A Specific LSD1/KDM1A Isoform Regulates Neuronal Differentiation through H3K9 Demethylation
Lysine-specific demethylase 1 (LSD1) has been reported to repress and activate transcription by mediating histone H3K4me1/2 and H3K9me1/2 demethylation, respectively. The molecular mechanism that underlies this dual substrate specificity has remained unknown. Here we report that an isoform of LSD1,...
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Veröffentlicht in: | Molecular cell 2015-03, Vol.57 (6), p.957-970 |
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description | Lysine-specific demethylase 1 (LSD1) has been reported to repress and activate transcription by mediating histone H3K4me1/2 and H3K9me1/2 demethylation, respectively. The molecular mechanism that underlies this dual substrate specificity has remained unknown. Here we report that an isoform of LSD1, LSD1+8a, does not have the intrinsic capability to demethylate H3K4me2. Instead, LSD1+8a mediates H3K9me2 demethylation in collaboration with supervillin (SVIL), a new LSD1+8a interacting protein. LSD1+8a knockdown increases H3K9me2, but not H3K4me2, levels at its target promoters and compromises neuronal differentiation. Importantly, SVIL co-localizes to LSD1+8a-bound promoters, and its knockdown mimics the impact of LSD1+8a loss, supporting SVIL as a cofactor for LSD1+8a in neuronal cells. These findings provide insight into mechanisms by which LSD1 mediates H3K9me demethylation and highlight alternative splicing as a means by which LSD1 acquires selective substrate specificities (H3K9 versus H3K4) to differentially control specific gene expression programs in neurons.
[Display omitted]
•LSD1+8a isoform does not have the intrinsic property to demethylate H3K4•LSD1+8a functions as a co-activator by demethylating the repressive H3K9me2 mark•LSD1+8a interacts with SVIL; LSD1+8a/SVIL-containing complex demethylates H3K9me2•SVIL regulates neuronal maturation by controlling LSD1+8a mediated H3K9 demethylation
Benoit Laurent et al. find that the neuro-enriched LSD1 isoform, LSD1+8a, mediates H3K9me2 demethylation in collaboration with the supervillin protein (SVIL), a new LSD1+8a partner. These findings highlight alternative splicing as a means by which LSD1 acquires selective substrate specificities (H3K9 versus H3K4) to control specific transcriptional programs in neurons. |
doi_str_mv | 10.1016/j.molcel.2015.01.010 |
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[Display omitted]
•LSD1+8a isoform does not have the intrinsic property to demethylate H3K4•LSD1+8a functions as a co-activator by demethylating the repressive H3K9me2 mark•LSD1+8a interacts with SVIL; LSD1+8a/SVIL-containing complex demethylates H3K9me2•SVIL regulates neuronal maturation by controlling LSD1+8a mediated H3K9 demethylation
Benoit Laurent et al. find that the neuro-enriched LSD1 isoform, LSD1+8a, mediates H3K9me2 demethylation in collaboration with the supervillin protein (SVIL), a new LSD1+8a partner. These findings highlight alternative splicing as a means by which LSD1 acquires selective substrate specificities (H3K9 versus H3K4) to control specific transcriptional programs in neurons.