PhpCNF-Y transcription factor infiltrates heterochromatin to generate cryptic intron-containing transcripts crucial for small RNA production
Abstract The assembly of repressive heterochromatin in eukaryotic genomes is crucial for silencing lineage-inappropriate genes and repetitive DNA elements. Paradoxically, transcription of repetitive elements within constitutive heterochromatin domains is required for RNA-based mechanisms, such as th...
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-55736-3 |
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| author | Manjit Kumar Srivastav H. Diego Folco Patroula Nathanailidou Anupa T Anil Drisya Vijayakumari Shweta Jain Jothy Dhakshnamoorthy Maura O’Neill Thorkell Andresson David Wheeler Shiv I. S. Grewal |
| author_facet | Manjit Kumar Srivastav H. Diego Folco Patroula Nathanailidou Anupa T Anil Drisya Vijayakumari Shweta Jain Jothy Dhakshnamoorthy Maura O’Neill Thorkell Andresson David Wheeler Shiv I. S. Grewal |
| author_sort | Manjit Kumar Srivastav |
| collection | DOAJ |
| description | Abstract The assembly of repressive heterochromatin in eukaryotic genomes is crucial for silencing lineage-inappropriate genes and repetitive DNA elements. Paradoxically, transcription of repetitive elements within constitutive heterochromatin domains is required for RNA-based mechanisms, such as the RNAi pathway, to target heterochromatin assembly proteins. However, the mechanism by which heterochromatic repeats are transcribed has been unclear. Using fission yeast, we show that the conserved trimeric transcription factor (TF) PhpCNF-Y complex can infiltrate constitutive heterochromatin via its histone-fold domains to transcribe repeat elements. PhpCNF-Y collaborates with a Zn-finger containing TF to bind repeat promoter regions with CCAAT boxes. Mutating either the TFs or the CCAAT binding site disrupts the transcription of heterochromatic repeats. Although repeat elements are transcribed from both strands, PhpCNF-Y-dependent transcripts originate from only one strand. These TF-driven transcripts contain multiple cryptic introns which are required for the generation of small interfering RNAs (siRNAs) via a mechanism involving the spliceosome and RNAi machinery. Our analyses show that siRNA production by this TF-mediated transcription pathway is critical for heterochromatin nucleation at target repeat loci. This study reveals a mechanism by which heterochromatic repeats are transcribed, initiating their own silencing by triggering a primary cascade that produces siRNAs necessary for heterochromatin nucleation. |
| format | Article |
| id | doaj-art-afb0766965844f518e812f62b9b8d59e |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-afb0766965844f518e812f62b9b8d59e2025-01-05T12:37:45ZengNature PortfolioNature Communications2041-17232025-01-0116111810.1038/s41467-024-55736-3PhpCNF-Y transcription factor infiltrates heterochromatin to generate cryptic intron-containing transcripts crucial for small RNA productionManjit Kumar Srivastav0H. Diego Folco1Patroula Nathanailidou2Anupa T Anil3Drisya Vijayakumari4Shweta Jain5Jothy Dhakshnamoorthy6Maura O’Neill7Thorkell Andresson8David Wheeler9Shiv I. S. Grewal10Laboratory of Biochemistry and Molecular Biology, National Cancer Institute, National Institutes of HealthLaboratory of Biochemistry and Molecular Biology, National Cancer Institute, National Institutes of HealthLaboratory of Biochemistry and Molecular Biology, National Cancer Institute, National Institutes of HealthLaboratory of Biochemistry and Molecular Biology, National Cancer Institute, National Institutes of HealthLaboratory of Biochemistry and Molecular Biology, National Cancer Institute, National Institutes of HealthLaboratory of Biochemistry and Molecular Biology, National Cancer Institute, National Institutes of HealthLaboratory of Biochemistry and Molecular Biology, National Cancer Institute, National Institutes of HealthCancer Research Technology Program, Frederick National Laboratory for Cancer ResearchCancer Research Technology Program, Frederick National Laboratory for Cancer ResearchLaboratory of Biochemistry and Molecular Biology, National Cancer Institute, National Institutes of HealthLaboratory of Biochemistry and Molecular Biology, National Cancer Institute, National Institutes of HealthAbstract The assembly of repressive heterochromatin in eukaryotic genomes is crucial for silencing lineage-inappropriate genes and repetitive DNA elements. Paradoxically, transcription of repetitive elements within constitutive heterochromatin domains is required for RNA-based mechanisms, such as the RNAi pathway, to target heterochromatin assembly proteins. However, the mechanism by which heterochromatic repeats are transcribed has been unclear. Using fission yeast, we show that the conserved trimeric transcription factor (TF) PhpCNF-Y complex can infiltrate constitutive heterochromatin via its histone-fold domains to transcribe repeat elements. PhpCNF-Y collaborates with a Zn-finger containing TF to bind repeat promoter regions with CCAAT boxes. Mutating either the TFs or the CCAAT binding site disrupts the transcription of heterochromatic repeats. Although repeat elements are transcribed from both strands, PhpCNF-Y-dependent transcripts originate from only one strand. These TF-driven transcripts contain multiple cryptic introns which are required for the generation of small interfering RNAs (siRNAs) via a mechanism involving the spliceosome and RNAi machinery. Our analyses show that siRNA production by this TF-mediated transcription pathway is critical for heterochromatin nucleation at target repeat loci. This study reveals a mechanism by which heterochromatic repeats are transcribed, initiating their own silencing by triggering a primary cascade that produces siRNAs necessary for heterochromatin nucleation.https://doi.org/10.1038/s41467-024-55736-3 |
| spellingShingle | Manjit Kumar Srivastav H. Diego Folco Patroula Nathanailidou Anupa T Anil Drisya Vijayakumari Shweta Jain Jothy Dhakshnamoorthy Maura O’Neill Thorkell Andresson David Wheeler Shiv I. S. Grewal PhpCNF-Y transcription factor infiltrates heterochromatin to generate cryptic intron-containing transcripts crucial for small RNA production Nature Communications |
| title | PhpCNF-Y transcription factor infiltrates heterochromatin to generate cryptic intron-containing transcripts crucial for small RNA production |
| title_full | PhpCNF-Y transcription factor infiltrates heterochromatin to generate cryptic intron-containing transcripts crucial for small RNA production |
| title_fullStr | PhpCNF-Y transcription factor infiltrates heterochromatin to generate cryptic intron-containing transcripts crucial for small RNA production |
| title_full_unstemmed | PhpCNF-Y transcription factor infiltrates heterochromatin to generate cryptic intron-containing transcripts crucial for small RNA production |
| title_short | PhpCNF-Y transcription factor infiltrates heterochromatin to generate cryptic intron-containing transcripts crucial for small RNA production |
| title_sort | phpcnf y transcription factor infiltrates heterochromatin to generate cryptic intron containing transcripts crucial for small rna production |
| url | https://doi.org/10.1038/s41467-024-55736-3 |
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