UTX condensation underlies its tumour-suppressive activity
UTX (also known as KDM6A ) encodes a histone H3K27 demethylase and is an important tumour suppressor that is frequently mutated in human cancers 1 . However, as the demethylase activity of UTX is often dispensable for mediating tumour suppression and developmental regulation 2 – 8 , the underlying m...
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| Veröffentlicht in: | Nature (London) 2021-09, Vol.597 (7878), p.726-731 |
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| creator | Shi, Bi Li, Wei Song, Yansu Wang, Zhenjia Ju, Rui Ulman, Aleksandra Hu, Jing Palomba, Francesco Zhao, Yanfang Le, John Philip Jarrard, William Dimoff, David Digman, Michelle A. Gratton, Enrico Zang, Chongzhi Jiang, Hao |
| description | UTX
(also known as
KDM6A
) encodes a histone H3K27 demethylase and is an important tumour suppressor that is frequently mutated in human cancers
1
. However, as the demethylase activity of UTX is often dispensable for mediating tumour suppression and developmental regulation
2
–
8
, the underlying molecular activity of UTX remains unknown. Here we show that phase separation of UTX underlies its chromatin-regulatory activity in tumour suppression. A core intrinsically disordered region (cIDR) of UTX forms phase-separated liquid condensates, and cIDR loss caused by the most frequent cancer mutation of UTX is mainly responsible for abolishing tumour suppression. Deletion, mutagenesis and replacement assays of the intrinsically disordered region demonstrate a critical role of UTX condensation in tumour suppression and embryonic stem cell differentiation. As shown by reconstitution in vitro and engineered systems in cells, UTX recruits the histone methyltransferase MLL4 (also known as KMT2D) to the same condensates and enriches the H3K4 methylation activity of MLL4. Moreover, UTX regulates genome-wide histone modifications and high-order chromatin interactions in a condensation-dependent manner. We also found that UTY, the Y chromosome homologue of UTX with weaker tumour-suppressive activity, forms condensates with reduced molecular dynamics. These studies demonstrate a crucial biological function of liquid condensates with proper material states in enabling the tumour-suppressive activity of a chromatin regulator.
Phase separation properties are a major determinant of UTX activity in chromatin regulation in tumour suppression, and are dependent on a core intrinsically disordered region of the protein. |
| doi_str_mv | 10.1038/s41586-021-03903-7 |
| format | Article |
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(also known as
KDM6A
) encodes a histone H3K27 demethylase and is an important tumour suppressor that is frequently mutated in human cancers
1
. However, as the demethylase activity of UTX is often dispensable for mediating tumour suppression and developmental regulation
2
–
8
, the underlying molecular activity of UTX remains unknown. Here we show that phase separation of UTX underlies its chromatin-regulatory activity in tumour suppression. A core intrinsically disordered region (cIDR) of UTX forms phase-separated liquid condensates, and cIDR loss caused by the most frequent cancer mutation of UTX is mainly responsible for abolishing tumour suppression. Deletion, mutagenesis and replacement assays of the intrinsically disordered region demonstrate a critical role of UTX condensation in tumour suppression and embryonic stem cell differentiation. As shown by reconstitution in vitro and engineered systems in cells, UTX recruits the histone methyltransferase MLL4 (also known as KMT2D) to the same condensates and enriches the H3K4 methylation activity of MLL4. Moreover, UTX regulates genome-wide histone modifications and high-order chromatin interactions in a condensation-dependent manner. We also found that UTY, the Y chromosome homologue of UTX with weaker tumour-suppressive activity, forms condensates with reduced molecular dynamics. These studies demonstrate a crucial biological function of liquid condensates with proper material states in enabling the tumour-suppressive activity of a chromatin regulator.
