The nuclear matrix protein HNRNPU maintains 3D genome architecture globally in mouse hepatocytes

• Type of Material: Article
• Authors: Hui Fan, Fudan University; Pin Lv, Fudan University; Xiangru Huo, Fudan University; Jicheng Wu, Fudan University; Qianfeng Wang, Fudan University; Lu Cheng, Fudan University; Yun Liu, Fudan University; Qi-Qun Tang, Fudan University; Ling Zhang, Fudan University; Feng Zhang, Fudan University; Xiaoqi Zheng, