A histone modifier, ASXL1, interacts with NONO and is involved in paraspeckle formation in hematopoietic cells
Keita Yamamoto,
Susumu Goyama,
Shuhei Asada,
Takeshi Fujino,
Taishi Yonezawa,
Naru Sato,
Reina Takeda,
Akiho Tsuchiya,
Tomofusa Fukuyama,
Yosuke Tanaka,
Akihiko Yokoyama,
Hikaru Toya,
Ayana Kon,
Yasuhito Nannya,
Rena Onoguchi-Mizutani,
Shinichi Nakagawa,
Tetsuro Hirose,
Seishi Ogawa,
Nobuyoshi Akimitsu,
Toshio Kitamura
Affiliations
Keita Yamamoto
Division of Cellular Therapy, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
Susumu Goyama
Division of Cellular Therapy, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
Shuhei Asada
Division of Cellular Therapy, Institute of Medical Science, The University of Tokyo, Tokyo, Japan; The Institute of Laboratory Animals, Tokyo Women’s Medical University, Tokyo, Japan
Takeshi Fujino
Division of Cellular Therapy, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
Taishi Yonezawa
Division of Cellular Therapy, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
Naru Sato
Division of Cellular Therapy, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
Reina Takeda
Division of Cellular Therapy, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
Akiho Tsuchiya
Division of Cellular Therapy, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
Tomofusa Fukuyama
Division of Cellular Therapy, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
Yosuke Tanaka
Division of Cellular Therapy, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
Akihiko Yokoyama
National Cancer Center Tsuruoka Metabolomics Laboratory, Yamagata, Japan
Hikaru Toya
RNA Biology Laboratory, Faculty of Pharmaceutical Sciences, Hokkaido University, Hokkaido, Japan
Ayana Kon
Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan
Yasuhito Nannya
Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan
Rena Onoguchi-Mizutani
Isotope Science Center, The University of Tokyo, Tokyo, Japan
Shinichi Nakagawa
RNA Biology Laboratory, Faculty of Pharmaceutical Sciences, Hokkaido University, Hokkaido, Japan
Tetsuro Hirose
Graduate School of Frontier Biosciences, Osaka University, Suita, Japan
Seishi Ogawa
Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan
Nobuyoshi Akimitsu
Isotope Science Center, The University of Tokyo, Tokyo, Japan
Toshio Kitamura
Division of Cellular Therapy, Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Corresponding author
Summary: Paraspeckles are membraneless organelles formed through liquid-liquid phase separation and consist of multiple proteins and RNAs, including NONO, SFPQ, and NEAT1. The role of paraspeckles and the component NONO in hematopoiesis remains unknown. In this study, we show histone modifier ASXL1 is involved in paraspeckle formation. ASXL1 forms phase-separated droplets, upregulates NEAT1 expression, and increases NONO-NEAT1 interactions through the C-terminal intrinsically disordered region (IDR). In contrast, a pathogenic ASXL mutant (ASXL1-MT) lacking IDR does not support the interaction of paraspeckle components. Furthermore, paraspeckles are disrupted and Nono localization is abnormal in the cytoplasm of hematopoietic stem and progenitor cells (HSPCs) derived from ASXL1-MT knockin mice. Nono depletion and the forced expression of cytoplasmic NONO impair the repopulating potential of HSPCs, as does ASXL1-MT. Our study indicates a link between ASXL1 and paraspeckle components in the maintenance of normal hematopoiesis.
