Integrative analysis reveals functional and regulatory roles of H3K79me2 in mediating alternative splicing

Abstract Background Accumulating evidence suggests alternative splicing (AS) is a co-transcriptional splicing process not only controlled by RNA-binding splicing factors, but also mediated by epigenetic regulators, such as chromatin structure, nucleosome density, and histone modification. Aberrant A...
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Autor*in:	Tianbao Li [verfasserIn] Qi Liu [verfasserIn] Nick Garza [verfasserIn] Steven Kornblau [verfasserIn] Victor X. Jin [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2018

Schlagwörter:	Alternative Splicing H3K79me2 DOT1L AML

Übergeordnetes Werk:	In: Genome Medicine - BMC, 2016, 10(2018), 1, Seite 11
Übergeordnetes Werk:	volume:10 ; year:2018 ; number:1 ; pages:11

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.1186/s13073-018-0538-1

Katalog-ID:	DOAJ036759279

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520			\|a Abstract Background Accumulating evidence suggests alternative splicing (AS) is a co-transcriptional splicing process not only controlled by RNA-binding splicing factors, but also mediated by epigenetic regulators, such as chromatin structure, nucleosome density, and histone modification. Aberrant AS plays an important role in regulating various diseases, including cancers. Methods In this study, we integrated AS events derived from RNA-seq with H3K79me2 ChIP-seq data across 34 different normal and cancer cell types and found the higher enrichment of H3K79me2 in two AS types, skipping exon (SE) and alternative 3′ splice site (A3SS). Results Interestingly, by applying self-organizing map (SOM) clustering, we unveiled two clusters mainly comprised of blood cancer cell types with a strong correlation between H3K79me2 and SE. Remarkably, the expression of transcripts associated with SE was not significantly different from that of those not associated with SE, indicating the involvement of H3K79me2 in splicing has little impact on full mRNA transcription. We further showed that the deletion of DOT1L1, the sole H3K79 methyltransferase, impeded leukemia cell proliferation as well as switched exon skipping to the inclusion isoform in two MLL-rearranged acute myeloid leukemia cell lines. Our data demonstrate H3K79me2 was involved in mediating SE processing, which might in turn influence transformation and disease progression in leukemias. Conclusions Collectively, our work for the first time reveals that H3K79me2 plays functional and regulatory roles through a co-transcriptional splicing mechanism.
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allfields	10.1186/s13073-018-0538-1 doi (DE-627)DOAJ036759279 (DE-599)DOAJ1079512ea298478180a989a65398fb2e DE-627 ger DE-627 rakwb eng QH426-470 Tianbao Li verfasserin aut Integrative analysis reveals functional and regulatory roles of H3K79me2 in mediating alternative splicing 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Background Accumulating evidence suggests alternative splicing (AS) is a co-transcriptional splicing process not only controlled by RNA-binding splicing factors, but also mediated by epigenetic regulators, such as chromatin structure, nucleosome density, and histone modification. Aberrant AS plays an important role in regulating various diseases, including cancers. Methods In this study, we integrated AS events derived from RNA-seq with H3K79me2 ChIP-seq data across 34 different normal and cancer cell types and found the higher enrichment of H3K79me2 in two AS types, skipping exon (SE) and alternative 3′ splice site (A3SS). Results Interestingly, by applying self-organizing map (SOM) clustering, we unveiled two clusters mainly comprised of blood cancer cell types with a strong correlation between H3K79me2 and SE. Remarkably, the expression of transcripts associated with SE was not significantly different from that of those not associated with SE, indicating the involvement of H3K79me2 in splicing has little impact on full mRNA transcription. We further showed that the deletion of DOT1L1, the sole H3K79 methyltransferase, impeded leukemia cell proliferation as well as switched exon skipping to the inclusion isoform in two MLL-rearranged acute myeloid leukemia cell lines. Our data demonstrate H3K79me2 was involved in mediating SE processing, which might in turn influence transformation and disease progression in leukemias. Conclusions Collectively, our work for the first time reveals that H3K79me2 plays functional and regulatory roles through a co-transcriptional splicing mechanism. Alternative Splicing H3K79me2 DOT1L AML Medicine R Genetics Qi Liu verfasserin aut Nick Garza verfasserin aut Steven Kornblau verfasserin aut Victor X. Jin verfasserin aut In Genome Medicine BMC, 2016 10(2018), 1, Seite 11 (DE-627)594424275 (DE-600)2484394-5 1756994X nnns volume:10 year:2018 number:1 pages:11 https://doi.org/10.1186/s13073-018-0538-1 kostenfrei https://doaj.org/article/1079512ea298478180a989a65398fb2e kostenfrei http://link.springer.com/article/10.1186/s13073-018-0538-1 kostenfrei https://doaj.org/toc/1756-994X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 10 2018 1 11
