Unique roles for histone H3K9me states in RNAi and heritable silencing of transcription

doi:10.1038/nature23267

. 2017 Jul 27;547(7664):463-467.

doi: 10.1038/nature23267. Epub 2017 Jun 22.

Unique roles for histone H3K9me states in RNAi and heritable silencing of transcription

Gloria Jih^{1

2}, Nahid Iglesias^{1

2}, Mark A Currie^{1

2}, Natarajan V Bhanu³, Joao A Paulo¹, Steven P Gygi¹, Benjamin A Garcia³, Danesh Moazed^{1

2}

Affiliations

¹ Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA.
² Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts, USA.
³ Department of Biochemistry and Biophysics, Epigenetics Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

PMID: 28682306
PMCID: PMC5576860
DOI: 10.1038/nature23267

Unique roles for histone H3K9me states in RNAi and heritable silencing of transcription

Gloria Jih et al. Nature. 2017.

. 2017 Jul 27;547(7664):463-467.

doi: 10.1038/nature23267. Epub 2017 Jun 22.

Authors

Gloria Jih^{1

2}, Nahid Iglesias^{1

2}, Mark A Currie^{1

2}, Natarajan V Bhanu³, Joao A Paulo¹, Steven P Gygi¹, Benjamin A Garcia³, Danesh Moazed^{1

2}

Affiliations

¹ Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA.
² Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts, USA.
³ Department of Biochemistry and Biophysics, Epigenetics Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

PMID: 28682306
PMCID: PMC5576860
DOI: 10.1038/nature23267

Abstract

Heterochromatic DNA domains have important roles in the regulation of gene expression and maintenance of genome stability by silencing repetitive DNA elements and transposons. From fission yeast to mammals, heterochromatin assembly at DNA repeats involves the activity of small noncoding RNAs (sRNAs) associated with the RNA interference (RNAi) pathway. Typically, sRNAs, originating from long noncoding RNAs, guide Argonaute-containing effector complexes to complementary nascent RNAs to initiate histone H3 lysine 9 di- and trimethylation (H3K9me2 and H3K9me3, respectively) and the formation of heterochromatin. H3K9me is in turn required for the recruitment of RNAi to chromatin to promote the amplification of sRNA. Yet, how heterochromatin formation, which silences transcription, can proceed by a co-transcriptional mechanism that also promotes sRNA generation remains paradoxical. Here, using Clr4, the fission yeast Schizosaccharomyces pombe homologue of mammalian SUV39H H3K9 methyltransferases, we design active-site mutations that block H3K9me3, but allow H3K9me2 catalysis. We show that H3K9me2 defines a functionally distinct heterochromatin state that is sufficient for RNAi-dependent co-transcriptional gene silencing at pericentromeric DNA repeats. Unlike H3K9me3 domains, which are transcriptionally silent, H3K9me2 domains are transcriptionally active, contain modifications associated with euchromatic transcription, and couple RNAi-mediated transcript degradation to the establishment of H3K9me domains. The two H3K9me states recruit reader proteins with different efficiencies, explaining their different downstream silencing functions. Furthermore, the transition from H3K9me2 to H3K9me3 is required for RNAi-independent epigenetic inheritance of H3K9me domains. Our findings demonstrate that H3K9me2 and H3K9me3 define functionally distinct chromatin states and uncover a mechanism for the formation of transcriptionally permissive heterochromatin that is compatible with its broadly conserved role in sRNA-mediated genome defence.

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Conflict of interest statement

The authors declare no competing financial interests.