Phase separation properties are a major determinant of UTX activity in chromatin regulation in tumour suppression, and are dependent on a core intrinsically disordered region of the protein.</description><identifier>ISSN: 0028-0836</identifier><identifier>EISSN: 1476-4687</identifier><identifier>DOI: 10.1038/s41586-021-03903-7</identifier><identifier>PMID: 34526716</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>38 ; 38/35 ; 38/39 ; 631/337/176 ; 631/45/612/100/2285 ; 631/57/2269 ; 631/67/1244 ; 82 ; 82/83 ; Amino acids ; Animals ; Cell Differentiation ; Chromatin ; Cloning ; Condensates ; Condensation ; Differentiation (biology) ; DNA methylation ; DNA-Binding Proteins - metabolism ; Embryonic Stem Cells - cytology ; Gene deletion ; Genes ; Genes, Tumor Suppressor ; Genomes ; HEK293 Cells ; Histone Demethylases - genetics ; Histone methyltransferase ; Histones ; Homology ; Humanities and Social Sciences ; Humans ; Intrinsically Disordered Proteins - genetics ; Leukemia ; Mice ; Molecular dynamics ; Morphology ; multidisciplinary ; Mutagenesis ; Mutation ; Neoplasm Proteins - metabolism ; Pancreatic cancer ; Phase separation ; Physiological aspects ; Protein Processing, Post-Translational ; Proteins ; Science ; Science (multidisciplinary) ; Stem cells ; THP-1 Cells ; Tumor suppressor genes ; Tumors</subject><ispartof>Nature (London), 2021-09, Vol.597 (7878), p.726-731</ispartof><rights>The Author(s), under exclusive licence to Springer Nature Limited 2021</rights><rights>2021. The Author(s), under exclusive licence to Springer Nature Limited.</rights><rights>COPYRIGHT 2021 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Sep 30, 2021</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c640t-f1bf90c8e1760614023454b589bd94cac32f4efcbab79a5da736f20ae77a4e983</citedby><cites>FETCH-LOGICAL-c640t-f1bf90c8e1760614023454b589bd94cac32f4efcbab79a5da736f20ae77a4e983</cites><orcidid>0000-0003-3566-5793 ; 0000-0003-4611-7100 ; 0000-0002-2249-2961 ; 0000-0002-8077-6890 ; 0000-0003-1890-9813</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/s41586-021-03903-7$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/s41586-021-03903-7$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>230,314,777,781,882,27905,27906,41469,42538,51300</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34526716$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Shi, Bi</creatorcontrib><creatorcontrib>Li, Wei</creatorcontrib><creatorcontrib>Song, Yansu</creatorcontrib><creatorcontrib>Wang, Zhenjia</creatorcontrib><creatorcontrib>Ju, Rui</creatorcontrib><creatorcontrib>Ulman, Aleksandra</creatorcontrib><creatorcontrib>Hu, Jing</creatorcontrib><creatorcontrib>Palomba, Francesco</creatorcontrib><creatorcontrib>Zhao, Yanfang</creatorcontrib><creatorcontrib>Le, John Philip</creatorcontrib><creatorcontrib>Jarrard, William</creatorcontrib><creatorcontrib>Dimoff, David</creatorcontrib><creatorcontrib>Digman, Michelle A.</creatorcontrib><creatorcontrib>Gratton, Enrico</creatorcontrib><creatorcontrib>Zang, Chongzhi</creatorcontrib><creatorcontrib>Jiang, Hao</creatorcontrib><title>UTX condensation underlies its tumour-suppressive activity</title><title>Nature (London)</title><addtitle>Nature</addtitle><addtitle>Nature</addtitle><description>UTX
(also known as
KDM6A
) encodes a histone H3K27 demethylase and is an important tumour suppressor that is frequently mutated in human cancers
1
. However, as the demethylase activity of UTX is often dispensable for mediating tumour suppression and developmental regulation
2
–
8
, the underlying molecular activity of UTX remains unknown. Here we show that phase separation of UTX underlies its chromatin-regulatory activity in tumour suppression. A core intrinsically disordered region (cIDR) of UTX forms phase-separated liquid condensates, and cIDR loss caused by the most frequent cancer mutation of UTX is mainly responsible for abolishing tumour suppression. Deletion, mutagenesis and replacement assays of the intrinsically disordered region demonstrate a critical role of UTX condensation in tumour suppression and embryonic stem cell differentiation. As shown by reconstitution in vitro and engineered systems in cells, UTX recruits the histone methyltransferase MLL4 (also known as KMT2D) to the same condensates and enriches the H3K4 methylation activity of MLL4. Moreover, UTX regulates genome-wide histone modifications and high-order chromatin interactions in a condensation-dependent manner. We also found that UTY, the Y chromosome homologue of UTX with weaker tumour-suppressive activity, forms condensates with reduced molecular dynamics. These studies demonstrate a crucial biological function of liquid condensates with proper material states in enabling the tumour-suppressive activity of a chromatin regulator.
