m6A RNA methylation of major satellite repeat transcripts facilitates chromatin association and RNA:DNA hybrid formation in mouse heterochromatin

Abstract Heterochromatin has essential functions in maintaining chromosome structure, in protecting genome integrity and in stabilizing gene expression programs. Heterochromatin is often nucleated by underlying DNA repeat sequences, such as major satellite repeats (MSR) and long interspersed nuclear...

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Veröffentlicht in:Nucleic acids research 2021-06, Vol.49 (10), p.5568-5587
Hauptverfasser: Duda, Katarzyna J, Ching, Reagan W, Jerabek, Lisa, Shukeir, Nicholas, Erikson, Galina, Engist, Bettina, Onishi-Seebacher, Megumi, Perrera, Valentina, Richter, Florian, Mittler, Gerhard, Fritz, Katharina, Helm, Mark, Knuckles, Philip, Bühler, Marc, Jenuwein, Thomas
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container_end_page 5587
container_issue 10
container_start_page 5568
container_title Nucleic acids research
container_volume 49
creator Duda, Katarzyna J
Ching, Reagan W
Jerabek, Lisa
Shukeir, Nicholas
Erikson, Galina
Engist, Bettina
Onishi-Seebacher, Megumi
Perrera, Valentina
Richter, Florian
Mittler, Gerhard
Fritz, Katharina
Helm, Mark
Knuckles, Philip
Bühler, Marc
Jenuwein, Thomas
description Abstract Heterochromatin has essential functions in maintaining chromosome structure, in protecting genome integrity and in stabilizing gene expression programs. Heterochromatin is often nucleated by underlying DNA repeat sequences, such as major satellite repeats (MSR) and long interspersed nuclear elements (LINE). In order to establish heterochromatin, MSR and LINE elements need to be transcriptionally competent and generate non-coding repeat RNA that remain chromatin associated. We explored whether these heterochromatic RNA, similar to DNA and histones, may be methylated, particularly for 5-methylcytosine (5mC) or methyl-6-adenosine (m6A). Our analysis in mouse ES cells identifies only background level of 5mC but significant enrichment for m6A on heterochromatic RNA. Moreover, MSR transcripts are a novel target for m6A RNA modification, and their m6A RNA enrichment is decreased in ES cells that are mutant for Mettl3 or Mettl14, which encode components of a central RNA methyltransferase complex. Importantly, MSR transcripts that are partially deficient in m6A RNA methylation display impaired chromatin association and have a reduced potential to form RNA:DNA hybrids. We propose that m6A modification of MSR RNA will enhance the functions of MSR repeat transcripts to stabilize mouse heterochromatin.
doi_str_mv 10.1093/nar/gkab364
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Heterochromatin is often nucleated by underlying DNA repeat sequences, such as major satellite repeats (MSR) and long interspersed nuclear elements (LINE). In order to establish heterochromatin, MSR and LINE elements need to be transcriptionally competent and generate non-coding repeat RNA that remain chromatin associated. We explored whether these heterochromatic RNA, similar to DNA and histones, may be methylated, particularly for 5-methylcytosine (5mC) or methyl-6-adenosine (m6A). Our analysis in mouse ES cells identifies only background level of 5mC but significant enrichment for m6A on heterochromatic RNA. Moreover, MSR transcripts are a novel target for m6A RNA modification, and their m6A RNA enrichment is decreased in ES cells that are mutant for Mettl3 or Mettl14, which encode components of a central RNA methyltransferase complex. Importantly, MSR transcripts that are partially deficient in m6A RNA methylation display impaired chromatin association and have a reduced potential to form RNA:DNA hybrids. We propose that m6A modification of MSR RNA will enhance the functions of MSR repeat transcripts to stabilize mouse heterochromatin.</description><identifier>ISSN: 0305-1048</identifier><identifier>ISSN: 1362-4962</identifier><identifier>EISSN: 1362-4962</identifier><identifier>DOI: 10.1093/nar/gkab364</identifier><identifier>PMID: 33999208</identifier><language>eng</language><publisher>England: Oxford University Press</publisher><subject>Adenosine - analogs &amp; derivatives ; Adenosine - metabolism ; Animals ; DNA - metabolism ; Gene regulation, Chromatin and Epigenetics ; Heterochromatin ; Methylation ; Mice ; Mouse Embryonic Stem Cells ; RNA - metabolism ; Tandem Repeat Sequences</subject><ispartof>Nucleic acids research, 2021-06, Vol.49 (10), p.5568-5587</ispartof><rights>The Author(s) 2021. 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Importantly, MSR transcripts that are partially deficient in m6A RNA methylation display impaired chromatin association and have a reduced potential to form RNA:DNA hybrids. 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Heterochromatin is often nucleated by underlying DNA repeat sequences, such as major satellite repeats (MSR) and long interspersed nuclear elements (LINE). In order to establish heterochromatin, MSR and LINE elements need to be transcriptionally competent and generate non-coding repeat RNA that remain chromatin associated. We explored whether these heterochromatic RNA, similar to DNA and histones, may be methylated, particularly for 5-methylcytosine (5mC) or methyl-6-adenosine (m6A). Our analysis in mouse ES cells identifies only background level of 5mC but significant enrichment for m6A on heterochromatic RNA. Moreover, MSR transcripts are a novel target for m6A RNA modification, and their m6A RNA enrichment is decreased in ES cells that are mutant for Mettl3 or Mettl14, which encode components of a central RNA methyltransferase complex. 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subjects Adenosine - analogs & derivatives
Adenosine - metabolism
Animals
DNA - metabolism
Gene regulation, Chromatin and Epigenetics
Heterochromatin
Methylation
Mice
Mouse Embryonic Stem Cells
RNA - metabolism
Tandem Repeat Sequences
title m6A RNA methylation of major satellite repeat transcripts facilitates chromatin association and RNA:DNA hybrid formation in mouse heterochromatin
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