Correlated protein-RNA associations and a requirement for HNRNPU in the long-range recruitment of Polycomb Repressive Complexes by the lncRNAs Airn and Kcnq1ot1
Year: 2026
Type: article
Abstract: The lncRNAs Airn and Kcnq1ot1 recruit Polycomb Repressive Complexes (PRCs) and repress genes over multi-megabase genomic intervals, but how they interact with proteins to direct repression remains poorly understood. We conducted formaldehyde-based RNA-immunoprecipitations (RIPs) of 27 proteins from mouse trophoblast stem cells (TSCs), using a protocol exhibiting similar signal-to-non-specific signal and post-lysis reassociation ratios as crosslinking immunoprecipitation (CLIP) and crosslinking affinity purification (CLAP). Patterns of protein associations across Airn and Kcnq1ot1 were more similar to each other than to nearly all other transcripts and partitioned to extents that mirrored the degree of repression each lncRNA induced, implying connections to mechanism. Indeed, HNRNPU, a factor essential for Xist’s localization to chromatin, was enriched over Airn and Kcnq1ot1 and required to maintain normal levels of PRC1- and PRC2-directed chromatin modifications across the Airn and Kcnq1ot1 target domains, yet was dispensable for both lncRNAs’ localization to chromatin and for their association with PRC1. HNRNPU depletion caused a greater reduction in PRC-directed chromatin modifications and gene repression across the inactive X and the ~ 15 Mb Airn target domain than across the ~ 3 Mb Kcnq1ot1 domain. Perhaps relatedly, HNRNPU depletion significantly reduced the overall levels of Xist and Airn but not Kcnq1ot1. Our study reports architectures of protein association along Airn and Kcnq1ot1 compared to the transcriptome at large, highlights shared and distinct features between the two lncRNAs, and provides new perspective on the role of HNRNPU in long-range chromatin regulation by lncRNAs.
DOI: 10.17615/a3p1-vg42
Institution: University of North Carolina at Chapel Hill
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: green
Funders: Guangdong Provincial Key Laboratory of Sensor Technology and Biomedical Instrument, National Science Foundation, Alpha-1 Foundation, Cancer Prevention and Research Institute of Texas, Velux Stiftung, Wellcome Trust, Shanghai Municipal Health Commission, Jiangsu Commission of Health, National Institute for Health and Care Research, British Lung Foundation, European Commission, Ian Potter Foundation, South African Medical Research Council, Fundação de Amparo à Pesquisa do Estado de São Paulo, National Natural Science Foundation of China, Asthma Australia, Bundesministerium für Bildung und Forschung, China Postdoctoral Science Foundation, Government of Jiangsu Province, Max-Planck-Gesellschaft, Natural Science Foundation of Jiangsu Province, KWF Kankerbestrijding, Natural Science Foundation of Hunan Province, Unitatea Executiva pentru Finantarea Invatamantului Superior, a Cercetarii, Dezvoltarii si Inovarii, Mental Health Australia, Natural Science Foundation of Shandong Province, Soochow University, Stichting Coolsingel, Yunnan Provincial Science and Technology Department, Peking Union Medical College, Priority Academic Program Development of Jiangsu Higher Education Institutions, Natural Science Foundation of Sichuan Province, Guangzhou Municipal Science and Technology Bureau, Cochrane South Africa, National Institutes of Health, Directorate for Biological Sciences, Canadian Institutes of Health Research, Engineering and Physical Sciences Research Council, National Health and Medical Research Council, Faculty of Medicine, Chiang Mai University, Young Scientists Fund, National Key Research and Development Program of China, School for Public Health Research, West China Hospital, Sichuan University, Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Shenzhen Science and Technology Innovation Program, Beijing Friendship Hospital, Capital Medical University, National Institute of General Medical Sciences, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Health Data Research UK, Hartwig Medical Foundation
OpenAlex ID: W7167640683