MeCP2 recognizes cytosine methylated tri-nucleotide and di-nucleotide sequences to tune transcription in the mammalian brain
Mutations in the gene encoding the methyl-CG binding protein MeCP2 cause several neurological disorders including Rett syndrome. The di-nucleotide methyl-CG (mCG) is the classical MeCP2 DNA recognition sequence, but additional methylated sequence targets have been reported. Here we show by in vitro...
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| creator | Lagger, Sabine Connelly, John C Schweikert, Gabriele Webb, Shaun Selfridge, Jim Ramsahoye, Bernard H Yu, Miao He, Chuan Sanguinetti, Guido Sowers, Lawrence C Walkinshaw, Malcolm D Bird, Adrian |
| description | Mutations in the gene encoding the methyl-CG binding protein MeCP2 cause several neurological disorders including Rett syndrome. The di-nucleotide methyl-CG (mCG) is the classical MeCP2 DNA recognition sequence, but additional methylated sequence targets have been reported. Here we show by in vitro and in vivo analyses that MeCP2 binding to non-CG methylated sites in brain is largely confined to the tri-nucleotide sequence mCAC. MeCP2 binding to chromosomal DNA in mouse brain is proportional to mCAC + mCG density and unexpectedly defines large genomic domains within which transcription is sensitive to MeCP2 occupancy. Our results suggest that MeCP2 integrates patterns of mCAC and mCG in the brain to restrain transcription of genes critical for neuronal function. |
| doi_str_mv | 10.1371/journal.pgen.1006793 |
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The di-nucleotide methyl-CG (mCG) is the classical MeCP2 DNA recognition sequence, but additional methylated sequence targets have been reported. Here we show by in vitro and in vivo analyses that MeCP2 binding to non-CG methylated sites in brain is largely confined to the tri-nucleotide sequence mCAC. MeCP2 binding to chromosomal DNA in mouse brain is proportional to mCAC + mCG density and unexpectedly defines large genomic domains within which transcription is sensitive to MeCP2 occupancy. Our results suggest that MeCP2 integrates patterns of mCAC and mCG in the brain to restrain transcription of genes critical for neuronal function.</description><identifier>ISSN: 1553-7404</identifier><identifier>ISSN: 1553-7390</identifier><identifier>EISSN: 1553-7404</identifier><identifier>DOI: 10.1371/journal.pgen.1006793</identifier><identifier>PMID: 28498846</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Animals ; Authorship ; Bioinformatics ; Biology ; Biology and life sciences ; Brain - metabolism ; Brain research ; CpG Islands ; Cytosine ; Cytosine - metabolism ; Deoxyribonucleic acid ; Dinucleotide Repeats ; Disease ; DNA ; DNA Methylation ; Epigenesis, Genetic ; Epigenetics ; Funding ; Gene expression ; Gene mutation ; Genetic aspects ; Genomes ; Hydration ; Informatics ; Laboratory animals ; Male ; Mammals ; MeCP2 protein ; Medicine and Health Sciences ; Methyl-CpG binding protein ; Methyl-CpG-Binding Protein 2 - genetics ; Methyl-CpG-Binding Protein 2 - metabolism ; Mice ; Mice, Inbred C57BL ; Mutation ; Nervous system diseases ; Neurological diseases ; Neurological disorders ; Nucleotide sequence ; Protein Binding ; Proteins ; Research and Analysis Methods ; Rett syndrome ; Rett Syndrome - genetics ; Stem cells ; Transcription ; Transcription (Genetics) ; Trinucleotide Repeats ; Veterinary medicine</subject><ispartof>PLoS genetics, 2017-05, Vol.13 (5), p.e1006793</ispartof><rights>COPYRIGHT 2017 Public Library of Science</rights><rights>2017 Public Library of Science. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Lagger S, Connelly JC, Schweikert G, Webb S, Selfridge J, Ramsahoye BH, et al. (2017) MeCP2 recognizes cytosine methylated tri-nucleotide and di-nucleotide sequences to tune transcription in the mammalian brain. PLoS Genet 13(5): e1006793. https://doi.org/10.1371/journal.pgen.1006793</rights><rights>2017 Lagger et al 2017 Lagger et al</rights><rights>2017 Public Library of Science. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Lagger S, Connelly JC, Schweikert G, Webb S, Selfridge J, Ramsahoye BH, et al. (2017) MeCP2 recognizes cytosine methylated tri-nucleotide and di-nucleotide sequences to tune transcription in the mammalian brain. PLoS Genet 13(5): e1006793. https://doi.org/10.1371/journal.pgen.1006793</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c792t-ea5969e9a60f7058fb39ab54849c14370d0288ea2919f597ade8ad9ef12a21c63</citedby><cites>FETCH-LOGICAL-c792t-ea5969e9a60f7058fb39ab54849c14370d0288ea2919f597ade8ad9ef12a21c63</cites><orcidid>0000-0002-6899-1870 ; 0000-0002-8600-0372 ; 0000-0002-3032-9910 ; 0000-0002-4956-3766</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5446194/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5446194/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79343,79344</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28498846$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lagger, Sabine</creatorcontrib><creatorcontrib>Connelly, John C</creatorcontrib><creatorcontrib>Schweikert, Gabriele</creatorcontrib><creatorcontrib>Webb, Shaun</creatorcontrib><creatorcontrib>Selfridge, Jim</creatorcontrib><creatorcontrib>Ramsahoye, Bernard H</creatorcontrib><creatorcontrib>Yu, Miao</creatorcontrib><creatorcontrib>He, Chuan</creatorcontrib><creatorcontrib>Sanguinetti, Guido</creatorcontrib><creatorcontrib>Sowers, Lawrence C</creatorcontrib><creatorcontrib>Walkinshaw, Malcolm D</creatorcontrib><creatorcontrib>Bird, Adrian</creatorcontrib><title>MeCP2 recognizes cytosine methylated tri-nucleotide and di-nucleotide sequences to tune transcription in the mammalian brain</title><title>PLoS genetics</title><addtitle>PLoS Genet</addtitle><description>Mutations in the gene encoding the methyl-CG binding protein MeCP2 cause several neurological disorders including Rett syndrome. The di-nucleotide methyl-CG (mCG) is the classical MeCP2 DNA recognition sequence, but additional methylated sequence targets have been reported. Here we show by in vitro and in vivo analyses that MeCP2 binding to non-CG methylated sites in brain is largely confined to the tri-nucleotide sequence mCAC. MeCP2 binding to chromosomal DNA in mouse brain is proportional to mCAC + mCG density and unexpectedly defines large genomic domains within which transcription is sensitive to MeCP2 occupancy. Our results suggest that MeCP2 integrates patterns of mCAC and mCG in the brain to restrain transcription of genes critical for neuronal function.</description><subject>Animals</subject><subject>Authorship</subject><subject>Bioinformatics</subject><subject>Biology</subject><subject>Biology and life sciences</subject><subject>Brain - metabolism</subject><subject>Brain research</subject><subject>CpG Islands</subject><subject>Cytosine</subject><subject>Cytosine - metabolism</subject><subject>Deoxyribonucleic acid</subject><subject>Dinucleotide Repeats</subject><subject>Disease</subject><subject>DNA</subject><subject>DNA Methylation</subject><subject>Epigenesis, Genetic</subject><subject>Epigenetics</subject><subject>Funding</subject><subject>Gene expression</subject><subject>Gene mutation</subject><subject>Genetic aspects</subject><subject>Genomes</subject><subject>Hydration</subject><subject>Informatics</subject><subject>Laboratory animals</subject><subject>Male</subject><subject>Mammals</subject><subject>MeCP2 protein</subject><subject>Medicine and Health Sciences</subject><subject>Methyl-CpG binding protein</subject><subject>Methyl-CpG-Binding Protein 2 - genetics</subject><subject>Methyl-CpG-Binding Protein 2 - metabolism</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mutation</subject><subject>Nervous system diseases</subject><subject>Neurological diseases</subject><subject>Neurological disorders</subject><subject>Nucleotide sequence</subject><subject>Protein Binding</subject><subject>Proteins</subject><subject>Research and Analysis Methods</subject><subject>Rett syndrome</subject><subject>Rett Syndrome - genetics</subject><subject>Stem cells</subject><subject>Transcription</subject><subject>Transcription (Genetics)</subject><subject>Trinucleotide Repeats</subject><subject>Veterinary