Nuclear Speckles Identified as Key Hubs for Gene Expression Regulation

UC Irvine researchers uncover the critical role of nuclear speckles as the major site of pre-mRNA 3′ end processing

Irvine, Calif., Jan. 10, 2025 — Scientists at the University of California, Irvine have discovered that nuclear speckles, a membraneless organelle within the nucleus, serve as central hubs for pre-mRNA 3′ end processing. This discovery advances the understanding of how spatial organization within cells impacts gene expression and could open new avenues for treating diseases influenced by RNA processing defects.

Published online today in Molecular Cell, the study reveals that RBBP6, a critical factor in pre-mRNA 3′ end processing, localizes to nuclear speckles via its intrinsically disordered region. This localization is essential for efficient pre-mRNA 3′ end processing in human cells, and the researchers found that over 50% of genes undergo 3′ end processing at nuclear speckles. These findings highlight the integrative role of nuclear speckles in coordinating transcription, splicing and 3′ end formation.

“Pre-mRNA 3′ end processing is a critical step in mRNA biogenesis, and its misregulation is associated with a variety of diseases, including cancer,” said corresponding author Yongsheng Shi, PhD, UC Irvine professor of microbiology and molecular genetics. “Our work, for the first time, identifies where pre-mRNA 3′ end processing occurs in the cell. By understanding this spatial organization, we can better decipher how disruptions in these processes contribute to disease.”

For years, the field has hypothesized the function of nuclear speckles in cells, particularly in the context of other mRNA processing steps, such as splicing. However, testing these functions directly has been challenging due to the complexity of RNA processing machineries. This research, led by first author Yoseop Yoon, PhD, tackled this challenge by identifying that RBBP6 localizes to nuclear speckles and distinguishing its functional domain from the domain responsible for localization. By making this distinction and employing advanced imaging, sequencing, and biochemical techniques, the researchers were able to directly test whether RBBP6’s localization to nuclear speckles is crucial for pre-mRNA 3′ end processing.

“In addition to its critical role in mRNA processing within nuclear speckles, RBBP6 also binds to many well-known tumor suppressor proteins, such as p53, via its long intrinsically disordered region,” said Shi. “These proteins are known to recruit their target genes to nuclear speckles to enhance gene expression, but the underlying mechanisms remain unknown. Our future work will explore these interactions and their implications in gene regulation and cancer.”

This study involved interdisciplinary collaboration, with contributions from researchers across UC Irvine, Columbia University and the University of Washington.

This work was supported by the National Institutes of Health under awards R35GM149294 and R01AI170840, R35GM118093, and R37CA252081; a Research Scholar Grant from the American Cancer Society (RSG-24-1249960-01-DMC); the Chan Zuckerberg Initiative and award DP2GM150017; and the Hewitt Foundation Postdoctoral Fellowship. Additional support was provided by UCI core facilities funded by P30CA062203, CA-62203, and NIH-S10OD032327-01.

For full details, refer to the study in Molecular Cell: "RBBP6 anchors pre-mRNA 3′ end processing to nuclear speckles for efficient gene expression.”