Figures

**Extended Data Figure 1. Analysis of mutant Clr4 proteins and their effect on histone H3K9me**
a, Western blot of N-terminal 3xFlag-tagged Clr4 showing that SET mutations (F449Y or I418P) or a chromo domain mutation (W31G) do not affect Clr4 protein stability (top). The same blot stained with Ponceau dye is shown as a loading control (bottom). Image represents 2 individual experiments. b, Flag purification of wild-type Clr4 and Clr4^F449Y showing both proteins are incorporated into the CLRC methyltransferase complex. c, Pull-down assays showing that wild-type Clr4 and Clr4^F449Y interact with recombinant GST-Swi6 with similar efficiency. d, Coomassie staining (top) and western blot (bottom) of histones enriched for H3K9me using Swi6 affinity pull-down from wild-type and *clr4^F449Y* cells showing that Clr4^F449Y primarily catalyzes H3K9me2. Image represents 3 individual experiments. e, Quantitative mass spectrometry of histones showing the redistribution of H3K9 methylation states in *clr4⁺* and *clr4^F449Y* cells. The histones were isolated using Swi6 affinity pull-down to increase detection sensitivity. See Extended Data Fig. 6 for quantitative mass spectrometry of H3 tail modifications in total wild-type histones. For gel source data, see Supplementary Figure 1.

**Extended Data Figure 2. ChIP analysis of H3K9me levels in wild-type *clr4⁺* and *clr4* mutant cells**
a, Map of the pericentromeric DNA region to the right of centromere 1. Arrowheads indicate the location of primers used for ChIP-qPCR in b and **c. b–c,** ChIP-qPCR analysis of H3K9me2 (b) and H3K9me3 (c) levels at the dg and dh repeats in cells with the indicated genotypes (*clr4^dead* = *clr4^{H410L, C412A}*). Error bars, s.d.; n = 3 biological replicates. d, Expanded view of H3K9me2 ChIP-seq reads mapped to the pericentromeric repeat regions on the right arm of chromosome 1 in *clr4Δ*, *clr4⁺*, *clr4^F449Y*, and *clr4^I418P* cells. The location of centromere 1 (*cen1*), innermost repeats (*imr1R*), outermost dg and dh repeats, and inverted repeat centromere (*IRC*) sequences are indicated. Chromosome 1 coordinates are indicated above the tracks. Reads were randomly assigned to the dg and dh repeats of each chromosome. e, Same as d but showing H3K9me3 ChIP-seq reads.

**Extended Data Figure 3. Clr4 mutants have reduced H3K9me spreading at mating type and telomeric regions**
**a–g,** ChIP-seq data showing changes in H3K9me2 and H3K9me3 levels outside of RNAi-dependent nucleation regions (indicated by solid black bars below tracks) at mating type (*mat*) and telomeric DNA regions (*tel1L, tel1R, tel2L, tel2R, tel3L, and tel3R*) in *clr4Δ*, *clr4⁺*, *clr4^F449Y*, and *clr4^I418P* cells. *tel3L* and *tel3R* represent reads from the rDNA repeats. H3K9me2 reads were randomly assigned to repeated sequences. The reads at *cenH* are therefore shared with those at the pericentromeric dg and dh repeats (with which *cenH* shares 98% sequence identity); H3K9me2 reads that map uniquely to the mating type locus are shown (a, right panel). When only unique reads are mapped, a large fraction of total reads corresponding to repeated sequences at centromeres, telomeres, and the *mat* locus, are removed. This changes the normalized peak heights, which are affected by fewer total mapped reads. Data is presented as reads per million (Y axis).

**Extended Data Figure 4. ChIP-qPCR analysis showing increased pol II levels at pericentromeric DNA repeats of *clr4* mutant cells**
a, Map showing the location of the heterochromatin reporter *ura4*⁺ inserted to the right of *cen1*. b, ChIP-qPCR data showing changes in the association of RNA pol II with the dg and dh pericentromeric DNA repeats in *clr4* mutant cells. qPCR primer locations are indicated by arrowheads in a. Error bars, s.d.; n = 3 biological replicates.

