Emerin interacts with histone methyltransferases to regulate repressive chromatin at the nuclear periphery
X-Linked Emery-Dreifuss muscular dystrophy is caused by mutations in the gene encoding emerin. Emerin is an inner nuclear membrane protein important for repressive chromatin organization at the nuclear periphery. Myogenic differentiation is a tightly regulated process characterized by genomic reorga...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-10-01
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| Series: | Frontiers in Cell and Developmental Biology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2022.1007120/full |
| _version_ | 1811228240125100032 |
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| author | Nicholas Marano James M. Holaska |
| author_facet | Nicholas Marano James M. Holaska |
| author_sort | Nicholas Marano |
| collection | DOAJ |
| description | X-Linked Emery-Dreifuss muscular dystrophy is caused by mutations in the gene encoding emerin. Emerin is an inner nuclear membrane protein important for repressive chromatin organization at the nuclear periphery. Myogenic differentiation is a tightly regulated process characterized by genomic reorganization leading to coordinated temporal expression of key transcription factors, including MyoD, Pax7, and Myf5. Emerin was shown to interact with repressive histone modification machinery, including HDAC3 and EZH2. Using emerin-null myogenic progenitor cells we established several EDMD-causing emerin mutant lines in the effort to understand how the functional interaction of emerin with HDAC3 regulates histone methyltransferase localization or function to organize repressive chromatin at the nuclear periphery. We found that, in addition to its interaction with HDAC3, emerin interacts with the histone methyltransferases EZH2 and G9a in myogenic progenitor cells. Further, we show enhanced binding of emerin HDAC3-binding mutants S54F and Q133H to EZH2 and G9a. Treatment with small molecule inhibitors of EZH2 and G9a reduced H3K9me2 or H3K27me3 throughout differentiation. EZH2 and G9a inhibitors impaired cell cycle withdrawal, differentiation commitment, and myotube formation in wildtype progenitors, while they had no effect on emerin-null progenitors. Interestingly, these inhibitors exacerbated the impaired differentiation of emerin S54F and Q133H mutant progenitors. Collectively, these results suggest the functional interaction between emerin and HDAC3, EZH2, and G9a are important for myogenic differentiation. |
| first_indexed | 2024-04-12T09:54:53Z |
| format | Article |
| id | doaj.art-f4b65b35a2604bada541343d89285a05 |
| institution | Directory Open Access Journal |
| issn | 2296-634X |
| language | English |
| last_indexed | 2024-04-12T09:54:53Z |
| publishDate | 2022-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cell and Developmental Biology |
| spelling | doaj.art-f4b65b35a2604bada541343d89285a052022-12-22T03:37:43ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2022-10-011010.3389/fcell.2022.10071201007120Emerin interacts with histone methyltransferases to regulate repressive chromatin at the nuclear peripheryNicholas MaranoJames M. HolaskaX-Linked Emery-Dreifuss muscular dystrophy is caused by mutations in the gene encoding emerin. Emerin is an inner nuclear membrane protein important for repressive chromatin organization at the nuclear periphery. Myogenic differentiation is a tightly regulated process characterized by genomic reorganization leading to coordinated temporal expression of key transcription factors, including MyoD, Pax7, and Myf5. Emerin was shown to interact with repressive histone modification machinery, including HDAC3 and EZH2. Using emerin-null myogenic progenitor cells we established several EDMD-causing emerin mutant lines in the effort to understand how the functional interaction of emerin with HDAC3 regulates histone methyltransferase localization or function to organize repressive chromatin at the nuclear periphery. We found that, in addition to its interaction with HDAC3, emerin interacts with the histone methyltransferases EZH2 and G9a in myogenic progenitor cells. Further, we show enhanced binding of emerin HDAC3-binding mutants S54F and Q133H to EZH2 and G9a. Treatment with small molecule inhibitors of EZH2 and G9a reduced H3K9me2 or H3K27me3 throughout differentiation. EZH2 and G9a inhibitors impaired cell cycle withdrawal, differentiation commitment, and myotube formation in wildtype progenitors, while they had no effect on emerin-null progenitors. Interestingly, these inhibitors exacerbated the impaired differentiation of emerin S54F and Q133H mutant progenitors. Collectively, these results suggest the functional interaction between emerin and HDAC3, EZH2, and G9a are important for myogenic differentiation.https://www.frontiersin.org/articles/10.3389/fcell.2022.1007120/fullemerinEmery-Dreifuss muscular dystrophymyogenic differentiationrepressive chromatinEZH2G9a |
| spellingShingle | Nicholas Marano James M. Holaska Emerin interacts with histone methyltransferases to regulate repressive chromatin at the nuclear periphery Frontiers in Cell and Developmental Biology emerin Emery-Dreifuss muscular dystrophy myogenic differentiation repressive chromatin EZH2 G9a |
| title | Emerin interacts with histone methyltransferases to regulate repressive chromatin at the nuclear periphery |
| title_full | Emerin interacts with histone methyltransferases to regulate repressive chromatin at the nuclear periphery |
| title_fullStr | Emerin interacts with histone methyltransferases to regulate repressive chromatin at the nuclear periphery |
| title_full_unstemmed | Emerin interacts with histone methyltransferases to regulate repressive chromatin at the nuclear periphery |
| title_short | Emerin interacts with histone methyltransferases to regulate repressive chromatin at the nuclear periphery |
| title_sort | emerin interacts with histone methyltransferases to regulate repressive chromatin at the nuclear periphery |
| topic | emerin Emery-Dreifuss muscular dystrophy myogenic differentiation repressive chromatin EZH2 G9a |
| url | https://www.frontiersin.org/articles/10.3389/fcell.2022.1007120/full |
| work_keys_str_mv | AT nicholasmarano emerininteractswithhistonemethyltransferasestoregulaterepressivechromatinatthenuclearperiphery AT jamesmholaska emerininteractswithhistonemethyltransferasestoregulaterepressivechromatinatthenuclearperiphery |