Phase separation properties are a major determinant of UTX activity in chromatin regulation in tumour suppression, and are dependent on a core intrinsically disordered region of the protein.</description><subject>38</subject><subject>38/35</subject><subject>38/39</subject><subject>631/337/176</subject><subject>631/45/612/100/2285</subject><subject>631/57/2269</subject><subject>631/67/1244</subject><subject>82</subject><subject>82/83</subject><subject>Amino acids</subject><subject>Animals</subject><subject>Cell Differentiation</subject><subject>Chromatin</subject><subject>Cloning</subject><subject>Condensates</subject><subject>Condensation</subject><subject>Differentiation (biology)</subject><subject>DNA methylation</subject><subject>DNA-Binding Proteins - metabolism</subject><subject>Embryonic Stem Cells - cytology</subject><subject>Gene deletion</subject><subject>Genes</subject><subject>Genes, Tumor Suppressor</subject><subject>Genomes</subject><subject>HEK293 Cells</subject><subject>Histone Demethylases - genetics</subject><subject>Histone methyltransferase</subject><subject>Histones</subject><subject>Homology</subject><subject>Humanities and Social Sciences</subject><subject>Humans</subject><subject>Intrinsically Disordered Proteins - genetics</subject><subject>Leukemia</subject><subject>Mice</subject><subject>Molecular dynamics</subject><subject>Morphology</subject><subject>multidisciplinary</subject><subject>Mutagenesis</subject><subject>Mutation</subject><subject>Neoplasm Proteins - metabolism</subject><subject>Pancreatic cancer</subject><subject>Phase separation</subject><subject>Physiological aspects</subject><subject>Protein Processing, Post-Translational</subject><subject>Proteins</subject><subject>Science</subject><subject>Science (multidisciplinary)</subject><subject>Stem cells</subject><subject>THP-1 Cells</subject><subject>Tumor suppressor 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condensation underlies its tumour-suppressive activity</title><author>Shi, Bi ; Li, Wei ; Song, Yansu ; Wang, Zhenjia ; Ju, Rui ; Ulman, Aleksandra ; Hu, Jing ; Palomba, Francesco ; Zhao, Yanfang ; Le, John Philip ; Jarrard, William ; Dimoff, David ; Digman, Michelle A. ; Gratton, Enrico ; Zang, Chongzhi ; Jiang, Hao</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c640t-f1bf90c8e1760614023454b589bd94cac32f4efcbab79a5da736f20ae77a4e983</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>38</topic><topic>38/35</topic><topic>38/39</topic><topic>631/337/176</topic><topic>631/45/612/100/2285</topic><topic>631/57/2269</topic><topic>631/67/1244</topic><topic>82</topic><topic>82/83</topic><topic>Amino acids</topic><topic>Animals</topic><topic>Cell Differentiation</topic><topic>Chromatin</topic><topic>Cloning</topic><topic>Condensates</topic><topic>Condensation</topic><topic>Differentiation (biology)</topic><topic>DNA methylation</topic><topic>DNA-Binding Proteins - metabolism</topic><topic>Embryonic Stem Cells - cytology</topic><topic>Gene deletion</topic><topic>Genes</topic><topic>Genes, Tumor Suppressor</topic><topic>Genomes</topic><topic>HEK293 Cells</topic><topic>Histone Demethylases - genetics</topic><topic>Histone methyltransferase</topic><topic>Histones</topic><topic>Homology</topic><topic>Humanities and Social Sciences</topic><topic>Humans</topic><topic>Intrinsically Disordered Proteins - genetics</topic><topic>Leukemia</topic><topic>Mice</topic><topic>Molecular dynamics</topic><topic>Morphology</topic><topic>multidisciplinary</topic><topic>Mutagenesis</topic><topic>Mutation</topic><topic>Neoplasm Proteins - metabolism</topic><topic>Pancreatic cancer</topic><topic>Phase separation</topic><topic>Physiological aspects</topic><topic>Protein Processing, Post-Translational</topic><topic>Proteins</topic><topic>Science</topic><topic>Science (multidisciplinary)</topic><topic>Stem cells</topic><topic>THP-1 Cells</topic><topic>Tumor suppressor genes</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Shi, Bi</creatorcontrib><creatorcontrib>Li, Wei</creatorcontrib><creatorcontrib>Song, Yansu</creatorcontrib><creatorcontrib>Wang, Zhenjia</creatorcontrib><creatorcontrib>Ju, Rui</creatorcontrib><creatorcontrib>Ulman, Aleksandra</creatorcontrib><creatorcontrib>Hu, Jing</creatorcontrib><creatorcontrib>Palomba, Francesco</creatorcontrib><creatorcontrib>Zhao, Yanfang</creatorcontrib><creatorcontrib>Le, John Philip</creatorcontrib><creatorcontrib>Jarrard, William</creatorcontrib><creatorcontrib>Dimoff, David</creatorcontrib><creatorcontrib>Digman, Michelle A.</creatorcontrib><creatorcontrib>Gratton, Enrico</creatorcontrib><creatorcontrib>Zang, 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Chongzhi</au><au>Jiang, Hao</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>UTX condensation underlies its tumour-suppressive activity</atitle><jtitle>Nature (London)</jtitle><stitle>Nature</stitle><addtitle>Nature</addtitle><date>2021-09-30</date><risdate>2021</risdate><volume>597</volume><issue>7878</issue><spage>726</spage><epage>731</epage><pages>726-731</pages><issn>0028-0836</issn><eissn>1476-4687</eissn><abstract>UTX