**Extended Data Figure 5. Clr4 mutant cells have increased levels of Chp1 and activating histone marks at pericentromeric DNA repeats**
a, ChIP-qPCR showing increased Chp1 recruitment to pericentromeric DNA repeats. Error bars, s.d.; n = 3 biological replicates. b, ChIP-seq data showing increased Chp1 reads mapping to pericentromeric regions of chromosome 2 in *clr4^F449Y* and *clr4^I418P* mutants compared to wild-type (wt) cells. c, Same as b, but showing pericentromeric regions of chromosome 3. d, ChIP-qPCR analysis of Flag-Ago1 recruitment to pericentromeric DNA repeats in wild-type *clr4⁺* and *clr4^F449Y* cells. Error bars, s.d.; n = 3 biological replicates. **e–h,** ChIP-qPCR analysis of H3K4me3 (e) and H3K36me3 (f) levels at pericentromeric DNA repeats in wild-type *clr4⁺* and *clr4* mutant cells. *dg2* primer location is indicated by empty arrowhead. Error bars, s.d.; n = 3 biological replicates. g, ChIP-seq data showing increased H3K14ac mapped reads at pericentromeric regions of chromosome 1 in *clr4^F449Y* cells. h, ChIP-seq data showing increased H4K16ac mapped reads at pericentromeric regions of chromosome 1 in *clr4^F449Y* cells. Data is presented as reads per million (Y axis).

**Extended Data Figure 6. Quantitative mass spectrometry of histone H3 tail modifications**
a, Steps for the isolation of chromatin-bound histones and their analysis by liquid chromatography and tandem mass spectrometry (LC/MS/MS). b, Results of quantitative mass spectrometry analysis of modifications associated with the indicated H3 tail tryptic peptide in wild-type (wt) and *clr4Δ* cells.

**Extended Data Figure 7. H3K9me2 precedes H3K9me3 during heterochromatin establishment**
a,Ten-fold serial dilution of cells plated on non-selective (N/S) and FOA-containing (+ FOA) medium to evaluate re-establishment of *otr1R::ura4⁺* silencing at 0, 3, 5, 7 hours after TSA removal. Untreated and *clr4Δ* cells serve as positive and negative control for *otr1R::ura4⁺* silencing, respectively. Image represents 3 individual experiments. b, H3K9me2 ChIP-seq reads mapped to pericentromeric repeats to the right of *cen1* in untreated and TSA-treated cells at the indicated time points following TSA removal. The highlighted region (darker blue) displayed the greatest loss of H3K9 methylation resulting from TSA treatment. Read ratio (indicated on the right) was obtained by normalizing the sum of reads mapping to the highlighted region for TSA-treated compared to untreated cells. c, Same as b, but showing H3K9me3 ChIP-seq reads. See Fig. 2g for ChIP-qPCR analysis.

**Extended Data Figure 8. Chp2 and Swi6 are not required for the formation of H3K9me2 or me3 domains at pericentromeric DNA repeats**
**a–b,** ChIP-seq data showing that unlike Chp1, Chp2 and Swi6 are not required for RNAi-mediated H3K9 methylation, as indicated by similar levels of H3K9me2 (a) and H3K9me3 (b) mapped reads at pericentromeric regions of chromosome 1 in wild-type (wt), *chp2Δ*, and *swi6Δ* cells. *clr4Δ* serves as a control for specificity of the anti-H3K9me antibodies. Data is presented as reads per million (Y axis).

