Publications by authors named "Nicholas A Kent"

16 Publications

  • Page 1 of 1

Nucleosome dynamics of human iPSC during neural differentiation.

EMBO Rep 2019 06 29;20(6). Epub 2019 Apr 29.

School of Biosciences, Cardiff University, Cardiff, UK

Nucleosome positioning is important for neurodevelopment, and genes mediating chromatin remodelling are strongly associated with human neurodevelopmental disorders. To investigate changes in nucleosome positioning during neural differentiation, we generate genome-wide nucleosome maps from an undifferentiated human-induced pluripotent stem cell (hiPSC) line and after its differentiation to the neural progenitor cell (NPC) stage. We find that nearly 3% of nucleosomes are highly positioned in NPC, but significantly, there are eightfold fewer positioned nucleosomes in pluripotent cells, indicating increased positioning during cell differentiation. Positioned nucleosomes do not strongly correlate with active chromatin marks or gene transcription. Unexpectedly, we find a small population of nucleosomes that occupy similar positions in pluripotent and neural progenitor cells and are found at binding sites of the key gene regulators NRSF/REST and CTCF Remarkably, the presence of these nucleosomes appears to be independent of the associated regulatory complexes. Together, these results present a scenario in human cells, where positioned nucleosomes are sparse and dynamic, but may act to alter gene expression at a distance via the structural conformation at sites of chromatin regulation.
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http://dx.doi.org/10.15252/embr.201846960DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6549019PMC
June 2019

Genome-wide chromatin mapping with size resolution reveals a dynamic sub-nucleosomal landscape in Arabidopsis.

PLoS Genet 2017 Sep 13;13(9):e1006988. Epub 2017 Sep 13.

Cardiff School of Biosciences, Cardiff University, Cardiff, Wales, United Kingdom.

All eukaryotic genomes are packaged as chromatin, with DNA interlaced with both regularly patterned nucleosomes and sub-nucleosomal-sized protein structures such as mobile and labile transcription factors (TF) and initiation complexes, together forming a dynamic chromatin landscape. Whilst details of nucleosome position in Arabidopsis have been previously analysed, there is less understanding of their relationship to more dynamic sub-nucleosomal particles (subNSPs) defined as protected regions shorter than the ~150bp typical of nucleosomes. The genome-wide profile of these subNSPs has not been previously analysed in plants and this study investigates the relationship of dynamic bound particles with transcriptional control. Here we combine differential micrococcal nuclease (MNase) digestion and a modified paired-end sequencing protocol to reveal the chromatin structure landscape of Arabidopsis cells across a wide particle size range. Linking this data to RNAseq expression analysis provides detailed insight into the relationship of identified DNA-bound particles with transcriptional activity. The use of differential digestion reveals sensitive positions, including a labile -1 nucleosome positioned upstream of the transcription start site (TSS) of active genes. We investigated the response of the chromatin landscape to changes in environmental conditions using light and dark growth, given the large transcriptional changes resulting from this simple alteration. The resulting shifts in the suites of expressed and repressed genes show little correspondence to changes in nucleosome positioning, but led to significant alterations in the profile of subNSPs upstream of TSS both globally and locally. We examined previously mapped positions for the TFs PIF3, PIF4 and CCA1, which regulate light responses, and found that changes in subNSPs co-localized with these binding sites. This small particle structure is detected only under low levels of MNase digestion and is lost on more complete digestion of chromatin to nucleosomes. We conclude that wide-spectrum analysis of the Arabidopsis genome by differential MNase digestion allows detection of sensitive features hereto obscured, and the comparisons between genome-wide subNSP profiles reveals dynamic changes in their distribution, particularly at distinct genomic locations (i.e. 5'UTRs). The method here employed allows insight into the complex influence of genetic and extrinsic factors in modifying the sub-nucleosomal landscape in association with transcriptional changes.
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http://dx.doi.org/10.1371/journal.pgen.1006988DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5597176PMC
September 2017

Regulation of nucleosome positioning by a CHD Type III chromatin remodeler and its relationship to developmental gene expression in .

