environmental conditions and developmental signals, revealing a connection between RNAi and developmental gene
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The positioning of the nucleosome by ATP-dependent remodellers provides the fundamental chromatin environment for the regulation of diverse cellular processes acting on the underlying DNA. Recently, genome-wide nucleosome mapping has revealed more detailed information on the chromatin-remodelling factors. Here, we report that the Schizosaccharomyces pombe CHD remodeller, Hrp3, is a global regulator that drives proper nucleosome positioning and nucleosome stability.

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Regulation of transposable elements (TEs) is critical to the integrity of the host genome. The fission yeast Schizosaccharomyces pombe homologs of mammalian CENP-B perform a host genome surveillance role by controlling Tf2 long terminal repeat (LTR) retrotransposons. However, the mechanisms by which CENP-Bs effect their functions are ill defined.

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The assembly of heterochromatin in eukaryotic genomes is critical for diverse chromosomal events including regulation of gene expression, silencing of repetitive DNA elements, proper segregation of chromosomes and maintenance of genomic integrity. Previous studies have shown that noncoding RNAs and the RNA interference (RNAi) machinery promote the assembly of heterochromatin that serves as a multipurpose platform for targeting effectors involved in various chromosomal processes. Recent work has revealed that RNAi-independent mechanisms, involving RNA processing activities that utilize both noncoding and coding RNAs, operate in the assembly of heterochromatin.

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Facultative heterochromatin that changes during cellular differentiation coordinates regulated gene expression, but its assembly is poorly understood. Here, we describe facultative heterochromatin islands in fission yeast and show that their formation at meiotic genes requires factors that eliminate meiotic messenger RNAs (mRNAs) during vegetative growth. Blocking production of meiotic mRNA or loss of RNA elimination factors, including Mmi1 and Red1 proteins, abolishes heterochromatin islands.

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Schizosaccharomyces pombe cells switch mating type by replacing genetic information at the expressed mat1 locus with sequences copied from mat2-P or mat3-M silent donor loci. The choice of donor locus is dictated by cell type, such that mat2 is the preferred donor in M cells and mat3 is the preferred donor in P cells. Donor choice involves a recombination-promoting complex (RPC) containing Swi2 and Swi5.

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Heterochromatin assembly at Schizosaccharomyces pombe centromeres involves a self-reinforcing loop mechanism wherein chromatin-bound RNAi factors facilitate targeting of Clr4-Rik1 methyltransferase. However, the initial nucleation of heterochromatin has remained elusive. We show that cells lacking Mlo3, a protein involved in mRNP biogenesis and RNA quality control, assemble functional heterochromatin in RNAi-deficient cells.

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Pervasive transcription of eukaryotic genomes generates a plethora of noncoding RNAs. In fission yeast, the heterochromatin factor Clr4/Suv39 methyltransferase facilitates RNA interference (RNAi)-mediated processing of centromeric transcripts into small interfering RNAs (siRNAs). Clr4 also mediates degradation of antisense RNAs at euchromatic loci, but the underlying mechanism has remained elusive.

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Heterochromatin impacts various nuclear processes by providing a recruiting platform for diverse chromosomal proteins. In fission yeast, HP1 proteins Chp2 and Swi6, which bind to methylated histone H3 lysine 9, associate with SHREC (Snf2/HDAC repressor complex) and Clr6 histone deacetylases (HDACs) involved in heterochromatic silencing. However, heterochromatic silencing machinery is not fully defined.

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A strand-specific transcriptome sequencing strategy, directional ligation sequencing or DeLi-seq, was employed to profile antisense transcriptome of Schizosaccharomyces pombe. Under both normal and heat shock conditions, we found that polyadenylated antisense transcripts are broadly expressed while distinct expression patterns were observed for protein-coding and non-coding loci. Dominant antisense expression is enriched in protein-coding genes involved in meiosis or stress response pathways.

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Article Synopsis
  • Recent studies in eukaryotic genomes show that transcription occurs not just in protein-coding genes, leading to the creation of antisense and non-coding RNAs (ncRNAs).
  • Research on organisms like Schizosaccharomyces pombe indicates that these ncRNAs are important for assembling heterochromatin, which plays a key role in gene regulation and various chromosomal processes.
  • Heterochromatin factors are now found to suppress antisense RNAs at euchromatic regions, highlighting significant pathways that influence the epigenetic regulation of genomes.
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The eukaryotic genome is a complex three-dimensional entity residing in the nucleus. We present evidence that Pol III-transcribed genes such as tRNA and 5S rRNA genes can localize to centromeres and contribute to a global genome organization. Furthermore, we find that ectopic insertion of Pol III genes into a non-Pol III gene locus results in the centromeric localization of the locus.

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Eukaryotic transcriptomes are characterized by widespread transcription of noncoding and antisense RNAs, which is linked to key chromosomal processes, such as chromatin remodelling, gene regulation and heterochromatin assembly. However, these transcripts can be deleterious, and their accumulation is suppressed by several mechanisms including degradation by the nuclear exosome. The mechanisms by which cells differentiate coding RNAs from transcripts targeted for degradation are not clear.

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Conserved chromosomal HP1 proteins capable of binding to histone H3 methylated at lysine 9 are believed to provide a dynamic platform for the recruitment and/or spreading of various regulatory proteins involved in diverse chromosomal processes. The fission yeast Schizosaccharomyces pombe HP1 family members Chp2 and Swi6 are important for heterochromatin assembly and transcriptional silencing, but their precise roles are not fully understood. Here, we show that Swi6 and Chp2 associate with histone deacetylase (HDAC) protein complexes containing class I HDAC Clr6 and class II HDAC Clr3 (a component of Snf2/HDAC repressor complex), which are critical for transcriptional silencing of centromeric repeats targeted by the heterochromatin machinery.

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Heterochromatin is dynamically regulated during the cell cycle and in response to developmental signals. Recent findings from diverse systems suggest an extensive role for transcription in the assembly of heterochromatin, highlighting the emerging theme that transcription and noncoding RNAs can provide the initial scaffold for the formation of heterochromatin, which serves as a versatile recruiting platform for diverse factors involved in many cellular processes.

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An epistasis map (E-MAP) was constructed in the fission yeast, Schizosaccharomyces pombe, by systematically measuring the phenotypes associated with pairs of mutations. This high-density, quantitative genetic interaction map focused on various aspects of chromosome function, including transcription regulation and DNA repair/replication. The E-MAP uncovered a previously unidentified component of the RNA interference (RNAi) machinery (rsh1) and linked the RNAi pathway to several other biological processes.

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