medicine</subject><issn>1553-7404</issn><issn>1553-7390</issn><issn>1553-7404</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNqVk11rFDEUhgdRbK3-A9EBQfRi12TyMZMboRQ_CtWKX7fhbObMbspMsiYZseKPN-tuy470QslFwsnzvsk5ySmKh5TMKavpiws_Bgf9fL1EN6eEyFqxW8UhFYLNak747b31QXEvxgtCmGhUfbc4qBqumobLw-LXOzz5UJUBjV86-xNjaS6Tj9ZhOWBaXfaQsC1TsDM3mh59si2W4NqynUQifhvRmSxPvkxjVqcALppg18l6V1pXplW2hGGA3oIrFwGsu1_c6aCP-GA3HxVfXr_6fPJ2dnb-5vTk-GxmalWlGYJQUqECSbqaiKZbMAULwXMShnJWk5ZUTYNQKao6oWposYFWYUcrqKiR7Kh4vPVd9z7qXeGipooSLpmsRCZOt0Tr4UKvgx0gXGoPVv8J-LDUEJLN-WoKSlRkoao2q7mRjZGiA1QMiZAoTfZ6uTttXAzYGnS5Fv3EdLrj7Eov_XctOJdU8WzwbGcQfC5rTHqw0WDfg0M_5ns3SlEqZEMy-uQv9ObsdtQScgLWdT6fazam-pgrVjPG6ipT8xuoPFocrPEOO5vjE8HziSAzCX-kJYwx6tNPH_-Dff_v7PnXKft0j10h9GkVfT9ufl2cgnwLmuBjDNhdPwgletNQV5XTm4bSu4bKskf7j3ktuuog9htgyBuc</recordid><startdate>20170512</startdate><enddate>20170512</enddate><creator>Lagger, Sabine</creator><creator>Connelly, John C</creator><creator>Schweikert, Gabriele</creator><creator>Webb, Shaun</creator><creator>Selfridge, Jim</creator><creator>Ramsahoye, Bernard H</creator><creator>Yu, Miao</creator><creator>He, Chuan</creator><creator>Sanguinetti, Guido</creator><creator>Sowers, Lawrence C</creator><creator>Walkinshaw, Malcolm D</creator><creator>Bird, Adrian</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</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>IOV</scope><scope>ISN</scope><scope>ISR</scope><scope>3V.</scope><scope>7QP</scope><scope>7QR</scope><scope>7SS</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>P64</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0002-6899-1870</orcidid><orcidid>https://orcid.org/0000-0002-8600-0372</orcidid><orcidid>https://orcid.org/0000-0002-3032-9910</orcidid><orcidid>https://orcid.org/0000-0002-4956-3766</orcidid></search><sort><creationdate>20170512</creationdate><title>MeCP2 recognizes cytosine methylated tri-nucleotide and di-nucleotide sequences to tune transcription in the mammalian brain</title><author>Lagger, Sabine ; Connelly, John C ; Schweikert, Gabriele ; Webb, Shaun ; Selfridge, Jim ; Ramsahoye, Bernard H ; Yu, Miao ; He, Chuan ; Sanguinetti, Guido ; Sowers, Lawrence C ; Walkinshaw, Malcolm D ; Bird, Adrian</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c792t-ea5969e9a60f7058fb39ab54849c14370d0288ea2919f597ade8ad9ef12a21c63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Animals</topic><topic>Authorship</topic><topic>Bioinformatics</topic><topic>Biology</topic><topic>Biology and life sciences</topic><topic>Brain - 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The di-nucleotide methyl-CG (mCG) is the classical MeCP2 DNA recognition sequence, but additional methylated sequence targets have been reported. Here we show by in vitro and in vivo analyses that MeCP2 binding to non-CG methylated sites in brain is largely confined to the tri-nucleotide sequence mCAC. MeCP2 binding to chromosomal DNA in mouse brain is proportional to mCAC + mCG density and unexpectedly defines large genomic domains within which transcription is sensitive to MeCP2 occupancy. 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| source | Public Library of Science (PLoS) Journals Open Access; MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central |
| subjects | Animals Authorship Bioinformatics Biology Biology and life sciences Brain - metabolism Brain research CpG Islands Cytosine Cytosine - metabolism Deoxyribonucleic acid Dinucleotide Repeats Disease DNA DNA Methylation Epigenesis, Genetic Epigenetics Funding Gene expression Gene mutation Genetic aspects Genomes Hydration Informatics Laboratory animals Male Mammals MeCP2 protein Medicine and Health Sciences Methyl-CpG binding protein Methyl-CpG-Binding Protein 2 - genetics Methyl-CpG-Binding Protein 2 - metabolism Mice Mice, Inbred C57BL Mutation Nervous system diseases Neurological diseases Neurological disorders Nucleotide sequence Protein Binding Proteins Research and Analysis Methods Rett syndrome Rett Syndrome - genetics Stem cells Transcription Transcription (Genetics) Trinucleotide Repeats Veterinary medicine |
| title | MeCP2 recognizes cytosine methylated tri-nucleotide and di-nucleotide sequences to tune transcription in the mammalian brain |
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