The histone mark H3K36me2 recruits DNMT3A and shapes the intergenic DNA methylation landscape
Enzymes that catalyse CpG methylation in DNA, including the DNA methyltransferases 1 (DNMT1), 3A (DNMT3A) and 3B (DNMT3B), are indispensable for mammalian tissue development and homeostasis 1 – 4 . They are also implicated in human developmental disorders and cancers 5 – 8 , supporting the critical...
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| Veröffentlicht in: | Nature (London) 2019-09, Vol.573 (7773), p.281-286 |
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| creator | Weinberg, Daniel N. Papillon-Cavanagh, Simon Chen, Haifen Yue, Yuan Chen, Xiao Rajagopalan, Kartik N. Horth, Cynthia McGuire, John T. Xu, Xinjing Nikbakht, Hamid Lemiesz, Agata E. Marchione, Dylan M. Marunde, Matthew R. Meiners, Matthew J. Cheek, Marcus A. Keogh, Michael-Christopher Bareke, Eric Djedid, Anissa Harutyunyan, Ashot S. Jabado, Nada Garcia, Benjamin A. Li, Haitao Allis, C. David Majewski, Jacek Lu, Chao |
| description | Enzymes that catalyse CpG methylation in DNA, including the DNA methyltransferases 1 (DNMT1), 3A (DNMT3A) and 3B (DNMT3B), are indispensable for mammalian tissue development and homeostasis
1
–
4
. They are also implicated in human developmental disorders and cancers
5
–
8
, supporting the critical role of DNA methylation in the specification and maintenance of cell fate. Previous studies have suggested that post-translational modifications of histones are involved in specifying patterns of DNA methyltransferase localization and DNA methylation at promoters and actively transcribed gene bodies
9
–
11
. However, the mechanisms that control the establishment and maintenance of intergenic DNA methylation remain poorly understood. Tatton–Brown–Rahman syndrome (TBRS) is a childhood overgrowth disorder that is defined by germline mutations in
DNMT3A
. TBRS shares clinical features with Sotos syndrome (which is caused by haploinsufficiency of
NSD1
, a histone methyltransferase that catalyses the dimethylation of histone H3 at K36 (H3K36me2)
8
,
12
,
13
), which suggests that there is a mechanistic link between these two diseases. Here we report that NSD1-mediated H3K36me2 is required for the recruitment of DNMT3A and maintenance of DNA methylation at intergenic regions. Genome-wide analysis shows that the binding and activity of DNMT3A colocalize with H3K36me2 at non-coding regions of euchromatin. Genetic ablation of
Nsd1
and its paralogue
Nsd2
in mouse cells results in a redistribution of DNMT3A to H3K36me3-modified gene bodies and a reduction in the methylation of intergenic DNA. Blood samples from patients with Sotos syndrome and
NSD1
-mutant tumours also exhibit hypomethylation of intergenic DNA. The PWWP domain of DNMT3A shows dual recognition of H3K36me2 and H3K36me3 in vitro, with a higher binding affinity towards H3K36me2 that is abrogated by TBRS-derived missense mutations. Together, our study reveals a
trans
-chromatin regulatory pathway that connects aberrant intergenic CpG methylation to human neoplastic and developmental overgrowth.
