Cell-type differential targeting of SETDB1 prevents aberrant CTCF binding, chromatin looping, and cis-regulatory interactions
Abstract SETDB1 is an essential histone methyltransferase that deposits histone H3 lysine 9 trimethylation (H3K9me3) to transcriptionally repress genes and repetitive elements. The function of differential H3K9me3 enrichment between cell-types remains unclear. Here, we demonstrate mutual exclusivity...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-44578-0 |
| _version_ | 1797363044380049408 |
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| author | Phoebe Lut Fei Tam Ming Fung Cheung Lu Yan Chan Danny Leung |
| author_facet | Phoebe Lut Fei Tam Ming Fung Cheung Lu Yan Chan Danny Leung |
| author_sort | Phoebe Lut Fei Tam |
| collection | DOAJ |
| description | Abstract SETDB1 is an essential histone methyltransferase that deposits histone H3 lysine 9 trimethylation (H3K9me3) to transcriptionally repress genes and repetitive elements. The function of differential H3K9me3 enrichment between cell-types remains unclear. Here, we demonstrate mutual exclusivity of H3K9me3 and CTCF across mouse tissues from different developmental timepoints. We analyze SETDB1 depleted cells and discover that H3K9me3 prevents aberrant CTCF binding independently of DNA methylation and H3K9me2. Such sites are enriched with SINE B2 retrotransposons. Moreover, analysis of higher-order genome architecture reveals that large chromatin structures including topologically associated domains and subnuclear compartments, remain intact in SETDB1 depleted cells. However, chromatin loops and local 3D interactions are disrupted, leading to transcriptional changes by modifying pre-existing chromatin landscapes. Specific genes with altered expression show differential interactions with dysregulated cis-regulatory elements. Collectively, we find that cell-type specific targets of SETDB1 maintain cellular identities by modulating CTCF binding, which shape nuclear architecture and transcriptomic networks. |
| first_indexed | 2024-03-08T16:16:11Z |
| format | Article |
| id | doaj.art-4247321103df4c3bba07fe656dcf790f |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-08T16:16:11Z |
| publishDate | 2024-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-4247321103df4c3bba07fe656dcf790f2024-01-07T12:34:23ZengNature PortfolioNature Communications2041-17232024-01-0115111510.1038/s41467-023-44578-0Cell-type differential targeting of SETDB1 prevents aberrant CTCF binding, chromatin looping, and cis-regulatory interactionsPhoebe Lut Fei Tam0Ming Fung Cheung1Lu Yan Chan2Danny Leung3Division of Life Science, The Hong Kong University of Science and Technology, Clear Water BayDivision of Life Science, The Hong Kong University of Science and Technology, Clear Water BayDivision of Life Science, The Hong Kong University of Science and Technology, Clear Water BayDivision of Life Science, The Hong Kong University of Science and Technology, Clear Water BayAbstract SETDB1 is an essential histone methyltransferase that deposits histone H3 lysine 9 trimethylation (H3K9me3) to transcriptionally repress genes and repetitive elements. The function of differential H3K9me3 enrichment between cell-types remains unclear. Here, we demonstrate mutual exclusivity of H3K9me3 and CTCF across mouse tissues from different developmental timepoints. We analyze SETDB1 depleted cells and discover that H3K9me3 prevents aberrant CTCF binding independently of DNA methylation and H3K9me2. Such sites are enriched with SINE B2 retrotransposons. Moreover, analysis of higher-order genome architecture reveals that large chromatin structures including topologically associated domains and subnuclear compartments, remain intact in SETDB1 depleted cells. However, chromatin loops and local 3D interactions are disrupted, leading to transcriptional changes by modifying pre-existing chromatin landscapes. Specific genes with altered expression show differential interactions with dysregulated cis-regulatory elements. Collectively, we find that cell-type specific targets of SETDB1 maintain cellular identities by modulating CTCF binding, which shape nuclear architecture and transcriptomic networks.https://doi.org/10.1038/s41467-023-44578-0 |
| spellingShingle | Phoebe Lut Fei Tam Ming Fung Cheung Lu Yan Chan Danny Leung Cell-type differential targeting of SETDB1 prevents aberrant CTCF binding, chromatin looping, and cis-regulatory interactions Nature Communications |
| title | Cell-type differential targeting of SETDB1 prevents aberrant CTCF binding, chromatin looping, and cis-regulatory interactions |
| title_full | Cell-type differential targeting of SETDB1 prevents aberrant CTCF binding, chromatin looping, and cis-regulatory interactions |
| title_fullStr | Cell-type differential targeting of SETDB1 prevents aberrant CTCF binding, chromatin looping, and cis-regulatory interactions |
| title_full_unstemmed | Cell-type differential targeting of SETDB1 prevents aberrant CTCF binding, chromatin looping, and cis-regulatory interactions |
| title_short | Cell-type differential targeting of SETDB1 prevents aberrant CTCF binding, chromatin looping, and cis-regulatory interactions |
| title_sort | cell type differential targeting of setdb1 prevents aberrant ctcf binding chromatin looping and cis regulatory interactions |
| url | https://doi.org/10.1038/s41467-023-44578-0 |
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