spelling	10.1186/s13073-018-0538-1 doi (DE-627)DOAJ036759279 (DE-599)DOAJ1079512ea298478180a989a65398fb2e DE-627 ger DE-627 rakwb eng QH426-470 Tianbao Li verfasserin aut Integrative analysis reveals functional and regulatory roles of H3K79me2 in mediating alternative splicing 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Background Accumulating evidence suggests alternative splicing (AS) is a co-transcriptional splicing process not only controlled by RNA-binding splicing factors, but also mediated by epigenetic regulators, such as chromatin structure, nucleosome density, and histone modification. Aberrant AS plays an important role in regulating various diseases, including cancers. Methods In this study, we integrated AS events derived from RNA-seq with H3K79me2 ChIP-seq data across 34 different normal and cancer cell types and found the higher enrichment of H3K79me2 in two AS types, skipping exon (SE) and alternative 3′ splice site (A3SS). Results Interestingly, by applying self-organizing map (SOM) clustering, we unveiled two clusters mainly comprised of blood cancer cell types with a strong correlation between H3K79me2 and SE. Remarkably, the expression of transcripts associated with SE was not significantly different from that of those not associated with SE, indicating the involvement of H3K79me2 in splicing has little impact on full mRNA transcription. We further showed that the deletion of DOT1L1, the sole H3K79 methyltransferase, impeded leukemia cell proliferation as well as switched exon skipping to the inclusion isoform in two MLL-rearranged acute myeloid leukemia cell lines. Our data demonstrate H3K79me2 was involved in mediating SE processing, which might in turn influence transformation and disease progression in leukemias. Conclusions Collectively, our work for the first time reveals that H3K79me2 plays functional and regulatory roles through a co-transcriptional splicing mechanism. Alternative Splicing H3K79me2 DOT1L AML Medicine R Genetics Qi Liu verfasserin aut Nick Garza verfasserin aut Steven Kornblau verfasserin aut Victor X. Jin verfasserin aut In Genome Medicine BMC, 2016 10(2018), 1, Seite 11 (DE-627)594424275 (DE-600)2484394-5 1756994X nnns volume:10 year:2018 number:1 pages:11 https://doi.org/10.1186/s13073-018-0538-1 kostenfrei https://doaj.org/article/1079512ea298478180a989a65398fb2e kostenfrei http://link.springer.com/article/10.1186/s13073-018-0538-1 kostenfrei https://doaj.org/toc/1756-994X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 10 2018 1 11
allfields_unstemmed	10.1186/s13073-018-0538-1 doi (DE-627)DOAJ036759279 (DE-599)DOAJ1079512ea298478180a989a65398fb2e DE-627 ger DE-627 rakwb eng QH426-470 Tianbao Li verfasserin aut Integrative analysis reveals functional and regulatory roles of H3K79me2 in mediating alternative splicing 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Background Accumulating evidence suggests alternative splicing (AS) is a co-transcriptional splicing process not only controlled by RNA-binding splicing factors, but also mediated by epigenetic regulators, such as chromatin structure, nucleosome density, and histone modification. Aberrant AS plays an important role in regulating various diseases, including cancers. Methods In this study, we integrated AS events derived from RNA-seq with H3K79me2 ChIP-seq data across 34 different normal and cancer cell types and found the higher enrichment of H3K79me2 in two AS types, skipping exon (SE) and alternative 3′ splice site (A3SS). Results Interestingly, by applying self-organizing map (SOM) clustering, we unveiled two clusters mainly comprised of blood cancer cell types with a strong correlation between H3K79me2 and SE. Remarkably, the expression of transcripts associated with SE was not significantly different from that of those not associated with SE, indicating the involvement of H3K79me2 in splicing has little impact on full mRNA transcription. We further showed that the deletion of DOT1L1, the sole H3K79 methyltransferase, impeded leukemia cell proliferation as well as switched exon skipping to the inclusion isoform in two MLL-rearranged acute myeloid leukemia cell lines. Our data demonstrate H3K79me2 was involved in mediating SE processing, which might in turn influence transformation and disease progression in leukemias. Conclusions Collectively, our work for the first time reveals that H3K79me2 plays functional and regulatory roles through a co-transcriptional splicing mechanism. Alternative Splicing H3K79me2 DOT1L AML Medicine R Genetics Qi Liu verfasserin aut Nick Garza verfasserin aut Steven Kornblau verfasserin aut Victor X. Jin verfasserin aut In Genome Medicine BMC, 2016 10(2018), 1, Seite 11 (DE-627)594424275 (DE-600)2484394-5 1756994X nnns volume:10 year:2018 number:1 pages:11 https://doi.org/10.1186/s13073-018-0538-1 kostenfrei https://doaj.org/article/1079512ea298478180a989a65398fb2e kostenfrei http://link.springer.com/article/10.1186/s13073-018-0538-1 kostenfrei https://doaj.org/toc/1756-994X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 10 2018 1 11