**Extended Data Fig 9. H3K9me states regulate the recruitment of HP1 proteins and Clr4**
a, Swi6 ChIP-qPCR analysis at dg and dh. Error bars, s.d.; n = 3 biological replicates. b, Live cell imaging using confocal microscopy showing the localization of GFP-Swi6 and Cut11-mCherry in *clr4⁺*, *clr4^F449Y*, and *clr4Δ* cells. In wild-type *clr4⁺* cells, GFP-Swi6 foci representing centromeres, telomeres, and the mating type locus are predominantly localized at the nuclear periphery (marked by Cut11-mCherry nuclear pore component). These peripheral GFP-Swi6 foci are lost in *clr4Δ* cells, but in *clr4^F449Y* cells, in which H3K9me2 is restricted primarily to pericentromeric repeats, one fluorescent focus corresponding to centromeres, which cluster at the nuclear periphery independently of H3K9me, is maintained. The peripheral GFP-Swi6 focus in *clr4^F449Y* cells is weaker than that in *clr4⁺* cells, which is likely due to the lower affinity of Swi6 for H3K9me2 relative to H3K9me3. Correspondingly, diffused GFP-Swi6 signals are observed throughout the nucleoplasm in *clr4^F449Y* cells. Three representative cells for each genotype are presented. 18/18 *clr4⁺*, 15/16 *clr4^F449Y*, and 0/10 *clr4Δ* cells had perinuclear localization of GFP-Swi6. **c–g,** Flag-Chp2 (c), and Flag-Clr3 (d), H3K9me3 (e), H3K9me2 (f), and Flag-Clr4 (g) ChIP-qPCR analysis at dg and dh in *clr4* wild-type and mutant cells. Error bars, s.d.; n = 3 biological replicates.

**Extended Data Figure 10. H3K9me3 is required for epigenetic inheritance of H3K9 methylation**
**a–b,** ChIP-qPCR analysis showing loss of H3K9me2 at the *10xtetO-ade6*⁺ reporter gene (a) and the adjacent *mug135⁺* gene (b) upon the release of tethered TetR-Clr4-I by the addition of tetracycline (− tet versus + tet). c, ChIP-qPCR analysis showing loss of H3K9me2 at pericentromeric dg and dh DNA repeats in *ago1Δ clr4^I418P* double mutant cells. Arrowheads indicate the location of primers used for ChIP-qPCR. Error bars, s.d.; n = 3 biological replicates.

**Figure 1. Clr4 SET domain mutations that block H3K9me3 result in defective TGS**
a, Diagram illustrating location of the Clr4 chromo (CD) and SET domains, and the mutations used in this study (top). Sequence alignment for the SET domain region containing these mutations in the indicated methyltransferases (bottom). b, Crystal structure of *N. crassa* DIM-5 catalytic pocket in complex with a histone H3 N-terminal peptide (yellow), showing side chain of lysine 9 in the catalytic pocket. DIM-5 F294 (corresponding to *S. pombe* F449) is depicted in green; DIM-5 I263 (corresponding to *S. pombe* I418) is depicted in blue (PDB ID: 1PEG). c, H3K9me2 ChIP-seq reads mapped to the pericentromeric repeat regions on the right arm of chromosome 1 in *clr4Δ*, *clr4⁺*, *clr4^F449Y*, and *clr4^I418P* cells. Location of centromere 1 (*cen1*), innermost repeats (*imr1R*), outermost dg and dh repeats, and inverted repeat centromere (*IRC*) sequences are indicated. Top: Chromosome 1 coordinates. Right: sum of normalized reads mapping to chromosome 1 pericentromeric regions. Reads were randomly assigned to the dg and dh repeats of each chromosome and are presented as reads per million (rpm, Y axis). d, Same as c but showing H3K9me3 ChIP-seq reads. e, Left: *otr1R::ura4⁺* transgene silencing assay (see Extended Data Fig. 4a for insert location). N/S, non-selective medium; - Ura, minus uracil medium; + FOA, 5-FOA-containing medium. Image represents 3 individual experiments. Right: RT-qPCR analysis of *otr1R::ura4⁺* transcript. Error bars, s.d.; n = 3 biological replicates. f, Same as c, but showing pol II ChIP-seq reads. Arrowheads indicate primer locations for ChIP-qPCR analysis (see Extended Data Fig. 4). g, RT-qPCR analysis of dg and dh transcripts. Values are shown as fold increase in RNA levels in mutant over *clr4⁺* cells. Error bars, s.d.; n = 3 biological replicates.

