2026-06-26 マウントサイナイ医療システム（MSHS）
＜関連情報＞
- https://www.mountsinai.org/about/newsroom/2026/new-research-links-eating-disorders-and-obsessive-compulsive-disorder-through-shared-brain-gene-expression-changes
- https://www.cell.com/molecular-cell/fulltext/S1097-2765(26)00382-5
RNA結合タンパク質の大規模テザー型スクリーニングにより、ポリ(A)部位選択の新規調節因子が明らかになった Convergent molecular signatures across eating disorders and obsessive-compulsive disorder in the human brain
Pratibha Jagannatha ∙ Yoseop Yoon ∙ Samuel B. Landry ∙ … ∙ Brenton R. Graveley ∙ Yongsheng Shi ∙ Gene W. Yeo
Molecular Cell Published:June 26, 2026
DOI:https://doi.org/10.1016/j.molcel.2026.06.011
Graphical abstract
Highlights
- Large-scale tethering screen of RBPs identifies activators of poly(A) site selection
- Most PAS selection activators were not previously linked to APA
- Protein language modeling predicts PAS selection activators from sequence alone
- GRB2 and RNPS1 directly engage the CPA machinery to modulate APA
Summary
Alternative polyadenylation (APA) generates transcript isoforms with distinct 3′ ends, yet the repertoire of its protein regulators remains poorly defined. Using a large-scale tethered function screen, we profiled 879 human RNA-binding proteins (RBPs) and identified 63 high-confidence activators of poly(A) site (PAS) selection, most of which were not previously linked to APA. We validated these factors by knockdown PAS-seq, RNA sequencing (RNA-seq), and enhanced cross-linking and immunoprecipitation (eCLIP) analyses and developed a fine-tuned protein language model that predicts PAS selection activators and their key functional domains. We then mechanistically dissected two unexpected hits: GRB2, a signaling adaptor protein, and RNPS1, a peripheral component of the exon junction complex (EJC). Both regulate APA, at least in part, through direct interactions with distinct subunits of the cleavage and polyadenylation (CPA) machinery. Together, our study provides a comprehensive resource of APA-regulating RBPs and uncovers unexpected roles of signaling and EJC factors in APA regulation.