allfieldsGer	10.1186/s13073-018-0538-1 doi (DE-627)DOAJ036759279 (DE-599)DOAJ1079512ea298478180a989a65398fb2e DE-627 ger DE-627 rakwb eng QH426-470 Tianbao Li verfasserin aut Integrative analysis reveals functional and regulatory roles of H3K79me2 in mediating alternative splicing 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Background Accumulating evidence suggests alternative splicing (AS) is a co-transcriptional splicing process not only controlled by RNA-binding splicing factors, but also mediated by epigenetic regulators, such as chromatin structure, nucleosome density, and histone modification. Aberrant AS plays an important role in regulating various diseases, including cancers. Methods In this study, we integrated AS events derived from RNA-seq with H3K79me2 ChIP-seq data across 34 different normal and cancer cell types and found the higher enrichment of H3K79me2 in two AS types, skipping exon (SE) and alternative 3′ splice site (A3SS). Results Interestingly, by applying self-organizing map (SOM) clustering, we unveiled two clusters mainly comprised of blood cancer cell types with a strong correlation between H3K79me2 and SE. Remarkably, the expression of transcripts associated with SE was not significantly different from that of those not associated with SE, indicating the involvement of H3K79me2 in splicing has little impact on full mRNA transcription. We further showed that the deletion of DOT1L1, the sole H3K79 methyltransferase, impeded leukemia cell proliferation as well as switched exon skipping to the inclusion isoform in two MLL-rearranged acute myeloid leukemia cell lines. Our data demonstrate H3K79me2 was involved in mediating SE processing, which might in turn influence transformation and disease progression in leukemias. Conclusions Collectively, our work for the first time reveals that H3K79me2 plays functional and regulatory roles through a co-transcriptional splicing mechanism. Alternative Splicing H3K79me2 DOT1L AML Medicine R Genetics Qi Liu verfasserin aut Nick Garza verfasserin aut Steven Kornblau verfasserin aut Victor X. Jin verfasserin aut In Genome Medicine BMC, 2016 10(2018), 1, Seite 11 (DE-627)594424275 (DE-600)2484394-5 1756994X nnns volume:10 year:2018 number:1 pages:11 https://doi.org/10.1186/s13073-018-0538-1 kostenfrei https://doaj.org/article/1079512ea298478180a989a65398fb2e kostenfrei http://link.springer.com/article/10.1186/s13073-018-0538-1 kostenfrei https://doaj.org/toc/1756-994X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 10 2018 1 11
allfieldsSound	10.1186/s13073-018-0538-1 doi (DE-627)DOAJ036759279 (DE-599)DOAJ1079512ea298478180a989a65398fb2e DE-627 ger DE-627 rakwb eng QH426-470 Tianbao Li verfasserin aut Integrative analysis reveals functional and regulatory roles of H3K79me2 in mediating alternative splicing 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Background Accumulating evidence suggests alternative splicing (AS) is a co-transcriptional splicing process not only controlled by RNA-binding splicing factors, but also mediated by epigenetic regulators, such as chromatin structure, nucleosome density, and histone modification. Aberrant AS plays an important role in regulating various diseases, including cancers. Methods In this study, we integrated AS events derived from RNA-seq with H3K79me2 ChIP-seq data across 34 different normal and cancer cell types and found the higher enrichment of H3K79me2 in two AS types, skipping exon (SE) and alternative 3′ splice site (A3SS). Results Interestingly, by applying self-organizing map (SOM) clustering, we unveiled two clusters mainly comprised of blood cancer cell types with a strong correlation between H3K79me2 and SE. Remarkably, the expression of transcripts associated with SE was not significantly different from that of those not associated with SE, indicating the involvement of H3K79me2 in splicing has little impact on full mRNA transcription. We further showed that the deletion of DOT1L1, the sole H3K79 methyltransferase, impeded leukemia cell proliferation as well as switched exon skipping to the inclusion isoform in two MLL-rearranged acute myeloid leukemia cell lines. Our data demonstrate H3K79me2 was involved in mediating SE processing, which might in turn influence transformation and disease progression in leukemias. Conclusions Collectively, our work for the first time reveals that H3K79me2 plays functional and regulatory roles through a co-transcriptional splicing mechanism. Alternative Splicing H3K79me2 DOT1L AML Medicine R Genetics Qi Liu verfasserin aut Nick Garza verfasserin aut Steven Kornblau verfasserin aut Victor X. Jin verfasserin aut In Genome Medicine BMC, 2016 10(2018), 1, Seite 11 (DE-627)594424275 (DE-600)2484394-5 1756994X nnns volume:10 year:2018 number:1 pages:11 https://doi.org/10.1186/s13073-018-0538-1 kostenfrei https://doaj.org/article/1079512ea298478180a989a65398fb2e kostenfrei http://link.springer.com/article/10.1186/s13073-018-0538-1 kostenfrei https://doaj.org/toc/1756-994X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 10 2018 1 11