H3K36me2 targets DNMT3A to intergenic regions and this process, together with H3K36me3-mediated recruitment of DNMT3B, has a key role in establishing and maintaining genomic DNA methylation landscapes. |
| doi_str_mv | 10.1038/s41586-019-1534-3 |
| format | Article |
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1
–
4
. They are also implicated in human developmental disorders and cancers
5
–
8
, supporting the critical role of DNA methylation in the specification and maintenance of cell fate. Previous studies have suggested that post-translational modifications of histones are involved in specifying patterns of DNA methyltransferase localization and DNA methylation at promoters and actively transcribed gene bodies
9
–
11
. However, the mechanisms that control the establishment and maintenance of intergenic DNA methylation remain poorly understood. Tatton–Brown–Rahman syndrome (TBRS) is a childhood overgrowth disorder that is defined by germline mutations in
DNMT3A
. TBRS shares clinical features with Sotos syndrome (which is caused by haploinsufficiency of
NSD1
, a histone methyltransferase that catalyses the dimethylation of histone H3 at K36 (H3K36me2)
8
,
12
,
13
), which suggests that there is a mechanistic link between these two diseases. Here we report that NSD1-mediated H3K36me2 is required for the recruitment of DNMT3A and maintenance of DNA methylation at intergenic regions. Genome-wide analysis shows that the binding and activity of DNMT3A colocalize with H3K36me2 at non-coding regions of euchromatin. Genetic ablation of
Nsd1
and its paralogue
Nsd2
in mouse cells results in a redistribution of DNMT3A to H3K36me3-modified gene bodies and a reduction in the methylation of intergenic DNA. Blood samples from patients with Sotos syndrome and
NSD1
-mutant tumours also exhibit hypomethylation of intergenic DNA. The PWWP domain of DNMT3A shows dual recognition of H3K36me2 and H3K36me3 in vitro, with a higher binding affinity towards H3K36me2 that is abrogated by TBRS-derived missense mutations. Together, our study reveals a
trans
-chromatin regulatory pathway that connects aberrant intergenic CpG methylation to human neoplastic and developmental overgrowth.
H3K36me2 targets DNMT3A to intergenic regions and this process, together with H3K36me3-mediated recruitment of DNMT3B, has a key role in establishing and maintaining genomic DNA methylation landscapes.</description><identifier>ISSN: 0028-0836</identifier><identifier>EISSN: 1476-4687</identifier><identifier>DOI: 10.1038/s41586-019-1534-3</identifier><identifier>PMID: 31485078</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>101/58 ; 13/106 ; 38/91 ; 42/41 ; 631/136/142 ; 631/1647/2210/2211 ; 631/208/176/1988 ; 631/337/100/2285 ; 631/67/1536 ; Ablation ; Analysis ; Animals ; Binding ; Bioinformatics ; Cell fate ; Cell Line ; Children ; Chromatin ; CpG islands ; Deoxyribonucleic acid ; Developmental disabilities ; DNA ; DNA (Cytosine-5-)-Methyltransferases - metabolism ; DNA Methylation ; DNA methyltransferase ; DNA, Intergenic - metabolism ; DNMT1 protein ; Euchromatin ; Gene expression ; Genome-Wide Association Study ; Genomes ; Genomics ; Growth Disorders - genetics ; Growth Disorders - physiopathology ; Haploinsufficiency ; Histone H3 ; Histone methyltransferase ; Histones ; Histones - metabolism ; Homeostasis ; Humanities and Social Sciences ; Humans ; Letter ; Localization ; Maintenance ; Mass spectrometry ; Methylation ; Methyltransferases ; Mice ; Missense mutation ; multidisciplinary ; Mutation ; Post-translation ; Post-translational modification ; Protein Binding ; Protein Domains ; Protein Transport ; Robinson, J ; Science ; Science (multidisciplinary) ; Scientific imaging ; Sotos Syndrome - genetics ; Sotos Syndrome - physiopathology ; Tumors</subject><ispartof>Nature (London), 2019-09, Vol.573 (7773), p.281-286</ispartof><rights>The Author(s), under exclusive licence to Springer Nature Limited 2019</rights><rights>COPYRIGHT 2019 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Sep 12, 2019</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c684t-3e8e4f6bb54aef13120169200c54bf42baf7f6b97c880fe242d81ad3ba1cef103</citedby><cites>FETCH-LOGICAL-c684t-3e8e4f6bb54aef13120169200c54bf42baf7f6b97c880fe242d81ad3ba1cef103</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/s41586-019-1534-3$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/s41586-019-1534-3$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31485078$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Weinberg, Daniel N.