Genome Res 2017 04 22;27(4):591-600. Epub 2017 Mar 22.

School of Biosciences, Cardiff University, Cardiff, CF10 3AX, United Kingdom.

Nucleosome placement and repositioning can direct transcription of individual genes; however, the precise interactions of these events are complex and largely unresolved at the whole-genome level. The Chromodomain-Helicase-DNA binding (CHD) Type III proteins are a subfamily of SWI2/SNF2 proteins that control nucleosome positioning and are associated with several complex human disorders, including CHARGE syndrome and autism. Type III CHDs are required for multicellular development of animals and but are absent in plants and yeast. These CHDs can mediate nucleosome translocation in vitro, but their in vivo mechanism is unknown. Here, we use genome-wide analysis of nucleosome positioning and transcription profiling to investigate the in vivo relationship between nucleosome positioning and gene expression during development of wild-type (WT) and mutant cells lacking ChdC, a Type III CHD protein ortholog. We demonstrate major nucleosome positional changes associated with developmental gene regulation in WT. Loss of caused an increase of intragenic nucleosome spacing and misregulation of gene expression, affecting ∼50% of the genes that are repositioned during WT development. These analyses demonstrate active nucleosome repositioning during multicellular development, establish an in vivo function of CHD Type III chromatin remodeling proteins in this process, and reveal the detailed relationship between nucleosome positioning and gene regulation, as cells transition between developmental states.
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http://dx.doi.org/10.1101/gr.216309.116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5378177PMC
April 2017

Abo1, a conserved bromodomain AAA-ATPase, maintains global nucleosome occupancy and organisation.

EMBO Rep 2016 Jan 18;17(1):79-93. Epub 2015 Nov 18.

Institute for Cell & Molecular Biosciences, Newcastle University, Newcastle, UK

Maintenance of the correct level and organisation of nucleosomes is crucial for genome function. Here, we uncover a role for a conserved bromodomain AAA-ATPase, Abo1, in the maintenance of nucleosome architecture in fission yeast. Cells lacking abo1(+) experience both a reduction and mis-positioning of nucleosomes at transcribed sequences in addition to increased intragenic transcription, phenotypes that are hallmarks of defective chromatin re-establishment behind RNA polymerase II. Abo1 is recruited to gene sequences and associates with histone H3 and the histone chaperone FACT. Furthermore, the distribution of Abo1 on chromatin is disturbed by impaired FACT function. The role of Abo1 extends to some promoters and also to silent heterochromatin. Abo1 is recruited to pericentromeric heterochromatin independently of the HP1 ortholog, Swi6, where it enforces proper nucleosome occupancy. Consequently, loss of Abo1 alleviates silencing and causes elevated chromosome mis-segregation. We suggest that Abo1 provides a histone chaperone function that maintains nucleosome architecture genome-wide.
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http://dx.doi.org/10.15252/embr.201540476DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4718406PMC
January 2016

The impact of the HIRA histone chaperone upon global nucleosome architecture.

Cell Cycle 2015 ;14(1):123-34

a Institute for Cell & Molecular Biosciences ; Newcastle University ; Newcastle upon Tyne , UK.

HIRA is an evolutionarily conserved histone chaperone that mediates replication-independent nucleosome assembly and is important for a variety of processes such as cell cycle progression, development, and senescence. Here we have used a chromatin sequencing approach to determine the genome-wide contribution of HIRA to nucleosome organization in Schizosaccharomyces pombe. Cells lacking HIRA experience a global reduction in nucleosome occupancy at gene sequences, consistent with the proposed role for HIRA in chromatin reassembly behind elongating RNA polymerase II. In addition, we find that at its target promoters, HIRA commonly maintains the full occupancy of the -1 nucleosome. HIRA does not affect global chromatin structure at replication origins or in rDNA repeats but is required for nucleosome occupancy in silent regions of the genome. Nucleosome organization associated with the heterochromatic (dg-dh) repeats located at the centromere is perturbed by loss of HIRA function and furthermore HIRA is required for normal nucleosome occupancy at Tf2 LTR retrotransposons. Overall, our data indicate that HIRA plays an important role in maintaining nucleosome architecture at both euchromatic and heterochromatic loci.
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http://dx.doi.org/10.4161/15384101.2014.967123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4614360PMC
September 2015

An alternative beads-on-a-string chromatin architecture in Thermococcus kodakarensis.

