Chromatin-associated lncRNA-splicing factor condensates regulate hypoxia responsive RNA processing of genes pre-positioned near nuclear speckles

Song, Y. J.; Shinn, M. K.; Bangru, S.; Wang, Y.; Sun, Q.; Hao, Q.; Chaturvedi, P.; Freier, S. M.; Perez-Pinera, P.; Nelson, E. R.; Belmont, A. S.; Guttman, M.; Prasantth, S. G.; Kalsotra, A.; Pappu, R. V.; Kannanganattu, P. V.

doi:10.1101/2024.10.31.621310

bioRxiv · 10.1101/2024.10.31.621310

Chromatin-associated lncRNA-splicing factor condensates regulate hypoxia responsive RNA processing of genes pre-positioned near nuclear speckles

Song, Y. J.·Shinn, M. K.·Bangru, S.·Wang, Y.·Sun, Q.·Hao, Q.·Chaturvedi, P.·Freier, S. M.·Perez-Pinera, P.·Nelson, E. R.·Belmont, A. S.·Guttman, M.·Prasantth, S. G.·Kalsotra, A.·Pappu, R. V.·Kannanganattu, P. V.

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Abstract

Hypoxia-induced alternative splicing (AS) regulates tumor progression and metastasis. Little is known about how such AS is controlled and whether higher-order genome and nuclear domain (ND) organizations dictate these processes. We observe that hypoxia-responsive alternatively spliced genes position near nuclear speckle (NS), the ND that enhances splicing efficiency. NS-resident MALAT1 long noncoding RNA, induced in response to hypoxia, regulates hypoxia-responsive AS. MALAT1 achieves this by organizing the SR-family of splicing factor, SRSF1, near NS and regulating the binding of SRSF1 to pre-mRNAs. Mechanistically, MALAT1 enhances the recruitment of SRSF1 to elongating RNA polymerase II (pol II) by promoting the formation of phase-separated condensates of SRSF1, which are preferentially recognized by pol II. During hypoxia, MALAT1 regulates spatially organized AS by establishing a threshold SRSF1 concentration near NSs, potentially by forming condensates, critical for pol II-mediated recruitment of SRSF1 to pre-mRNAs.

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Song, Y. J., Shinn, M. K., Bangru, S., Wang, Y., Sun, Q., Hao, Q., Chaturvedi, P., Freier, S. M., Perez-Pinera, P., Nelson, E. R., Belmont, A. S., Guttman, M., Prasantth, S. G., Kalsotra, A., Pappu, R. V., Kannanganattu, P. V.. 2024-10-31. Chromatin-associated lncRNA-splicing factor condensates regulate hypoxia responsive RNA processing of genes pre-positioned near nuclear speckles. https://doi.org/10.1101/2024.10.31.621310

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