</creatorcontrib><creatorcontrib>Papillon-Cavanagh, Simon</creatorcontrib><creatorcontrib>Chen, Haifen</creatorcontrib><creatorcontrib>Yue, Yuan</creatorcontrib><creatorcontrib>Chen, Xiao</creatorcontrib><creatorcontrib>Rajagopalan, Kartik N.</creatorcontrib><creatorcontrib>Horth, Cynthia</creatorcontrib><creatorcontrib>McGuire, John T.</creatorcontrib><creatorcontrib>Xu, Xinjing</creatorcontrib><creatorcontrib>Nikbakht, Hamid</creatorcontrib><creatorcontrib>Lemiesz, Agata E.</creatorcontrib><creatorcontrib>Marchione, Dylan M.</creatorcontrib><creatorcontrib>Marunde, Matthew R.</creatorcontrib><creatorcontrib>Meiners, Matthew J.</creatorcontrib><creatorcontrib>Cheek, Marcus A.</creatorcontrib><creatorcontrib>Keogh, Michael-Christopher</creatorcontrib><creatorcontrib>Bareke, Eric</creatorcontrib><creatorcontrib>Djedid, Anissa</creatorcontrib><creatorcontrib>Harutyunyan, Ashot S.</creatorcontrib><creatorcontrib>Jabado, Nada</creatorcontrib><creatorcontrib>Garcia, Benjamin A.</creatorcontrib><creatorcontrib>Li, Haitao</creatorcontrib><creatorcontrib>Allis, C. David</creatorcontrib><creatorcontrib>Majewski, Jacek</creatorcontrib><creatorcontrib>Lu, Chao</creatorcontrib><title>The histone mark H3K36me2 recruits DNMT3A and shapes the intergenic DNA methylation landscape</title><title>Nature (London)</title><addtitle>Nature</addtitle><addtitle>Nature</addtitle><description>Enzymes that catalyse CpG methylation in DNA, including the DNA methyltransferases 1 (DNMT1), 3A (DNMT3A) and 3B (DNMT3B), are indispensable for mammalian tissue development and homeostasis
1
–
4
. They are also implicated in human developmental disorders and cancers
5
–
8
, supporting the critical role of DNA methylation in the specification and maintenance of cell fate. Previous studies have suggested that post-translational modifications of histones are involved in specifying patterns of DNA methyltransferase localization and DNA methylation at promoters and actively transcribed gene bodies
9
–
11
. However, the mechanisms that control the establishment and maintenance of intergenic DNA methylation remain poorly understood. Tatton–Brown–Rahman syndrome (TBRS) is a childhood overgrowth disorder that is defined by germline mutations in
DNMT3A
. TBRS shares clinical features with Sotos syndrome (which is caused by haploinsufficiency of
NSD1
, a histone methyltransferase that catalyses the dimethylation of histone H3 at K36 (H3K36me2)
8
,
12
,
13
), which suggests that there is a mechanistic link between these two diseases. Here we report that NSD1-mediated H3K36me2 is required for the recruitment of DNMT3A and maintenance of DNA methylation at intergenic regions. Genome-wide analysis shows that the binding and activity of DNMT3A colocalize with H3K36me2 at non-coding regions of euchromatin. Genetic ablation of
Nsd1
and its paralogue
Nsd2
in mouse cells results in a redistribution of DNMT3A to H3K36me3-modified gene bodies and a reduction in the methylation of intergenic DNA. Blood samples from patients with Sotos syndrome and
NSD1
-mutant tumours also exhibit hypomethylation of intergenic DNA. The PWWP domain of DNMT3A shows dual recognition of H3K36me2 and H3K36me3 in vitro, with a higher binding affinity towards H3K36me2 that is abrogated by TBRS-derived missense mutations. Together, our study reveals a
trans
-chromatin regulatory pathway that connects aberrant intergenic CpG methylation to human neoplastic and developmental overgrowth.
