Systematic identification of post-transcriptional regulatory modules
Abstract In our cells, a limited number of RNA binding proteins (RBPs) are responsible for all aspects of RNA metabolism across the entire transcriptome. To accomplish this, RBPs form regulatory units that act on specific target regulons. However, the landscape of RBP combinatorial interactions rema...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2024-09-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-52215-7 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850179030418980864 |
|---|---|
| author | Matvei Khoroshkin Andrey Buyan Martin Dodel Albertas Navickas Johnny Yu Fathima Trejo Anthony Doty Rithvik Baratam Shaopu Zhou Sean B. Lee Tanvi Joshi Kristle Garcia Benedict Choi Sohit Miglani Vishvak Subramanyam Hailey Modi Christopher Carpenter Daniel Markett M. Ryan Corces Faraz K. Mardakheh Ivan V. Kulakovskiy Hani Goodarzi |
| author_facet | Matvei Khoroshkin Andrey Buyan Martin Dodel Albertas Navickas Johnny Yu Fathima Trejo Anthony Doty Rithvik Baratam Shaopu Zhou Sean B. Lee Tanvi Joshi Kristle Garcia Benedict Choi Sohit Miglani Vishvak Subramanyam Hailey Modi Christopher Carpenter Daniel Markett M. Ryan Corces Faraz K. Mardakheh Ivan V. Kulakovskiy Hani Goodarzi |
| author_sort | Matvei Khoroshkin |
| collection | DOAJ |
| description | Abstract In our cells, a limited number of RNA binding proteins (RBPs) are responsible for all aspects of RNA metabolism across the entire transcriptome. To accomplish this, RBPs form regulatory units that act on specific target regulons. However, the landscape of RBP combinatorial interactions remains poorly explored. Here, we perform a systematic annotation of RBP combinatorial interactions via multimodal data integration. We build a large-scale map of RBP protein neighborhoods by generating in vivo proximity-dependent biotinylation datasets of 50 human RBPs. In parallel, we use CRISPR interference with single-cell readout to capture transcriptomic changes upon RBP knockdowns. By combining these physical and functional interaction readouts, along with the atlas of RBP mRNA targets from eCLIP assays, we generate an integrated map of functional RBP interactions. We then use this map to match RBPs to their context-specific functions and validate the predicted functions biochemically for four RBPs. This study provides a detailed map of RBP interactions and deconvolves them into distinct regulatory modules with annotated functions and target regulons. This multimodal and integrative framework provides a principled approach for studying post-transcriptional regulatory processes and enriches our understanding of their underlying mechanisms. |
| format | Article |
| id | doaj-art-e0a9c0d9b7a0471c8ee72df7e5f560df |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-09-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-e0a9c0d9b7a0471c8ee72df7e5f560df2025-08-20T02:18:35ZengNature PortfolioNature Communications2041-17232024-09-0115112110.1038/s41467-024-52215-7Systematic identification of post-transcriptional regulatory modulesMatvei Khoroshkin0Andrey Buyan1Martin Dodel2Albertas Navickas3Johnny Yu4Fathima Trejo5Anthony Doty6Rithvik Baratam7Shaopu Zhou8Sean B. Lee9Tanvi Joshi10Kristle Garcia11Benedict Choi12Sohit Miglani13Vishvak Subramanyam14Hailey Modi15Christopher Carpenter16Daniel Markett17M. Ryan Corces18Faraz K. Mardakheh19Ivan V. Kulakovskiy20Hani Goodarzi21Department of Biochemistry and Biophysics, University of California, San FranciscoInstitute of Protein Research, Russian Academy of SciencesCentre for Cancer Cell and Molecular Biology, Barts Cancer Institute, Queen Mary University of LondonDepartment of Biochemistry and Biophysics, University of California, San FranciscoDepartment of Biochemistry and Biophysics, University of California, San FranciscoCollege of Arts and Sciences, University of San FranciscoCollege of Arts and Sciences, University of San FranciscoDepartment of Biochemistry and Biophysics, University of California, San FranciscoDepartment of Biochemistry and Biophysics, University of California, San FranciscoDepartment of Biochemistry and Biophysics, University of California, San FranciscoDepartment of Biochemistry and Biophysics, University of California, San FranciscoDepartment of Biochemistry and Biophysics, University of California, San FranciscoDepartment of Biochemistry and Biophysics, University of California, San FranciscoDepartment of Biochemistry and Biophysics, University of California, San FranciscoDepartment of Biochemistry and Biophysics, University of California, San FranciscoGladstone Institute of Neurological