EMBO Rep 2013 Aug 9;14(8):711-7. Epub 2013 Jul 9.

Department of Bacteriology, Osaka Dental University, Osaka 573-1121, Japan.

We have applied chromatin sequencing technology to the euryarchaeon Thermococcus kodakarensis, which is known to possess histone-like proteins. We detect positioned chromatin particles of variable sizes associated with lengths of DNA differing as multiples of 30 bp (ranging from 30 bp to >450 bp) consistent with formation from dynamic polymers of the archaeal histone dimer. T. kodakarensis chromatin particles have distinctive underlying DNA sequence suggesting a genomic particle-positioning code and are excluded from gene-regulatory DNA suggesting a functional organization. Beads-on-a-string chromatin is therefore conserved between eukaryotes and archaea but can derive from deployment of histone-fold proteins in a variety of multimeric forms.
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http://dx.doi.org/10.1038/embor.2013.94DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3736136PMC
August 2013

The INO80 chromatin remodeling complex prevents polyploidy and maintains normal chromatin structure at centromeres.

Genes Dev 2012 Dec;26(23):2590-603

MRC Genome Damage and Stability Centre, University of Sussex, Brighton BN1 9RQ, United Kingdom.

The INO80 chromatin remodeling complex functions in transcriptional regulation, DNA repair, and replication. Here we uncover a novel role for INO80 in regulating chromosome segregation. First, we show that the conserved Ies6 subunit is critical for INO80 function in vivo. Strikingly, we found that loss of either Ies6 or the Ino80 catalytic subunit results in rapid increase in ploidy. One route to polyploidy is through chromosome missegregation due to aberrant centromere structure, and we found that loss of either Ies6 or Ino80 leads to defective chromosome segregation. Importantly, we show that chromatin structure flanking centromeres is altered in cells lacking these subunits and that these alterations occur not in the Cse4-containing centromeric nucleosome, but in pericentric chromatin. We provide evidence that these effects are mediated through misincorporation of H2A.Z, and these findings indicate that H2A.Z-containing pericentric chromatin, as in higher eukaryotes with regional centromeres, is important for centromere function in budding yeast. These data reveal an important additional mechanism by which INO80 maintains genome stability.
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http://dx.doi.org/10.1101/gad.199976.112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3521627PMC
December 2012

SWI/SNF-like chromatin remodeling factor Fun30 supports point centromere function in S. cerevisiae.

PLoS Genet 2012 Sep 27;8(9):e1002974. Epub 2012 Sep 27.

Nuclear Dynamics, Babraham Institute, Cambridge, United Kingdom.

Budding yeast centromeres are sequence-defined point centromeres and are, unlike in many other organisms, not embedded in heterochromatin. Here we show that Fun30, a poorly understood SWI/SNF-like chromatin remodeling factor conserved in humans, promotes point centromere function through the formation of correct chromatin architecture at centromeres. Our determination of the genome-wide binding and nucleosome positioning properties of Fun30 shows that this enzyme is consistently enriched over centromeres and that a majority of CENs show Fun30-dependent changes in flanking nucleosome position and/or CEN core micrococcal nuclease accessibility. Fun30 deletion leads to defects in histone variant Htz1 occupancy genome-wide, including at and around most centromeres. FUN30 genetically interacts with CSE4, coding for the centromere-specific variant of histone H3, and counteracts the detrimental effect of transcription through centromeres on chromosome segregation and suppresses transcriptional noise over centromere CEN3. Previous work has shown a requirement for fission yeast and mammalian homologs of Fun30 in heterochromatin assembly. As centromeres in budding yeast are not embedded in heterochromatin, our findings indicate a direct role of Fun30 in centromere chromatin by promoting correct chromatin architecture.
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http://dx.doi.org/10.1371/journal.pgen.1002974DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3459985PMC
September 2012

The two different isoforms of the RSC chromatin remodeling complex play distinct roles in DNA damage responses.