H3K36me2 targets DNMT3A to intergenic regions and this process, together with H3K36me3-mediated recruitment of DNMT3B, has a key role in establishing and maintaining genomic DNA methylation landscapes.</description><subject>101/58</subject><subject>13/106</subject><subject>38/91</subject><subject>42/41</subject><subject>631/136/142</subject><subject>631/1647/2210/2211</subject><subject>631/208/176/1988</subject><subject>631/337/100/2285</subject><subject>631/67/1536</subject><subject>Ablation</subject><subject>Analysis</subject><subject>Animals</subject><subject>Binding</subject><subject>Bioinformatics</subject><subject>Cell fate</subject><subject>Cell Line</subject><subject>Children</subject><subject>Chromatin</subject><subject>CpG islands</subject><subject>Deoxyribonucleic acid</subject><subject>Developmental disabilities</subject><subject>DNA</subject><subject>DNA (Cytosine-5-)-Methyltransferases - metabolism</subject><subject>DNA Methylation</subject><subject>DNA methyltransferase</subject><subject>DNA, Intergenic - metabolism</subject><subject>DNMT1 protein</subject><subject>Euchromatin</subject><subject>Gene expression</subject><subject>Genome-Wide Association Study</subject><subject>Genomes</subject><subject>Genomics</subject><subject>Growth Disorders - genetics</subject><subject>Growth Disorders - physiopathology</subject><subject>Haploinsufficiency</subject><subject>Histone H3</subject><subject>Histone methyltransferase</subject><subject>Histones</subject><subject>Histones - metabolism</subject><subject>Homeostasis</subject><subject>Humanities and Social Sciences</subject><subject>Humans</subject><subject>Letter</subject><subject>Localization</subject><subject>Maintenance</subject><subject>Mass spectrometry</subject><subject>Methylation</subject><subject>Methyltransferases</subject><subject>Mice</subject><subject>Missense mutation</subject><subject>multidisciplinary</subject><subject>Mutation</subject><subject>Post-translation</subject><subject>Post-translational modification</subject><subject>Protein Binding</subject><subject>Protein Domains</subject><subject>Protein Transport</subject><subject>Robinson, J</subject><subject>Science</subject><subject>Science (multidisciplinary)</subject><subject>Scientific imaging</subject><subject>Sotos Syndrome - genetics</subject><subject>Sotos Syndrome - physiopathology</subject><subject>Tumors</subject><issn>0028-0836</issn><issn>1476-4687</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BEC</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNp10stu1DAUBmALgei08ABskAUbWKT4mjjLUbm0ooAEwxJZjudkxiWXqe1I7dtzRlMogwZlESn-zi_r5CfkGWennEnzJimuTVkwXhdcS1XIB2TGVVUWqjTVQzJjTJiCGVkekeOUrhhjmlfqMTmSXBnNKjMjPxZroOuQ8jgA7V38Sc_lR1n2IGgEH6eQE337-dNCzqkbljSt3QYSzTgUhgxxBUPwCOa0h7y-7VwO40A7pMmjfEIeta5L8PTufUK-v3-3ODsvLr98uDibXxa-NCoXEgyotmwarRy0XHLBeFkLxrxWTatE49oKj-vKG8NaEEosDXdL2Tju0TN5Ql7tcjdxvJ4gZduH5KHDi8A4JSuE0Zxzw2ukL_-hV-MUB7wdqlrW2ghW3auV68CGoR1zdH4bauclE1wzLbZZxQGFO4HoOlxoG_Dznn9xwPtNuLZ_o9MDCJ8l9MEfTH29N4Amw01euSkle_Ht677lO-vjmFKE1m5iwN9-azmz207ZXacsdspuO2Ulzjy_29jU9LD8M_G7RAjEDiQ8GlYQ71f6_9RfRHfQng</recordid><startdate>201909</startdate><enddate>201909</enddate><creator>Weinberg, Daniel N.</creator><creator>Papillon-Cavanagh, Simon</creator><creator>Chen, Haifen</creator><creator>Yue, Yuan</creator><creator>Chen, Xiao</creator><creator>Rajagopalan, Kartik N.</creator><creator>Horth, Cynthia</creator><creator>McGuire, John T.