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Low level DUX4 expression disrupts myogenesis through deregulation of myogenic gene expression
Loss of silencing of the DUX4 gene on chromosome 4 causes facioscapulohumeral muscular dystrophy. While high level DUX4 expression induces apoptosis, the effects of low level DUX4 expression on human myogenic cells are not well understood. Low levels and sporadic expression of DUX4 have been reporte...
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| Published in: | Scientific reports 2018-11, Vol.8 (1), p.16957-12, Article 16957 |
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| creator | Bosnakovski, Darko Gearhart, Micah D. Toso, Erik A. Ener, Elizabeth T. Choi, Si Ho Kyba, Michael |
| description | Loss of silencing of the
DUX4
gene on chromosome 4 causes facioscapulohumeral muscular dystrophy. While high level DUX4 expression induces apoptosis, the effects of low level DUX4 expression on human myogenic cells are not well understood. Low levels and sporadic expression of DUX4 have been reported in FSHD biopsy samples and myoblast cultures. Here, we show that a large set of human myogenic genes is rapidly deregulated by DUX4, including
MYOD1
and
MYF5
, which are efficiently repressed even by low, non-toxic levels of DUX4. Human myoblasts modified to express low nontoxic levels of DUX4 were significantly impaired from differentiating into myotubes
in vitro
. Surprisingly, inhibition of differentiation does not require the transcriptional activation domain, thus is likely a feature of all mammalian DUX genes. DUX4 does not bind near the
MYF5
gene, but has a prominent ChIP-seq peak within the
MYF5
−118 kb enhancer. We find that when DUX4 binds at this site, it directs enhancer activity towards a nearby transcriptional start site for a noncoding nonfunctional RNA we name
DIME
(DUX4-induced MYF5 enhancer) transcript. These data highlight the anti-myogenic properties of DUX4 in human myogenic progenitor cells, and provide an example of enhancer disruption in the downregulation of
MYF5
. |
| doi_str_mv | 10.1038/s41598-018-35150-8 |
| format | article |
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DUX4
gene on chromosome 4 causes facioscapulohumeral muscular dystrophy. While high level DUX4 expression induces apoptosis, the effects of low level DUX4 expression on human myogenic cells are not well understood. Low levels and sporadic expression of DUX4 have been reported in FSHD biopsy samples and myoblast cultures. Here, we show that a large set of human myogenic genes is rapidly deregulated by DUX4, including
MYOD1
and
MYF5
, which are efficiently repressed even by low, non-toxic levels of DUX4. Human myoblasts modified to express low nontoxic levels of DUX4 were significantly impaired from differentiating into myotubes
in vitro
. Surprisingly, inhibition of differentiation does not require the transcriptional activation domain, thus is likely a feature of all mammalian DUX genes. DUX4 does not bind near the
MYF5
gene, but has a prominent ChIP-seq peak within the
MYF5
−118 kb enhancer. We find that when DUX4 binds at this site, it directs enhancer activity towards a nearby transcriptional start site for a noncoding nonfunctional RNA we name
DIME
(DUX4-induced MYF5 enhancer) transcript. These data highlight the anti-myogenic properties of DUX4 in human myogenic progenitor cells, and provide an example of enhancer disruption in the downregulation of
MYF5
.</description><identifier>ISSN: 2045-2322</identifier><identifier>EISSN: 2045-2322</identifier><identifier>DOI: 10.1038/s41598-018-35150-8</identifier><identifier>PMID: 30446688</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13 ; 38 ; 631/208/199 ; 631/80 ; Apoptosis ; Biopsy ; Chromosome 4 ; Deregulation ; Dystrophy ; Gene expression ; Humanities and Social Sciences ; Kinases ; multidisciplinary ; Muscular dystrophy ; Myf5 gene ; Myoblasts ; Myogenesis ; Myotubes ; Progenitor cells ; Ribonucleic acid ; RNA ; Science ; Science (multidisciplinary) ; Stem cells ; Transcription activation</subject><ispartof>Scientific reports, 2018-11, Vol.8 (1), p.16957-12, Article 16957</ispartof><rights>The Author(s) 2018</rights><rights>2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c474t-dc107eeff9b86ce20abf92104b976f6d41660c95e2eaa8dcd34ba4ad519ba47d3</citedby><cites>FETCH-LOGICAL-c474t-dc107eeff9b86ce20abf92104b976f6d41660c95e2eaa8dcd34ba4ad519ba47d3</cites><orcidid>0000-0002-5579-7534</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.proquest.com/docview/2134280117/fulltextPDF?pq-origsite=primo$$EPDF$$P50$$Gproquest$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.proquest.com/docview/2134280117?pq-origsite=primo$$EHTML$$P50$$Gproquest$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,25752,27923,27924,37011,44589,53790,53792,74897</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30446688$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Bosnakovski, Darko</creatorcontrib><creatorcontrib>Gearhart, Micah D.