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authorswithroles_txt_mv	Tianbao Li @@aut@@ Qi Liu @@aut@@ Nick Garza @@aut@@ Steven Kornblau @@aut@@ Victor X. Jin @@aut@@
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Aberrant AS plays an important role in regulating various diseases, including cancers. Methods In this study, we integrated AS events derived from RNA-seq with H3K79me2 ChIP-seq data across 34 different normal and cancer cell types and found the higher enrichment of H3K79me2 in two AS types, skipping exon (SE) and alternative 3′ splice site (A3SS). Results Interestingly, by applying self-organizing map (SOM) clustering, we unveiled two clusters mainly comprised of blood cancer cell types with a strong correlation between H3K79me2 and SE. Remarkably, the expression of transcripts associated with SE was not significantly different from that of those not associated with SE, indicating the involvement of H3K79me2 in splicing has little impact on full mRNA transcription. We further showed that the deletion of DOT1L1, the sole H3K79 methyltransferase, impeded leukemia cell proliferation as well as switched exon skipping to the inclusion isoform in two MLL-rearranged acute myeloid leukemia cell lines. Our data demonstrate H3K79me2 was involved in mediating SE processing, which might in turn influence transformation and disease progression in leukemias. 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callnumber-first	Q - Science
author	Tianbao Li
spellingShingle	Tianbao Li misc QH426-470 misc Alternative Splicing misc H3K79me2 misc DOT1L misc AML misc Medicine misc R misc Genetics Integrative analysis reveals functional and regulatory roles of H3K79me2 in mediating alternative splicing
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topic_title	QH426-470 Integrative analysis reveals functional and regulatory roles of H3K79me2 in mediating alternative splicing Alternative Splicing H3K79me2 DOT1L AML
topic	misc QH426-470 misc Alternative Splicing misc H3K79me2 misc DOT1L misc AML misc Medicine misc R misc Genetics
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title	Integrative analysis reveals functional and regulatory roles of H3K79me2 in mediating alternative splicing
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title_full	Integrative analysis reveals functional and regulatory roles of H3K79me2 in mediating alternative splicing
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title_sort	integrative analysis reveals functional and regulatory roles of h3k79me2 in mediating alternative splicing
callnumber	QH426-470
title_auth	Integrative analysis reveals functional and regulatory roles of H3K79me2 in mediating alternative splicing
abstract	Abstract Background Accumulating evidence suggests alternative splicing (AS) is a co-transcriptional splicing process not only controlled by RNA-binding splicing factors, but also mediated by epigenetic regulators, such as chromatin structure, nucleosome density, and histone modification. Aberrant AS plays an important role in regulating various diseases, including cancers. Methods In this study, we integrated AS events derived from RNA-seq with H3K79me2 ChIP-seq data across 34 different normal and cancer cell types and found the higher enrichment of H3K79me2 in two AS types, skipping exon (SE) and alternative 3′ splice site (A3SS). Results Interestingly, by applying self-organizing map (SOM) clustering, we unveiled two clusters mainly comprised of blood cancer cell types with a strong correlation between H3K79me2 and SE. Remarkably, the expression of transcripts associated with SE was not significantly different from that of those not associated with SE, indicating the involvement of H3K79me2 in splicing has little impact on full mRNA transcription. We further showed that the deletion of DOT1L1, the sole H3K79 methyltransferase, impeded leukemia cell proliferation as well as switched exon skipping to the inclusion isoform in two MLL-rearranged acute myeloid leukemia cell lines. Our data demonstrate H3K79me2 was involved in mediating SE processing, which might in turn influence transformation and disease progression in leukemias. Conclusions Collectively, our work for the first time reveals that H3K79me2 plays functional and regulatory roles through a co-transcriptional splicing mechanism.