(also known as
KDM6A
) encodes a histone H3K27 demethylase and is an important tumour suppressor that is frequently mutated in human cancers
1
. However, as the demethylase activity of UTX is often dispensable for mediating tumour suppression and developmental regulation
2
–
8
, the underlying molecular activity of UTX remains unknown. Here we show that phase separation of UTX underlies its chromatin-regulatory activity in tumour suppression. A core intrinsically disordered region (cIDR) of UTX forms phase-separated liquid condensates, and cIDR loss caused by the most frequent cancer mutation of UTX is mainly responsible for abolishing tumour suppression. Deletion, mutagenesis and replacement assays of the intrinsically disordered region demonstrate a critical role of UTX condensation in tumour suppression and embryonic stem cell differentiation. As shown by reconstitution in vitro and engineered systems in cells, UTX recruits the histone methyltransferase MLL4 (also known as KMT2D) to the same condensates and enriches the H3K4 methylation activity of MLL4. Moreover, UTX regulates genome-wide histone modifications and high-order chromatin interactions in a condensation-dependent manner. We also found that UTY, the Y chromosome homologue of UTX with weaker tumour-suppressive activity, forms condensates with reduced molecular dynamics. These studies demonstrate a crucial biological function of liquid condensates with proper material states in enabling the tumour-suppressive activity of a chromatin regulator.
Phase separation properties are a major determinant of UTX activity in chromatin regulation in tumour suppression, and are dependent on a core intrinsically disordered region of the protein.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>34526716</pmid><doi>10.1038/s41586-021-03903-7</doi><tpages>6</tpages><orcidid>https://orcid.org/0000-0003-3566-5793</orcidid><orcidid>https://orcid.org/0000-0003-4611-7100</orcidid><orcidid>https://orcid.org/0000-0002-2249-2961</orcidid><orcidid>https://orcid.org/0000-0002-8077-6890</orcidid><orcidid>https://orcid.org/0000-0003-1890-9813</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0028-0836 |
| ispartof | Nature (London), 2021-09, Vol.597 (7878), p.726-731 |
| issn | 0028-0836 1476-4687 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_9008583 |
| source | MEDLINE; Nature Journals Online; SpringerLink Journals - AutoHoldings |
| subjects | 38 38/35 38/39 631/337/176 631/45/612/100/2285 631/57/2269 631/67/1244 82 82/83 Amino acids Animals Cell Differentiation Chromatin Cloning Condensates Condensation Differentiation (biology) DNA methylation DNA-Binding Proteins - metabolism Embryonic Stem Cells - cytology Gene deletion Genes Genes, Tumor Suppressor Genomes HEK293 Cells Histone Demethylases - genetics Histone methyltransferase Histones Homology Humanities and Social Sciences Humans Intrinsically Disordered Proteins - genetics Leukemia Mice Molecular dynamics Morphology multidisciplinary Mutagenesis Mutation Neoplasm Proteins - metabolism Pancreatic cancer Phase separation Physiological aspects Protein Processing, Post-Translational Proteins Science Science (multidisciplinary) Stem cells THP-1 Cells Tumor suppressor genes Tumors |
| title | UTX condensation underlies its tumour-suppressive activity |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-17T13%3A40%3A46IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=UTX%20condensation%20underlies%20its%20tumour-suppressive%20activity&rft.jtitle=Nature%20(London)&rft.au=Shi,%20Bi&rft.date=2021-09-30&rft.volume=597&rft.issue=7878&rft.spage=726&rft.epage=731&rft.pages=726-731&rft.issn=0028-0836&rft.eissn=1476-4687&rft_id=info:doi/10.1038/s41586-021-03903-7&rft_dat=%3Cgale_pubme%3EA677261629%3C/gale_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2719404750&rft_id=info:pmid/34526716&rft_galeid=A677261629&rfr_iscdi=true |