</creator><creator>Xu, Xinjing</creator><creator>Nikbakht, Hamid</creator><creator>Lemiesz, Agata E.</creator><creator>Marchione, Dylan M.</creator><creator>Marunde, Matthew R.</creator><creator>Meiners, Matthew J.</creator><creator>Cheek, Marcus A.</creator><creator>Keogh, Michael-Christopher</creator><creator>Bareke, Eric</creator><creator>Djedid, Anissa</creator><creator>Harutyunyan, Ashot S.</creator><creator>Jabado, Nada</creator><creator>Garcia, Benjamin A.</creator><creator>Li, Haitao</creator><creator>Allis, C. David</creator><creator>Majewski, Jacek</creator><creator>Lu, Chao</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7ST</scope><scope>7T5</scope><scope>7TG</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>88G</scope><scope>88I</scope><scope>8AF</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BEC</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>BKSAR</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M2M</scope><scope>M2O</scope><scope>M2P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>MBDVC</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PCBAR</scope><scope>PDBOC</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PSYQQ</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>Q9U</scope><scope>R05</scope><scope>RC3</scope><scope>S0X</scope><scope>SOI</scope><scope>7X8</scope></search><sort><creationdate>201909</creationdate><title>The histone mark H3K36me2 recruits DNMT3A and shapes the intergenic DNA methylation landscape</title><author>Weinberg, Daniel N. ; Papillon-Cavanagh, Simon ; Chen, Haifen ; Yue, Yuan ; Chen, Xiao ; Rajagopalan, Kartik N. ; Horth, Cynthia ; McGuire, John T. ; Xu, Xinjing ; Nikbakht, Hamid ; Lemiesz, Agata E. ; Marchione, Dylan M. ; Marunde, Matthew R. ; Meiners, Matthew J. ; Cheek, Marcus A. ; Keogh, Michael-Christopher ; Bareke, Eric ; Djedid, Anissa ; Harutyunyan, Ashot S. ; Jabado, Nada ; Garcia, Benjamin A. ; Li, Haitao ; Allis, C. David ; Majewski, Jacek ; Lu, Chao</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c684t-3e8e4f6bb54aef13120169200c54bf42baf7f6b97c880fe242d81ad3ba1cef103</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>101/58</topic><topic>13/106</topic><topic>38/91</topic><topic>42/41</topic><topic>631/136/142</topic><topic>631/1647/2210/2211</topic><topic>631/208/176/1988</topic><topic>631/337/100/2285</topic><topic>631/67/1536</topic><topic>Ablation</topic><topic>Analysis</topic><topic>Animals</topic><topic>Binding</topic><topic>Bioinformatics</topic><topic>Cell fate</topic><topic>Cell Line</topic><topic>Children</topic><topic>Chromatin</topic><topic>CpG islands</topic><topic>Deoxyribonucleic acid</topic><topic>Developmental disabilities</topic><topic>DNA</topic><topic>DNA (Cytosine-5-)-Methyltransferases - metabolism</topic><topic>DNA Methylation</topic><topic>DNA methyltransferase</topic><topic>DNA, Intergenic - metabolism</topic><topic>DNMT1 protein</topic><topic>Euchromatin</topic><topic>Gene expression</topic><topic>Genome-Wide Association Study</topic><topic>Genomes</topic><topic>Genomics</topic><topic>Growth Disorders - genetics</topic><topic>Growth Disorders - physiopathology</topic><topic>Haploinsufficiency</topic><topic>Histone H3</topic><topic>Histone methyltransferase</topic><topic>Histones</topic><topic>Histones - metabolism</topic><topic>Homeostasis</topic><topic>Humanities and Social