Mediator Promotes CENP-A Incorporation at Fission Yeast Centromeres

Carlsten, Jonas; Szilágyi, Zsolt; Liu, Beidong; López, Marcela Dávila; Szászi, Erzsébet; Djupedal, Ingela; Nyström, Thomas; Ekwall, Karl; Gustafsson, Claes M.; Zhu, Xuefeng

doi:10.1128/mcb.00374-12

Cited by 23 publications

(27 citation statements)

References 64 publications

(73 reference statements)

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“…Consistent with our conclusions, a very recent study by Zhu and colleagues [45], published during the writing of this article, reports an accumulation of centromeric non-coding RNA and reduced processing of the dh repeat transcript into siRNA in a med20Δ strain. In addition, an independent large-scale epistasis map revealed genetic interactions between subunits of the Mediator and RNAi and heterochromatin components [29].…”

Section: Discussionsupporting

confidence: 92%

Mediator regulates non-coding RNA transcription at fission yeast centromeres

Thorsen

Hansen

Venturi

et al. 2012

Epigenetics & Chromatin

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BackgroundIn fission yeast, centromeric heterochromatin is necessary for the fidelity of chromosome segregation. Propagation of heterochromatin in dividing cells requires RNA interference (RNAi) and transcription of centromeric repeats by RNA polymerase II during the S phase of the cell cycle.ResultsWe found that the Med8-Med18-Med20 submodule of the Mediator complex is required for the transcriptional regulation of native centromeric dh and dg repeats and for the silencing of reporter genes inserted in centromeric heterochromatin. Mutations in the Med8-Med18-Med20 submodule did not alter Mediator occupancy at centromeres; however, they led to an increased recruitment of RNA polymerase II to centromeres and reduced levels of centromeric H3K9 methylation accounting for the centromeric desilencing. Further, we observed that Med18 and Med20 were required for efficient processing of dh transcripts into siRNA. Consistent with defects in centromeric heterochromatin, cells lacking Med18 or Med20 displayed elevated rates of mitotic chromosome loss.ConclusionsOur data demonstrate a role for the Med8-Med18-Med20 Mediator submodule in the regulation of non-coding RNA transcription at Schizosaccharomyces pombe centromeres. In wild-type cells this submodule limits RNA polymerase II access to the heterochromatic DNA of the centromeres. Additionally, the submodule may act as an assembly platform for the RNAi machinery or regulate the activity of the RNAi pathway. Consequently, Med8-Med18-Med20 is required for silencing of centromeres and proper mitotic chromosome segregation.

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Section: Discussionsupporting

confidence: 92%

Mediator regulates non-coding RNA transcription at fission yeast centromeres

Thorsen

Hansen

Venturi

et al. 2012

Epigenetics & Chromatin

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“…Recently, two reports showed that MHD was important for heterochromatin formation at pericentromeres [34], [35]. However, there are several discrepancies between their data and ours.…”

Section: Discussioncontrasting

confidence: 72%

“…Indeed, recent reports suggest a negative role of MHD subunits (Med18 and Med20) in heterochromatic transcription, based on the observation of an increase in the transcription of pericentromeric ncRNA in Mediator mutants [34], [35]. However, it is difficult to state conclusively whether the observed increase is due to the direct effects of the absence of Mediator because it is also possible that the deletion of Mediator subunits causes disruption of the heterochromatin, which secondarily induces an increase in transcription.…”

Section: Resultsmentioning

confidence: 99%

“…These results indicate that MHD is somehow involved in siRNA production after transcription of ncRNA. MHD is localized at the transcribed region in pericentromeric repeats (Figure S4; [34], [35] and is required for transcription in heterochromatin, suggesting that it directly functions in the coupling of transcription of heterochromatic ncRNA by RNAPII and processing of the siRNA by RNAi machinery. Retention of RNAi factors at the pericentromeric repeats in med18Δ cells and the requirement for MHD in heterochromatin formation via the artificial tethering of the RITS complex to RNA suggest that MHD functions after RITS associates with heterochromatic repeats and/or target RNA.…”