</description><identifier>ISSN: 1097-2765</identifier><identifier>EISSN: 1097-4164</identifier><identifier>DOI: 10.1016/j.molcel.2015.01.010</identifier><identifier>PMID: 25684206</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Alternative Splicing ; Cell Differentiation ; Cell Movement ; Gene Expression Regulation ; Gene Knockdown Techniques ; HeLa Cells ; Histone Demethylases - genetics ; Histone Demethylases - metabolism ; Histones - genetics ; Histones - metabolism ; Humans ; Lysine - metabolism ; Membrane Proteins - genetics ; Membrane Proteins - metabolism ; Methylation ; Microfilament Proteins - genetics ; Microfilament Proteins - metabolism ; Neurons - cytology ; Neurons - metabolism ; Promoter Regions, Genetic ; Protein Isoforms - metabolism</subject><ispartof>Molecular cell, 2015-03, Vol.57 (6), p.957-970</ispartof><rights>2015 Elsevier Inc.</rights><rights>Copyright © 2015 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c599t-70bd0bdab08f11c631e1e81feb5396428f1912c33cfe9fa5b786091ecd4f30323</citedby><cites>FETCH-LOGICAL-c599t-70bd0bdab08f11c631e1e81feb5396428f1912c33cfe9fa5b786091ecd4f30323</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.molcel.2015.01.010$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>230,315,782,786,887,3552,27931,27932,46002</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25684206$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Laurent, Benoit</creatorcontrib><creatorcontrib>Ruitu, Lv</creatorcontrib><creatorcontrib>Murn, Jernej</creatorcontrib><creatorcontrib>Hempel, Kristina</creatorcontrib><creatorcontrib>Ferrao, Ryan</creatorcontrib><creatorcontrib>Xiang, Yang</creatorcontrib><creatorcontrib>Liu, Shichong</creatorcontrib><creatorcontrib>Garcia, Benjamin A.</creatorcontrib><creatorcontrib>Wu, Hao</creatorcontrib><creatorcontrib>Wu, Feizhen</creatorcontrib><creatorcontrib>Steen, Hanno</creatorcontrib><creatorcontrib>Shi, Yang</creatorcontrib><title>A Specific LSD1/KDM1A Isoform Regulates Neuronal Differentiation through H3K9 Demethylation</title><title>Molecular cell</title><addtitle>Mol Cell</addtitle><description>Lysine-specific demethylase 1 (LSD1) has been reported to repress and activate transcription by mediating histone H3K4me1/2 and H3K9me1/2 demethylation, respectively. The molecular mechanism that underlies this dual substrate specificity has remained unknown. Here we report that an isoform of LSD1, LSD1+8a, does not have the intrinsic capability to demethylate H3K4me2. Instead, LSD1+8a mediates H3K9me2 demethylation in collaboration with supervillin (SVIL), a new LSD1+8a interacting protein. LSD1+8a knockdown increases H3K9me2, but not H3K4me2, levels at its target promoters and compromises neuronal differentiation. Importantly, SVIL co-localizes to LSD1+8a-bound promoters, and its knockdown mimics the impact of LSD1+8a loss, supporting SVIL as a cofactor for LSD1+8a in neuronal cells. These findings provide insight into mechanisms by which LSD1 mediates H3K9me demethylation and highlight alternative splicing as a means by which LSD1 acquires selective substrate specificities (H3K9 versus H3K4) to differentially control specific gene expression programs in neurons.
[Display omitted]
•LSD1+8a isoform does not have the intrinsic property to demethylate H3K4•LSD1+8a functions as a co-activator by demethylating the repressive H3K9me2 mark•LSD1+8a interacts with SVIL; LSD1+8a/SVIL-containing complex demethylates H3K9me2•SVIL regulates neuronal maturation by controlling LSD1+8a mediated H3K9 demethylation