Sciences</topic><topic>Humans</topic><topic>Letter</topic><topic>Localization</topic><topic>Maintenance</topic><topic>Mass spectrometry</topic><topic>Methylation</topic><topic>Methyltransferases</topic><topic>Mice</topic><topic>Missense mutation</topic><topic>multidisciplinary</topic><topic>Mutation</topic><topic>Post-translation</topic><topic>Post-translational modification</topic><topic>Protein Binding</topic><topic>Protein Domains</topic><topic>Protein Transport</topic><topic>Robinson, J</topic><topic>Science</topic><topic>Science (multidisciplinary)</topic><topic>Scientific imaging</topic><topic>Sotos Syndrome - genetics</topic><topic>Sotos Syndrome - physiopathology</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Weinberg, Daniel N.</creatorcontrib><creatorcontrib>Papillon-Cavanagh, Simon</creatorcontrib><creatorcontrib>Chen, Haifen</creatorcontrib><creatorcontrib>Yue, Yuan</creatorcontrib><creatorcontrib>Chen, Xiao</creatorcontrib><creatorcontrib>Rajagopalan, Kartik N.</creatorcontrib><creatorcontrib>Horth, Cynthia</creatorcontrib><creatorcontrib>McGuire, John T.</creatorcontrib><creatorcontrib>Xu, Xinjing</creatorcontrib><creatorcontrib>Nikbakht, Hamid</creatorcontrib><creatorcontrib>Lemiesz, Agata E.</creatorcontrib><creatorcontrib>Marchione, Dylan M.</creatorcontrib><creatorcontrib>Marunde, Matthew R.</creatorcontrib><creatorcontrib>Meiners, Matthew J.</creatorcontrib><creatorcontrib>Cheek, Marcus A.</creatorcontrib><creatorcontrib>Keogh, Michael-Christopher</creatorcontrib><creatorcontrib>Bareke, Eric</creatorcontrib><creatorcontrib>Djedid, Anissa</creatorcontrib><creatorcontrib>Harutyunyan, Ashot S.</creatorcontrib><creatorcontrib>Jabado, Nada</creatorcontrib><creatorcontrib>Garcia, Benjamin A.</creatorcontrib><creatorcontrib>Li, Haitao</creatorcontrib><creatorcontrib>Allis, C. 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Academic</collection><jtitle>Nature (London)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Weinberg, Daniel N.</au><au>Papillon-Cavanagh, Simon</au><au>Chen, Haifen</au><au>Yue, Yuan</au><au>Chen, Xiao</au><au>Rajagopalan, Kartik N.</au><au>Horth, Cynthia</au><au>McGuire, John T.</au><au>Xu, Xinjing</au><au>Nikbakht, Hamid</au><au>Lemiesz, Agata E.</au><au>Marchione, Dylan M.</au><au>Marunde, Matthew R.</au><au>Meiners, Matthew J.</au><au>Cheek, Marcus A.</au><au>Keogh, Michael-Christopher</au><au>Bareke, Eric</au><au>Djedid, Anissa</au><au>Harutyunyan, Ashot S.</au><au>Jabado, Nada</au><au>Garcia, Benjamin A.</au><au>Li, Haitao</au><au>Allis, C. David</au><au>Majewski, Jacek</au><au>Lu, Chao</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The histone mark H3K36me2 recruits DNMT3A and shapes the intergenic DNA methylation landscape</atitle><jtitle>Nature (London)</jtitle><stitle>Nature</stitle><addtitle>Nature</addtitle><date>2019-09</date><risdate>2019</risdate><volume>573</volume><issue>7773</issue><spage>281</spage><epage>286</epage><pages>281-286</pages><issn>0028-0836</issn><eissn>1476-4687</eissn><abstract>Enzymes that catalyse CpG methylation in DNA, including the DNA methyltransferases 1 (DNMT1), 3A (DNMT3A) and 3B (DNMT3B), are indispensable for mammalian tissue development and homeostasis
1
–
4
. They are also implicated in human developmental disorders and cancers
5
–
8
, supporting the critical role of DNA methylation in the specification and maintenance of cell fate. Previous studies have suggested that post-translational modifications of histones are involved in specifying patterns of DNA methyltransferase localization and DNA methylation at promoters and actively transcribed gene bodies