PLoS One 2012 16;7(2):e32016. Epub 2012 Feb 16.

Medical Research Council Genome Damage and Stability Centre, University of Sussex, Falmer, Brighton, United Kingdom.

The RSC chromatin remodeling complex has been implicated in contributing to DNA double-strand break (DSB) repair in a number of studies. Both survival and levels of H2A phosphorylation in response to damage are reduced in the absence of RSC. Importantly, there is evidence for two isoforms of this complex, defined by the presence of either Rsc1 or Rsc2. Here, we investigated whether the two isoforms of RSC provide distinct contributions to DNA damage responses. First, we established that the two isoforms of RSC differ in the presence of Rsc1 or Rsc2 but otherwise have the same subunit composition. We found that both rsc1 and rsc2 mutant strains have intact DNA damage-induced checkpoint activity and transcriptional induction. In addition, both strains show reduced non-homologous end joining activity and have a similar spectrum of DSB repair junctions, suggesting perhaps that the two complexes provide the same functions. However, the hypersensitivity of a rsc1 strain cannot be complemented with an extra copy of RSC2, and likewise, the hypersensitivity of the rsc2 strain remains unchanged when an additional copy of RSC1 is present, indicating that the two proteins are unable to functionally compensate for one another in DNA damage responses. Rsc1, but not Rsc2, is required for nucleosome sliding flanking a DNA DSB. Interestingly, while swapping the domains from Rsc1 into the Rsc2 protein does not compromise hypersensitivity to DNA damage suggesting they are functionally interchangeable, the BAH domain from Rsc1 confers upon Rsc2 the ability to remodel chromatin at a DNA break. These data demonstrate that, despite the similarity between Rsc1 and Rsc2, the two different isoforms of RSC provide distinct functions in DNA damage responses, and that at least part of the functional specificity is dictated by the BAH domains.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0032016PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3281108PMC
August 2012

Chromatin particle spectrum analysis: a method for comparative chromatin structure analysis using paired-end mode next-generation DNA sequencing.

Nucleic Acids Res 2011 Mar 3;39(5):e26. Epub 2010 Dec 3.

Cardiff School of Biosciences, Cardiff University, Museum Avenue, Cardiff, CF10 3AX, UK.

Microarray and next-generation sequencing techniques which allow whole genome analysis of chromatin structure and sequence-specific protein binding are revolutionizing our view of chromosome architecture and function. However, many current methods in this field rely on biochemical purification of highly specific fractions of DNA prepared from chromatin digested with either micrococcal nuclease or DNaseI and are restricted in the parameters they can measure. Here, we show that a broad size-range of genomic DNA species, produced by partial micrococcal nuclease digestion of chromatin, can be sequenced using paired-end mode next-generation technology. The paired sequence reads, rather than DNA molecules, can then be size-selected and mapped as particle classes to the target genome. Using budding yeast as a model, we show that this approach reveals position and structural information for a spectrum of nuclease resistant complexes ranging from transcription factor-bound DNA elements up to mono- and poly-nucleosomes. We illustrate the utility of this approach in visualizing the MNase digestion landscape of protein-coding gene transcriptional start sites, and demonstrate a comparative analysis which probes the function of the chromatin-remodelling transcription factor Cbf1p.
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http://dx.doi.org/10.1093/nar/gkq1183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3061068PMC
March 2011

Repressive and non-repressive chromatin at native telomeres in Saccharomyces cerevisiae.

Epigenetics Chromatin 2009 Dec 2;2(1):18. Epub 2009 Dec 2.

1Department of Oncology, University of Western Ontario, Ontario, Canada.

Background: In Saccharomyces cerevisiae genes that are located close to a telomere can become transcriptionally repressed by an epigenetic process known as telomere position effect. There is large variation in the level of the telomere position effect among telomeres, with many native ends exhibiting little repression.