Benoit Laurent et al. find that the neuro-enriched LSD1 isoform, LSD1+8a, mediates H3K9me2 demethylation in collaboration with the supervillin protein (SVIL), a new LSD1+8a partner. These findings highlight alternative splicing as a means by which LSD1 acquires selective substrate specificities (H3K9 versus H3K4) to control specific transcriptional programs in neurons.</description><subject>Alternative Splicing</subject><subject>Cell Differentiation</subject><subject>Cell Movement</subject><subject>Gene Expression Regulation</subject><subject>Gene Knockdown Techniques</subject><subject>HeLa Cells</subject><subject>Histone Demethylases - genetics</subject><subject>Histone Demethylases - metabolism</subject><subject>Histones - genetics</subject><subject>Histones - metabolism</subject><subject>Humans</subject><subject>Lysine - metabolism</subject><subject>Membrane Proteins - genetics</subject><subject>Membrane Proteins - metabolism</subject><subject>Methylation</subject><subject>Microfilament Proteins - genetics</subject><subject>Microfilament Proteins - metabolism</subject><subject>Neurons - cytology</subject><subject>Neurons - metabolism</subject><subject>Promoter Regions, Genetic</subject><subject>Protein Isoforms - metabolism</subject><issn>1097-2765</issn><issn>1097-4164</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9UUtvEzEQthCIlsI_QMhHLkk960fWF6SoAVo1gEThxMHyeseJo911au9W6r_HJaHABemTZjSPbx4fIa-BzYGBOt_N-9g57OYVAzlnUMCekFNgejEToMTTo18tlDwhL3LeMQZC1vo5OamkqkXF1Cn5saQ3e3TBB0fXNys4v159giW9ytHH1NOvuJk6O2Kmn3FKcbAdXQXvMeEwBjuGONBxm-K02dJLfq3pCnsct_fdr9RL8szbLuOroz0j3z-8_3ZxOVt_-Xh1sVzPnNR6nC1Y0xbYhtUewCkOCFiDx0ZyrURVohoqx7nzqL2VzaJWTAO6VnjOeMXPyLsD735qemxd2S3ZzuxT6G26N9EG829mCFuziXdGcKW51oXg7ZEgxdsJ82j6kMtrOztgnLIBpaTQknFeSsWh1KWYc0L_OAaYedDF7MxBF_Ogi2FQwErbm79XfGz6LcSfG7A86i5gMtkFHBy2IaEbTRvD_yf8BORQoQw</recordid><startdate>20150319</startdate><enddate>20150319</enddate><creator>Laurent, Benoit</creator><creator>Ruitu, Lv</creator><creator>Murn, Jernej</creator><creator>Hempel, Kristina</creator><creator>Ferrao, Ryan</creator><creator>Xiang, Yang</creator><creator>Liu, Shichong</creator><creator>Garcia, Benjamin A.</creator><creator>Wu, Hao</creator><creator>Wu, Feizhen</creator><creator>Steen, Hanno</creator><creator>Shi, Yang</creator><general>Elsevier Inc</general><scope>6I.</scope><scope>AAFTH</scope><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>7X8</scope><scope>5PM</scope></search><sort><creationdate>20150319</creationdate><title>A Specific LSD1/KDM1A Isoform Regulates Neuronal Differentiation through H3K9 Demethylation</title><author>Laurent, Benoit ; Ruitu, Lv ; Murn, Jernej ; Hempel, Kristina ; Ferrao, Ryan ; Xiang, Yang ; Liu, Shichong ; Garcia, Benjamin A. ; Wu, Hao ; Wu, Feizhen ; Steen, Hanno ; Shi, Yang</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c599t-70bd0bdab08f11c631e1e81feb5396428f1912c33cfe9fa5b786091ecd4f30323</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Alternative Splicing</topic><topic>Cell Differentiation</topic><topic>Cell Movement</topic><topic>Gene Expression Regulation</topic><topic>Gene Knockdown Techniques</topic><topic>HeLa Cells</topic><topic>Histone Demethylases - genetics</topic><topic>Histone Demethylases - metabolism</topic><topic>Histones - genetics</topic><topic>Histones - metabolism</topic><topic>Humans</topic><topic>Lysine - metabolism</topic><topic>Membrane Proteins - genetics</topic><topic>Membrane Proteins - metabolism</topic><topic>Methylation</topic><topic>Microfilament Proteins - genetics</topic><topic>Microfilament Proteins - metabolism</topic><topic>Neurons - cytology</topic><topic>Neurons - metabolism</topic><topic>Promoter Regions, Genetic</topic><topic>Protein Isoforms - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Laurent, Benoit</creatorcontrib><creatorcontrib>Ruitu, Lv</creatorcontrib><creatorcontrib>Murn, Jernej</creatorcontrib><creatorcontrib>Hempel, Kristina</creatorcontrib><creatorcontrib>Ferrao, Ryan</creatorcontrib><creatorcontrib>Xiang, Yang</creatorcontrib><creatorcontrib>Liu, Shichong</creatorcontrib><creatorcontrib>Garcia, Benjamin A.