</creatorcontrib><creatorcontrib>Toso, Erik A.</creatorcontrib><creatorcontrib>Ener, Elizabeth T.</creatorcontrib><creatorcontrib>Choi, Si Ho</creatorcontrib><creatorcontrib>Kyba, Michael</creatorcontrib><title>Low level DUX4 expression disrupts myogenesis through deregulation of myogenic gene expression</title><title>Scientific reports</title><addtitle>Sci Rep</addtitle><addtitle>Sci Rep</addtitle><description>Loss of silencing of the
DUX4
gene on chromosome 4 causes facioscapulohumeral muscular dystrophy. While high level DUX4 expression induces apoptosis, the effects of low level DUX4 expression on human myogenic cells are not well understood. Low levels and sporadic expression of DUX4 have been reported in FSHD biopsy samples and myoblast cultures. Here, we show that a large set of human myogenic genes is rapidly deregulated by DUX4, including
MYOD1
and
MYF5
, which are efficiently repressed even by low, non-toxic levels of DUX4. Human myoblasts modified to express low nontoxic levels of DUX4 were significantly impaired from differentiating into myotubes
in vitro
. Surprisingly, inhibition of differentiation does not require the transcriptional activation domain, thus is likely a feature of all mammalian DUX genes. DUX4 does not bind near the
MYF5
gene, but has a prominent ChIP-seq peak within the
MYF5
−118 kb enhancer. We find that when DUX4 binds at this site, it directs enhancer activity towards a nearby transcriptional start site for a noncoding nonfunctional RNA we name
DIME
(DUX4-induced MYF5 enhancer) transcript. These data highlight the anti-myogenic properties of DUX4 in human myogenic progenitor cells, and provide an example of enhancer disruption in the downregulation of
MYF5
.</description><subject>13</subject><subject>38</subject><subject>631/208/199</subject><subject>631/80</subject><subject>Apoptosis</subject><subject>Biopsy</subject><subject>Chromosome 4</subject><subject>Deregulation</subject><subject>Dystrophy</subject><subject>Gene expression</subject><subject>Humanities and Social Sciences</subject><subject>Kinases</subject><subject>multidisciplinary</subject><subject>Muscular dystrophy</subject><subject>Myf5 gene</subject><subject>Myoblasts</subject><subject>Myogenesis</subject><subject>Myotubes</subject><subject>Progenitor cells</subject><subject>Ribonucleic acid</subject><subject>RNA</subject><subject>Science</subject><subject>Science (multidisciplinary)</subject><subject>Stem cells</subject><subject>Transcription activation</subject><issn>2045-2322</issn><issn>2045-2322</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>PIMPY</sourceid><recordid>eNp9kc9LwzAUx4MoTub-AQ9S8FxN0rRNL4LMnzDw4sCTIW1eu46uqUk73X9vauecF3N5gffJ5z3yReiM4EuCA35lGQkT7mPC_SAkIfb5ATqhmIU-DSg93LuP0MTaJXYnpAkjyTEaBZixKOL8BL3N9IdXwRoq73b-yjz4bAxYW-raU6U1XdNab7XRBdRgS-u1C6O7YuEpMFB0lWx7UOdbpMy8HtyTnKKjXFYWJts6RvP7u5fpoz97fnia3sz8jMWs9VVGcAyQ50nKowwolmmeUIJZmsRRHilGoghnSQgUpOQqUwFLJZMqJImrsQrG6HrwNl26ApVB3RpZicaUK2k2QstS_O3U5UIUei0iyrD7Tie42AqMfu_AtmKpO1O7nQUlAaMcExI7ig5UZrS1BvLdBIJFH4sYYhEuFvEdi-jV5_u77Z78hOCAYACsa9UFmN_Z_2i_AOohm6E</recordid><startdate>20181116</startdate><enddate>20181116</enddate><creator>Bosnakovski, Darko</creator><creator>Gearhart, Micah D.</creator><creator>Toso, Erik A.</creator><creator>Ener, Elizabeth T.</creator><creator>Choi, Si Ho</creator><creator>Kyba, Michael</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>C6C</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>88I</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2P</scope><scope>M7P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>Q9U</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-5579-7534</orcidid></search><sort><creationdate>20181116</creationdate><title>Low level DUX4 expression disrupts myogenesis through deregulation of myogenic gene expression</title><author>Bosnakovski, Darko ; Gearhart, Micah D. ; Toso, Erik A. ; Ener, Elizabeth T. ; Choi, Si Ho ; Kyba, Michael</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c474t-dc107eeff9b86ce20abf92104b976f6d41660c95e2eaa8dcd34ba4ad519ba47d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>13</topic><topic>38</topic><topic>631/208/199</topic><topic>631/80</topic><topic>Apoptosis</topic><topic>Biopsy</topic><topic>Chromosome 4</topic><topic>Deregulation</topic><topic>Dystrophy</topic><topic>Gene expression</topic><topic>Humanities and Social Sciences</topic><topic>Kinases</topic><topic>multidisciplinary</topic><topic>Muscular dystrophy</topic><topic>Myf5 gene</topic><topic>Myoblasts</topic><topic>Myogenesis</topic><topic>Myotubes</topic><topic>Progenitor cells</topic><topic>Ribonucleic acid</topic><topic>RNA</topic><topic>Science</topic><topic>Science (multidisciplinary)</topic><topic>Stem cells</topic><topic>Transcription activation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Bosnakovski, Darko</creatorcontrib><creatorcontrib>Gearhart, Micah D.</creatorcontrib><creatorcontrib>Toso, Erik A.</creatorcontrib><creatorcontrib>Ener, Elizabeth T.</creatorcontrib><creatorcontrib>Choi, Si Ho</creatorcontrib><creatorcontrib>Kyba, Michael</creatorcontrib><collection>SpringerOpen</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Science Database (Alumni Edition)</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>ProQuest Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Science Database</collection><collection>Biological Science Database</collection><collection>Publicly Available Content (ProQuest)</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central Basic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Scientific reports</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Bosnakovski, Darko</au><au>Gearhart, Micah D.</au><au>Toso, Erik A.</au><au>Ener, Elizabeth T.</au><au>Choi, Si Ho</au><au>Kyba, Michael</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Low level DUX4 expression disrupts myogenesis through deregulation of myogenic gene expression</atitle><jtitle>Scientific reports</jtitle><stitle>Sci Rep</stitle><addtitle>Sci Rep</addtitle><date>2018-11-16</date><risdate>2018</risdate><volume>8</volume><issue>1</issue><spage>16957</spage><epage>12</epage><pages>16957-12</pages><artnum>16957</artnum><issn>2045-2322</issn><eissn>2045-2322</eissn><abstract>Loss of silencing of the
DUX4
gene on chromosome 4 causes facioscapulohumeral muscular dystrophy. While high level DUX4 expression induces apoptosis, the effects of low level DUX4 expression on human myogenic cells are not well understood. Low levels and sporadic expression of DUX4 have been reported in FSHD biopsy samples and myoblast cultures. Here, we show that a large set of human myogenic genes is rapidly deregulated by DUX4, including
MYOD1
and
MYF5
, which are efficiently repressed even by low, non-toxic levels of DUX4. Human myoblasts modified to express low nontoxic levels of DUX4 were significantly impaired from differentiating into myotubes
in vitro
. Surprisingly, inhibition of differentiation does not require the transcriptional activation domain, thus is likely a feature of all mammalian DUX genes. DUX4 does not bind near the
MYF5
gene, but has a prominent ChIP-seq peak within the
MYF5
−118 kb enhancer. We find that when DUX4 binds at this site, it directs enhancer activity towards a nearby transcriptional start site for a noncoding nonfunctional RNA we name
DIME
(DUX4-induced MYF5 enhancer) transcript. These data highlight the anti-myogenic properties of DUX4 in human myogenic progenitor cells, and provide an example of enhancer disruption in the downregulation of
MYF5
.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>30446688</pmid><doi>10.1038/s41598-018-35150-8</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0002-5579-7534</orcidid><oa>free_for_read</oa></addata></record> |
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| source | Publicly Available Content (ProQuest); PubMed Central; Free Full-Text Journals in Chemistry; Springer Nature - nature.com Journals - Fully Open Access |
| subjects | 13 38 631/208/199 631/80 Apoptosis Biopsy Chromosome 4 Deregulation Dystrophy Gene expression Humanities and Social Sciences Kinases multidisciplinary Muscular dystrophy Myf5 gene Myoblasts Myogenesis Myotubes Progenitor cells Ribonucleic acid RNA Science Science (multidisciplinary) Stem cells Transcription activation |
| title | Low level DUX4 expression disrupts myogenesis through deregulation of myogenic gene expression |
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