Results: Chromatin analysis, using microccocal nuclease and indirect end labelling, reveals distinct patterns for ends with different silencing states. Differences were observed in the promoter accessibility of a subtelomeric reporter gene and a characteristic array of phased nucleosomes was observed on the centromere proximal side of core X at a repressive end. The silent information regulator proteins 2 - 4, the yKu heterodimer and the subtelomeric core X element are all required for the maintenance of the chromatin structure of repressive ends. However, gene deletions of particular histone modification proteins can eliminate the silencing without the disruption of this chromatin structure.

Conclusion: Our data identifies chromatin features that correlate with the silencing state and indicate that an array of phased nucleosomes is not sufficient for full repression.
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http://dx.doi.org/10.1186/1756-8935-2-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3225887PMC
December 2009

Dual chromatin remodeling roles for RSC during DNA double strand break induction and repair at the yeast MAT locus.

J Biol Chem 2007 Sep 25;282(38):27693-701. Epub 2007 Jul 25.

Genetics Unit, Department of Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, United Kingdom.

DNA double strand breaks (DSBs) are potentially serious chromosomal lesions. However, cells sometimes deliberately cleave their own DNA to facilitate certain chromosomal processes, and there is much interest in how such self-inflicted breaks are effectively managed. Eukaryotic DSBs occur in the context of chromatin and the RSC chromatin-remodeling ATPase complex has been shown to promote DSB repair at the budding yeast MAT locus DSB, created by the HO endonuclease during mating type switching. We show that the role of RSC at MAT is highly specialized. The Rsc1p subunit of RSC directs nucleosome sliding immediately after DSB creation at both MAT and generally and is required for efficient DNA damage-induced histone H2A phosphorylation and strand resection during repair by homologous recombination. However, the Rsc2p and Rsc7p subunits are additionally required to set up a basal MAT locus structure. This RSC-dependent chromatin structure at MAT ensures accessibility to the HO endonuclease. The RSC complex therefore has chromatin remodeling roles both before and after DSB induction at MAT, promoting both DNA cleavage and subsequent repair.
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http://dx.doi.org/10.1074/jbc.M704707200DOI Listing
September 2007

The Isw2 chromatin-remodeling ATPase cooperates with the Fkh2 transcription factor to repress transcription of the B-type cyclin gene CLB2.

Mol Cell Biol 2007 Apr 5;27(8):2848-60. Epub 2007 Feb 5.

Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, United Kingdom.

Forkhead (Fkh) transcription factors influence cell death, proliferation, and differentiation and the cell cycle. In Saccharomyces cerevisiae, Fkh2 both activates and represses transcription of CLB2, encoding a B-type cyclin. CLB2 is expressed during G(2)/M phase and repressed during G(1). Fkh2 recruits the coactivator Ndd1, an interaction which is promoted by Clb2/Cdk1-dependent phosphorylation of Ndd1, suggesting that CLB2 is autoregulated. Ndd1 is proposed to function by antagonizing Fkh2-mediated repression, but nothing is known about the mechanism. Here we ask how Fkh2 represses CLB2. We show that Fkh2 controls a repressive chromatin structure that initiates in the early coding region of CLB2 and spreads up the promoter during the M and G(1) phases. The Isw2 chromatin-remodeling ATPase cooperates with Fkh2 to remodel the chromatin and repress CLB2 expression throughout the cell cycle. In addition, the related factors Isw1 and Fkh1 configure the chromatin at the early coding region and negatively regulate CLB2 expression but only during G(2)/M phase. Thus, the cooperative actions of two forkhead transcription factors and two chromatin-remodeling ATPases combine to regulate CLB2. We propose that chromatin-mediated repression by Isw1 and Isw2 may serve to limit activation of CLB2 expression by the Clb2/Cdk1 kinase during G(2)/M and to fully repress expression during G(1).
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http://dx.doi.org/10.1128/MCB.01798-06DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1899929PMC
April 2007

RNA polymerase I in yeast transcribes dynamic nucleosomal rDNA.