Section: Discussionmentioning

confidence: 99%

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Mediator Directs Co-transcriptional Heterochromatin Assembly by RNA Interference-Dependent and -Independent Pathways

et al. 2013

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Heterochromatin at the pericentromeric repeats in fission yeast is assembled and spread by an RNAi-dependent mechanism, which is coupled with the transcription of non-coding RNA from the repeats by RNA polymerase II. In addition, Rrp6, a component of the nuclear exosome, also contributes to heterochromatin assembly and is coupled with non-coding RNA transcription. The multi-subunit complex Mediator, which directs initiation of RNA polymerase II-dependent transcription, has recently been suggested to function after initiation in processes such as elongation of transcription and splicing. However, the role of Mediator in the regulation of chromatin structure is not well understood. We investigated the role of Mediator in pericentromeric heterochromatin formation and found that deletion of specific subunits of the head domain of Mediator compromised heterochromatin structure. The Mediator head domain was required for Rrp6-dependent heterochromatin nucleation at the pericentromere and for RNAi-dependent spreading of heterochromatin into the neighboring region. In the latter process, Mediator appeared to contribute to efficient processing of siRNA from transcribed non-coding RNA, which was required for efficient spreading of heterochromatin. Furthermore, the head domain directed efficient transcription in heterochromatin. These results reveal a pivotal role for Mediator in multiple steps of transcription-coupled formation of pericentromeric heterochromatin. This observation further extends the role of Mediator to co-transcriptional chromatin regulation.

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“…Consistent with this, loss of factors required for the reassembly and stabilization of H3 nucleosomes behind RNA Pol II, such as FACTand Clr6-complex II, promotes CENP-A assembly in place of histone H3 in noncentromeric regions of the genome . Moreover, some subunits of the Mediator complex are required for CENP-A Cnp1 localization, and the reduced levels of CENP-A Cnp1 in Mediator mutants can be suppressed by RNA Pol II inhibitors (Carlsten et al 2012). This finding suggests that proper levels of centromeric transcription are critical to ensure inheritance of the functional centromere state.…”

Section: It Is Currently Unknown What Restricts Cenp-amentioning

confidence: 99%

Epigenetic Regulation of Chromatin States inSchizosaccharomyces pombe

Allshire

Ekwall

2015

Cold Spring Harb Perspect Biol

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173

191

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SUMMARYThis article discusses the advances made in epigenetic research using the model organism fission yeast Schizosaccharomyces pombe. S. pombe has been used for epigenetic research since the discovery of position effect variegation (PEV). This is a phenomenon in which a transgene inserted within heterochromatin is variably expressed, but can be stably inherited in subsequent cell generations. PEV occurs at centromeres, telomeres, ribosomal DNA (rDNA) loci, and mating-type regions of S. pombe chromosomes. Heterochromatin assembly in these regions requires enzymes that modify histones and the RNA interference (RNAi) machinery. One of the key histone-modifying enzymes is the lysine methyltransferase Clr4, which methylates histone H3 on lysine 9 (H3K9), a classic hallmark of heterochromatin. The kinetochore is assembled on specialized chromatin in which histone H3 is replaced by the variant CENP-A. Studies in fission yeast have contributed to our understanding of the establishment and maintenance of CENP-A chromatin and the epigenetic activation and inactivation of centromeres.Outline

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Mediator Promotes CENP-A Incorporation at Fission Yeast Centromeres

Cited by 23 publications

References 64 publications

Mediator regulates non-coding RNA transcription at fission yeast centromeres

Mediator regulates non-coding RNA transcription at fission yeast centromeres

Mediator Directs Co-transcriptional Heterochromatin Assembly by RNA Interference-Dependent and -Independent Pathways

Epigenetic Regulation of Chromatin States inSchizosaccharomyces pombe

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