**Figure 2. Transcription-permissive H3K9me2 helps recruit RNAi and precedes H3K9me3 establishment**
a, Model for recruitment of the RNAi machinery (RITS, RDRC, and Dcr1) and Clr4-containing CLRC to a nascent pericentromeric transcript. b, Northern blot of dg and dh siRNAs in cells with the indicated genotypes. Ratios are determined by fold increase in siRNA levels in mutants over wild-type (wt) cells. snoR69 was used as an internal control. For gel source data, see Supplementary Figure 1. Image represents 3 (dg siRNA) or 2 (dh siRNA) individual experiments. c, Chp1 ChIP-seq reads mapped to the pericentromeric repeat regions on the right arm of chromosome 1. Right, sum of normalized reads mapped to pericentromeric region to the right of cen1. Data is presented as reads per million (rpm, Y axis). Arrows indicate primer locations for ChIP-qPCR analysis in Extended Data Fig. 5. **d, e,** Same as c, but showing H3K4me3 (d) and H3K36me3 (e) ChIP-seq reads. Empty arrow indicates location for *dg2* primers in Extended Data Fig. 5. f, Experimental strategy for *de novo* H3K9me establishment. g, ChIP-qPCR data showing the recovery kinetics of H3K9me2 (blue) and H3K9me3 (red) at the *dh2* pericentromeric repeat. For each time point, H3K9me levels were normalized to that of untreated cells. Error bars, s.d.; n = 3 biological replicates.

**Figure 3. H3K9me states regulate the recruitment of HP1 proteins and Clr4**
**a–c,** Swi6 (a), Flag-Chp2 (b), and Flag-Clr3 (c) ChIP-seq reads mapped to pericentromeric repeats on the right arm of chromosome 1. Arrowheads indicate the location of primers for ChIP-qPCR analysis presented in Extended Data Fig. 9. d, Quantitative MS analysis of the association of chromo domain proteins with differentially methylated H3K9 peptides. e, Silver stain (top) and western blot (bottom) of proteins isolated by H3 tail peptides. For gel source data, see Supplementary Figure 1. f, Quantification of TMT-labeled peptides for the indicated protein. Error bars, s.d.; n = 3 biological replicates for me2 and me3 peptides. H3K9me3 (g), H3K9me2 (h), and Flag-Clr4 (i) ChIP-seq reads mapped as described for panels **a–c**.

**Figure 4. H3K9me3 is required for epigenetic inheritance**
a, Experimental strategy for testing requirements for epigenetic inheritance. b, Silencing assays of *10xtetO-ade6⁺* on low-adenine medium lacking tetracycline (− tet) or containing tetracycline (+ tet) to assess establishment and maintenance, respectively, in *epe1Δ* cells, which either lack endogenous *clr4⁺* (*clr4Δ*), or contain *clr4⁺*, *clr4^W31G*, or *clr4^I418P* alleles. Image represents 3 individual experiments. c, H3K9me2 ChIP-seq reads mapped to the *10xtetO-ade6⁺* region. Both *10xtetO-ade6⁺* (green) and *mug135⁺* (black dash) located 5 kb upstream of *10xtetO-ade6⁺* were used for ChIP-qPCR analysis (see Extended Data Fig. 10). d, Same as c, but after 24 hours of growth in + tet medium. e, H3K9me2 ChIP-seq reads mapped to pericentromeric repeats on the right of chromosome 1. The sum of normalized reads is indicated on the right. Data is presented as reads per million (rpm, Y axis). The bottom two tracks have a 10-fold expanded Y axis scale to highlight the complete loss of H3K9me2 in the *clr4^I418P ago1Δ* double mutant cells. f, Schematic summary of the unique roles of H3K9 methylation states. Top: H3K9me2 mediates co-transcriptional degradation of nascent transcripts (RNAi-CTGS) and H3K9me spreading. Bottom: The formation of H3K9me3 domains, which requires the chromo domain (CD) of Clr4, results in efficient recruitment of HP1 proteins and transcriptional gene silencing (RNAi-TGS). H3K9me3, but not H3K9me2, can be epigenetically inherited. See Extended Data section for additional discussion.