Nat Struct Mol Biol 2007 Feb 28;14(2):123-30. Epub 2007 Jan 28.

Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK.

RNA polymerase (Pol) I-transcribed ribosomal genes of budding yeast exist as a tandem array (about 150 repeats) with transcription units separated by spacer sequences. Half of these rDNAs are inactivated by repressive chromatin structure, whereas the rest exist in an open conformation transcribed by closely spaced Pol I elongation complexes. Whereas previous studies have suggested that active rDNA is devoid of nucleosomal structure, we demonstrate that active rDNA has nucleosomal structure, according to chromatin immunoprecipitation and biochemical fractionation. Using a yeast strain with reduced numbers of all actively transcribed rDNA repeats, we show that rDNA exists in a dynamic chromatin structure of unphased nucleosomes. Furthermore, it is associated with chromatin-remodeling enzymes Chd1p, Isw1p and Isw2p, whose inactivation causes defects in transcription termination. We suggest that Pol I transcription, like that of Pol II, may be modulated by specific chromatin structures.
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http://dx.doi.org/10.1038/nsmb1199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6941936PMC
February 2007

Cbf1p is required for chromatin remodeling at promoter-proximal CACGTG motifs in yeast.

J Biol Chem 2004 Jun 24;279(26):27116-23. Epub 2004 Apr 24.

Genetics Unit, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, United Kingdom.

Cbf1p is a basic-helix-loop-helix-zipper protein of Saccharomyces cerevisiae required for the function of centromeres and MET gene promoters, where it binds DNA via the consensus core motif CACRTG (R = A or G). At MET genes Cbf1p appears to function in both activator recruitment and chromatin-remodeling. Cbf1p has been implicated in the regulation of other genes, and CACRTG motifs are common in potential gene regulatory DNA. A recent genome-wide location analysis showed that the majority of intergenic CACGTG palindromes are bound by Cbf1p. Here we tested whether all potential Cbf1p binding motifs in the yeast genome are likely to be bound by Cbf1p using chromatin immunoprecipitation. We also tested which of the motifs are actually functional by assaying for Cbf1p-dependent chromatin remodeling. We show that Cbf1p binding and activity is restricted to palindromic CACGTG motifs in promoter-proximal regions. Cbf1p does not function through CACGTG motifs that occur in promoter-distal locations within coding regions nor where CACATG motifs occur alone except at centromeres. Cbf1p can be made to function at promoter-distal CACGTG motifs by overexpression, suggesting that the concentration of Cbf1p is normally limiting for binding and is biased to gene regulatory DNA by interactions with other factors. We conclude that Cbf1p is required for normal nucleosome positioning wherever the CACGTG motif occurs in gene regulatory DNA. Cbf1p has been shown to interact with the chromatin-remodeling ATPase Isw1p. Here we show that recruitment of Isw1p by Cbf1p is likely to be general but that Isw1p is only partially required for Cbf1p-dependent chromatin structures.
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http://dx.doi.org/10.1074/jbc.M403818200DOI Listing
June 2004

A role for chromatin remodeling in transcriptional termination by RNA polymerase II.

Mol Cell 2002 Dec;10(6):1441-52

Sir William Dunn School of Pathology, University of Oxford, South Parks Road, OX1 3RE, Oxford, United Kingdom.

Chromatin remodeling can facilitate the recruitment of RNA polymerase II (Pol II) to targeted promoters, as well as enhancing the level of transcription. Here, we describe a further key role for chromatin remodeling in transcriptional termination. Using a genetic screen in S. pombe, we identified the CHD-Mi2 class chromatin remodeling ATPase, Hrp1, as a termination factor. In S. cerevisiae, we show that transcriptional termination and chromatin structure at the 3' ends of three genes all depend on the activity of the Hrp1 homolog, Chd1p, either alone or redundantly with the ISWI ATPases, Isw1p, and Isw2p. We suggest that chromatin remodeling of termination regions is a necessary prelude to efficient Pol II termination.
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http://dx.doi.org/10.1016/s1097-2765(02)00778-5DOI Listing
December 2002