9
–
11
. However, the mechanisms that control the establishment and maintenance of intergenic DNA methylation remain poorly understood. Tatton–Brown–Rahman syndrome (TBRS) is a childhood overgrowth disorder that is defined by germline mutations in
DNMT3A
. TBRS shares clinical features with Sotos syndrome (which is caused by haploinsufficiency of
NSD1
, a histone methyltransferase that catalyses the dimethylation of histone H3 at K36 (H3K36me2)
8
,
12
,
13
), which suggests that there is a mechanistic link between these two diseases. Here we report that NSD1-mediated H3K36me2 is required for the recruitment of DNMT3A and maintenance of DNA methylation at intergenic regions. Genome-wide analysis shows that the binding and activity of DNMT3A colocalize with H3K36me2 at non-coding regions of euchromatin. Genetic ablation of
Nsd1
and its paralogue
Nsd2
in mouse cells results in a redistribution of DNMT3A to H3K36me3-modified gene bodies and a reduction in the methylation of intergenic DNA. Blood samples from patients with Sotos syndrome and
NSD1
-mutant tumours also exhibit hypomethylation of intergenic DNA. The PWWP domain of DNMT3A shows dual recognition of H3K36me2 and H3K36me3 in vitro, with a higher binding affinity towards H3K36me2 that is abrogated by TBRS-derived missense mutations. Together, our study reveals a
trans
-chromatin regulatory pathway that connects aberrant intergenic CpG methylation to human neoplastic and developmental overgrowth.
H3K36me2 targets DNMT3A to intergenic regions and this process, together with H3K36me3-mediated recruitment of DNMT3B, has a key role in establishing and maintaining genomic DNA methylation landscapes.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>31485078</pmid><doi>10.1038/s41586-019-1534-3</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0028-0836 |
| ispartof | Nature (London), 2019-09, Vol.573 (7773), p.281-286 |
| issn | 0028-0836 1476-4687 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_2285111819 |
| source | MEDLINE; SpringerLink Journals (MCLS); Nature |
| subjects | 101/58 13/106 38/91 42/41 631/136/142 631/1647/2210/2211 631/208/176/1988 631/337/100/2285 631/67/1536 Ablation Analysis Animals Binding Bioinformatics Cell fate Cell Line Children Chromatin CpG islands Deoxyribonucleic acid Developmental disabilities DNA DNA (Cytosine-5-)-Methyltransferases - metabolism DNA Methylation DNA methyltransferase DNA, Intergenic - metabolism DNMT1 protein Euchromatin Gene expression Genome-Wide Association Study Genomes Genomics Growth Disorders - genetics Growth Disorders - physiopathology Haploinsufficiency Histone H3 Histone methyltransferase Histones Histones - metabolism Homeostasis Humanities and Social Sciences Humans Letter Localization Maintenance Mass spectrometry Methylation Methyltransferases Mice Missense mutation multidisciplinary Mutation Post-translation Post-translational modification Protein Binding Protein Domains Protein Transport Robinson, J Science Science (multidisciplinary) Scientific imaging Sotos Syndrome - genetics Sotos Syndrome - physiopathology Tumors |
| title | The histone mark H3K36me2 recruits DNMT3A and shapes the intergenic DNA methylation landscape |
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