Systematic identification of post-transcriptional regulatory modules
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.
Authors
- Faraz K. Mardakheh (ORCID: https://orcid.org/0000-0003-3896-0827)
- M. Ryan Corces (ORCID: https://orcid.org/0000-0001-7465-7652)
- Daniel Markett (ORCID: https://orcid.org/0000-0003-0752-6681)
- Albertas Navickas (ORCID: https://orcid.org/0000-0003-0016-2643)
- Matvei Khoroshkin (ORCID: https://orcid.org/0000-0002-1744-6792)
- Sohit Miglani (ORCID: https://orcid.org/0000-0002-8075-320X)
- Anthony Doty
- Johnny Yu (ORCID: https://orcid.org/0000-0002-9857-4349)
- Rithvik Baratam
- Andrey Buyan (ORCID: https://orcid.org/0000-0001-9105-4028)
- Vishvak Subramanyam (ORCID: https://orcid.org/0000-0002-6144-8322)
- Hailey Modi (ORCID: https://orcid.org/0000-0001-6177-9087)
- Fathima Trejo
- Sean Bong Lee (ORCID: https://orcid.org/0000-0001-6211-3498)
- Ivan V. Kulakovskiy (ORCID: https://orcid.org/0000-0002-6554-8128)
- Kristle Garcia (ORCID: https://orcid.org/0000-0002-9868-8397)
- Christopher Carpenter (ORCID: https://orcid.org/0000-0001-5708-5381)
- Man Hung Choi (ORCID: https://orcid.org/0000-0001-6204-1690)
- Shaopu Zhou (ORCID: https://orcid.org/0000-0003-3451-5654)
- Hani Goodarzi (ORCID: https://orcid.org/0000-0002-9648-8949)
- Martin Dodel (ORCID: https://orcid.org/0009-0008-0323-9953)
- Tanvi Joshi (ORCID: https://orcid.org/0000-0002-2460-9107)
Institutions
- Centre National de la Recherche Scientifique (FR)
- Gladstone Institutes (US)
- Inserm (FR)
- Queen Mary University of London (GB)
- University of California, San Francisco (US)
- University of Oxford (GB)
- Institute of Protein Research (RU)
- Vavilov Institute of General Genetics (RU)
- UCSF Helen Diller Family Comprehensive Cancer Center (US)
- University of San Francisco (US)
- Institut Curie (FR)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-09-09
- DOI
- https://doi.org/10.1038/s41467-024-52215-7
- Citations
- 16
- Primary Topic
- RNA Research and Splicing
- Type
- article
- Field-Weighted Citation Impact
- 3.74
Funders
- Boehringer Ingelheim Fonds
- Medical Research Council