RNA quality control factors nucleate Clr4/SUV39H and trigger constitutive heterochromatin assembly

In eukaryotes, the Suv39 family of proteins tri-methylate lysine 9 of histone H3 (H3K9me) to form constitutive heterochromatin. However, how Suv39 proteins are nucleated at heterochromatin is not fully described. In the fission yeast, current models posit that Argonaute1-associated small RNAs (sRNAs...

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Bibliographic Details
Published in:	Cell Vol. 187; no. 13; p. 3262
Main Authors:	Khanduja, Jasbeer S, Joh, Richard I, Perez, Monica M, Paulo, Joao A, Palmieri, Christina M, Zhang, Jingyu, Gulka, Alex O D, Haas, Willhelm, Gygi, Steven P, Motamedi, Mo
Format:	Journal Article
Language:	English
Published:	United States 20-06-2024
Subjects:	Cell Cycle Proteins - metabolism Centromere - metabolism Heterochromatin - metabolism Histone-Lysine N-Methyltransferase - metabolism Histones - metabolism Methylation Methyltransferases - metabolism RNA, Long Noncoding - genetics RNA, Long Noncoding - metabolism Schizosaccharomyces - genetics Schizosaccharomyces - metabolism Schizosaccharomyces pombe Proteins - metabolism Sir2 long noncoding RNAs de novo heterochromatin formation MTREC/NURS Mtl1 H3K9 deacetylation and methylation Clr3 heterochromatin nucleation nuclear exosome Clr4/SUV39H
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Summary:	In eukaryotes, the Suv39 family of proteins tri-methylate lysine 9 of histone H3 (H3K9me) to form constitutive heterochromatin. However, how Suv39 proteins are nucleated at heterochromatin is not fully described. In the fission yeast, current models posit that Argonaute1-associated small RNAs (sRNAs) nucleate the sole H3K9 methyltransferase, Clr4/SUV39H, to centromeres. Here, we show that in the absence of all sRNAs and H3K9me, the Mtl1 and Red1 core (MTREC)/PAXT complex nucleates Clr4/SUV39H at a heterochromatic long noncoding RNA (lncRNA) at which the two H3K9 deacetylases, Sir2 and Clr3, also accumulate by distinct mechanisms. Iterative cycles of H3K9 deacetylation and methylation spread Clr4/SUV39H from the nucleation center in an sRNA-independent manner, generating a basal H3K9me state. This is acted upon by the RNAi machinery to augment and amplify the Clr4/H3K9me signal at centromeres to establish heterochromatin. Overall, our data reveal that lncRNAs and RNA quality control factors can nucleate heterochromatin and function as epigenetic silencers in eukaryotes.
ISSN:	1097-4172
DOI:	10.1016/j.cell.2024.04.042