DiseaseDepartment of Biochemistry and Biophysics, University of California, San FranciscoDepartment of Biochemistry and Biophysics, University of California, San FranciscoGladstone Institute of Neurological DiseaseCentre for Cancer Cell and Molecular Biology, Barts Cancer Institute, Queen Mary University of LondonInstitute of Protein Research, Russian Academy of SciencesDepartment of Biochemistry and Biophysics, University of California, San FranciscoAbstract In our cells, a limited number of RNA binding proteins (RBPs) are responsible for all aspects of RNA metabolism across the entire transcriptome. To accomplish this, RBPs form regulatory units that act on specific target regulons. However, the landscape of RBP combinatorial interactions remains poorly explored. Here, we perform a systematic annotation of RBP combinatorial interactions via multimodal data integration. We build a large-scale map of RBP protein neighborhoods by generating in vivo proximity-dependent biotinylation datasets of 50 human RBPs. In parallel, we use CRISPR interference with single-cell readout to capture transcriptomic changes upon RBP knockdowns. By combining these physical and functional interaction readouts, along with the atlas of RBP mRNA targets from eCLIP assays, we generate an integrated map of functional RBP interactions. We then use this map to match RBPs to their context-specific functions and validate the predicted functions biochemically for four RBPs. This study provides a detailed map of RBP interactions and deconvolves them into distinct regulatory modules with annotated functions and target regulons. This multimodal and integrative framework provides a principled approach for studying post-transcriptional regulatory processes and enriches our understanding of their underlying mechanisms.https://doi.org/10.1038/s41467-024-52215-7 |
| spellingShingle | Matvei Khoroshkin Andrey Buyan Martin Dodel Albertas Navickas Johnny Yu Fathima Trejo Anthony Doty Rithvik Baratam Shaopu Zhou Sean B. Lee Tanvi Joshi Kristle Garcia Benedict Choi Sohit Miglani Vishvak Subramanyam Hailey Modi Christopher Carpenter Daniel Markett M. Ryan Corces Faraz K. Mardakheh Ivan V. Kulakovskiy Hani Goodarzi Systematic identification of post-transcriptional regulatory modules Nature Communications |
| title | Systematic identification of post-transcriptional regulatory modules |
| title_full | Systematic identification of post-transcriptional regulatory modules |
| title_fullStr | Systematic identification of post-transcriptional regulatory modules |
| title_full_unstemmed | Systematic identification of post-transcriptional regulatory modules |
| title_short | Systematic identification of post-transcriptional regulatory modules |
| title_sort | systematic identification of post transcriptional regulatory modules |
| url | https://doi.org/10.1038/s41467-024-52215-7 |
| work_keys_str_mv | AT matveikhoroshkin systematicidentificationofposttranscriptionalregulatorymodules AT andreybuyan systematicidentificationofposttranscriptionalregulatorymodules AT martindodel systematicidentificationofposttranscriptionalregulatorymodules AT albertasnavickas systematicidentificationofposttranscriptionalregulatorymodules AT johnnyyu systematicidentificationofposttranscriptionalregulatorymodules AT fathimatrejo systematicidentificationofposttranscriptionalregulatorymodules AT anthonydoty systematicidentificationofposttranscriptionalregulatorymodules AT rithvikbaratam systematicidentificationofposttranscriptionalregulatorymodules AT shaopuzhou systematicidentificationofposttranscriptionalregulatorymodules AT seanblee systematicidentificationofposttranscriptionalregulatorymodules AT tanvijoshi systematicidentificationofposttranscriptionalregulatorymodules AT kristlegarcia systematicidentificationofposttranscriptionalregulatorymodules AT benedictchoi systematicidentificationofposttranscriptionalregulatorymodules AT sohitmiglani systematicidentificationofposttranscriptionalregulatorymodules AT vishvaksubramanyam systematicidentificationofposttranscriptionalregulatorymodules AT haileymodi systematicidentificationofposttranscriptionalregulatorymodules AT christophercarpenter systematicidentificationofposttranscriptionalregulatorymodules AT danielmarkett systematicidentificationofposttranscriptionalregulatorymodules AT mryancorces systematicidentificationofposttranscriptionalregulatorymodules AT farazkmardakheh systematicidentificationofposttranscriptionalregulatorymodules AT ivanvkulakovskiy systematicidentificationofposttranscriptionalregulatorymodules AT hanigoodarzi systematicidentificationofposttranscriptionalregulatorymodules |