</creatorcontrib><creatorcontrib>Wu, Hao</creatorcontrib><creatorcontrib>Wu, Feizhen</creatorcontrib><creatorcontrib>Steen, Hanno</creatorcontrib><creatorcontrib>Shi, Yang</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Molecular cell</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Laurent, Benoit</au><au>Ruitu, Lv</au><au>Murn, Jernej</au><au>Hempel, Kristina</au><au>Ferrao, Ryan</au><au>Xiang, Yang</au><au>Liu, Shichong</au><au>Garcia, Benjamin A.</au><au>Wu, Hao</au><au>Wu, Feizhen</au><au>Steen, Hanno</au><au>Shi, Yang</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A Specific LSD1/KDM1A Isoform Regulates Neuronal Differentiation through H3K9 Demethylation</atitle><jtitle>Molecular cell</jtitle><addtitle>Mol Cell</addtitle><date>2015-03-19</date><risdate>2015</risdate><volume>57</volume><issue>6</issue><spage>957</spage><epage>970</epage><pages>957-970</pages><issn>1097-2765</issn><eissn>1097-4164</eissn><abstract>Lysine-specific demethylase 1 (LSD1) has been reported to repress and activate transcription by mediating histone H3K4me1/2 and H3K9me1/2 demethylation, respectively. The molecular mechanism that underlies this dual substrate specificity has remained unknown. Here we report that an isoform of LSD1, LSD1+8a, does not have the intrinsic capability to demethylate H3K4me2. Instead, LSD1+8a mediates H3K9me2 demethylation in collaboration with supervillin (SVIL), a new LSD1+8a interacting protein. LSD1+8a knockdown increases H3K9me2, but not H3K4me2, levels at its target promoters and compromises neuronal differentiation. Importantly, SVIL co-localizes to LSD1+8a-bound promoters, and its knockdown mimics the impact of LSD1+8a loss, supporting SVIL as a cofactor for LSD1+8a in neuronal cells. These findings provide insight into mechanisms by which LSD1 mediates H3K9me demethylation and highlight alternative splicing as a means by which LSD1 acquires selective substrate specificities (H3K9 versus H3K4) to differentially control specific gene expression programs in neurons.
[Display omitted]
•LSD1+8a isoform does not have the intrinsic property to demethylate H3K4•LSD1+8a functions as a co-activator by demethylating the repressive H3K9me2 mark•LSD1+8a interacts with SVIL; LSD1+8a/SVIL-containing complex demethylates H3K9me2•SVIL regulates neuronal maturation by controlling LSD1+8a mediated H3K9 demethylation
Benoit Laurent et al. find that the neuro-enriched LSD1 isoform, LSD1+8a, mediates H3K9me2 demethylation in collaboration with the supervillin protein (SVIL), a new LSD1+8a partner. These findings highlight alternative splicing as a means by which LSD1 acquires selective substrate specificities (H3K9 versus H3K4) to control specific transcriptional programs in neurons.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>25684206</pmid><doi>10.1016/j.molcel.2015.01.010</doi><tpages>14</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Alternative Splicing Cell Differentiation Cell Movement Gene Expression Regulation Gene Knockdown Techniques HeLa Cells Histone Demethylases - genetics Histone Demethylases - metabolism Histones - genetics Histones - metabolism Humans Lysine - metabolism Membrane Proteins - genetics Membrane Proteins - metabolism Methylation Microfilament Proteins - genetics Microfilament Proteins - metabolism Neurons - cytology Neurons - metabolism Promoter Regions, Genetic Protein Isoforms - metabolism |
title | A Specific LSD1/KDM1A Isoform Regulates Neuronal Differentiation through H3K9 Demethylation |
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