abstractGer	Abstract Background Accumulating evidence suggests alternative splicing (AS) is a co-transcriptional splicing process not only controlled by RNA-binding splicing factors, but also mediated by epigenetic regulators, such as chromatin structure, nucleosome density, and histone modification. Aberrant AS plays an important role in regulating various diseases, including cancers. Methods In this study, we integrated AS events derived from RNA-seq with H3K79me2 ChIP-seq data across 34 different normal and cancer cell types and found the higher enrichment of H3K79me2 in two AS types, skipping exon (SE) and alternative 3′ splice site (A3SS). Results Interestingly, by applying self-organizing map (SOM) clustering, we unveiled two clusters mainly comprised of blood cancer cell types with a strong correlation between H3K79me2 and SE. Remarkably, the expression of transcripts associated with SE was not significantly different from that of those not associated with SE, indicating the involvement of H3K79me2 in splicing has little impact on full mRNA transcription. We further showed that the deletion of DOT1L1, the sole H3K79 methyltransferase, impeded leukemia cell proliferation as well as switched exon skipping to the inclusion isoform in two MLL-rearranged acute myeloid leukemia cell lines. Our data demonstrate H3K79me2 was involved in mediating SE processing, which might in turn influence transformation and disease progression in leukemias. Conclusions Collectively, our work for the first time reveals that H3K79me2 plays functional and regulatory roles through a co-transcriptional splicing mechanism.
abstract_unstemmed	Abstract Background Accumulating evidence suggests alternative splicing (AS) is a co-transcriptional splicing process not only controlled by RNA-binding splicing factors, but also mediated by epigenetic regulators, such as chromatin structure, nucleosome density, and histone modification. Aberrant AS plays an important role in regulating various diseases, including cancers. Methods In this study, we integrated AS events derived from RNA-seq with H3K79me2 ChIP-seq data across 34 different normal and cancer cell types and found the higher enrichment of H3K79me2 in two AS types, skipping exon (SE) and alternative 3′ splice site (A3SS). Results Interestingly, by applying self-organizing map (SOM) clustering, we unveiled two clusters mainly comprised of blood cancer cell types with a strong correlation between H3K79me2 and SE. Remarkably, the expression of transcripts associated with SE was not significantly different from that of those not associated with SE, indicating the involvement of H3K79me2 in splicing has little impact on full mRNA transcription. We further showed that the deletion of DOT1L1, the sole H3K79 methyltransferase, impeded leukemia cell proliferation as well as switched exon skipping to the inclusion isoform in two MLL-rearranged acute myeloid leukemia cell lines. Our data demonstrate H3K79me2 was involved in mediating SE processing, which might in turn influence transformation and disease progression in leukemias. Conclusions Collectively, our work for the first time reveals that H3K79me2 plays functional and regulatory roles through a co-transcriptional splicing mechanism.
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title_short	Integrative analysis reveals functional and regulatory roles of H3K79me2 in mediating alternative splicing
url	https://doi.org/10.1186/s13073-018-0538-1 https://doaj.org/article/1079512ea298478180a989a65398fb2e http://link.springer.com/article/10.1186/s13073-018-0538-1 https://doaj.org/toc/1756-994X
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up_date	2024-07-03T22:20:00.988Z
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We further showed that the deletion of DOT1L1, the sole H3K79 methyltransferase, impeded leukemia cell proliferation as well as switched exon skipping to the inclusion isoform in two MLL-rearranged acute myeloid leukemia cell lines. Our data demonstrate H3K79me2 was involved in mediating SE processing, which might in turn influence transformation and disease progression in leukemias. 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Integrative analysis reveals functional and regulatory roles of H3K79me2 in mediating alternative splicing

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