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Comment in

Chromatin: Probing a piRNA paradox.
Burgess DJ. Burgess DJ. Nat Rev Genet. 2017 Nov;18(11):638-639. doi: 10.1038/nrg.2017.76. Epub 2017 Sep 11. Nat Rev Genet. 2017. PMID: 28890535 No abstract available.

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References

1. Holoch D, Moazed D. RNA-mediated epigenetic regulation of gene expression. Nat Rev Genet. 2015;16:71–84. doi: 10.1038/nrg3863. - DOI - PMC - PubMed
1. Castel SE, Martienssen RA. RNA interference in the nucleus: roles for small RNAs in transcription, epigenetics and beyond. Nat Rev Genet. 2013;14:100–112. doi: 10.1038/nrg3355. - DOI - PMC - PubMed
1. Allshire RC, Ekwall K. Epigenetic Regulation of Chromatin States in Schizosaccharomyces pombe. Cold Spring Harb Perspect Biol. 2015;7:a018770. doi: 10.1101/cshperspect.a018770. - DOI - PMC - PubMed
1. Volpe TA, et al. Regulation of heterochromatic silencing and histone H3 lysine-9 methylation by RNAi. Science. 2002;297:1833–1837. - PubMed
1. Chan SW, et al. RNA silencing genes control de novo DNA methylation. Science. 2004;303:1336. - PubMed

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[1] Holoch D, Moazed D. RNA-mediated epigenetic regulation of gene expression. Nat Rev Genet. 2015;16:71–84. doi: 10.1038/nrg3863. - DOI - PMC - PubMed

[2] Holoch D, Moazed D. RNA-mediated epigenetic regulation of gene expression. Nat Rev Genet. 2015;16:71–84. doi: 10.1038/nrg3863. - DOI - PMC - PubMed

[3] Castel SE, Martienssen RA. RNA interference in the nucleus: roles for small RNAs in transcription, epigenetics and beyond. Nat Rev Genet. 2013;14:100–112. doi: 10.1038/nrg3355. - DOI - PMC - PubMed

[4] Castel SE, Martienssen RA. RNA interference in the nucleus: roles for small RNAs in transcription, epigenetics and beyond. Nat Rev Genet. 2013;14:100–112. doi: 10.1038/nrg3355. - DOI - PMC - PubMed

[5] Allshire RC, Ekwall K. Epigenetic Regulation of Chromatin States in Schizosaccharomyces pombe. Cold Spring Harb Perspect Biol. 2015;7:a018770. doi: 10.1101/cshperspect.a018770. - DOI - PMC - PubMed

[6] Allshire RC, Ekwall K. Epigenetic Regulation of Chromatin States in Schizosaccharomyces pombe. Cold Spring Harb Perspect Biol. 2015;7:a018770. doi: 10.1101/cshperspect.a018770. - DOI - PMC - PubMed

[7] Volpe TA, et al. Regulation of heterochromatic silencing and histone H3 lysine-9 methylation by RNAi. Science. 2002;297:1833–1837. - PubMed

[8] Volpe TA, et al. Regulation of heterochromatic silencing and histone H3 lysine-9 methylation by RNAi. Science. 2002;297:1833–1837. - PubMed

[9] Chan SW, et al. RNA silencing genes control de novo DNA methylation. Science. 2004;303:1336. - PubMed

[10] Chan SW, et al. RNA silencing genes control de novo DNA methylation. Science. 2004;303:1336. - PubMed

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Unique roles for histone H3K9me states in RNAi and heritable silencing of transcription

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Unique roles for histone H3K9me states in RNAi and heritable silencing of transcription

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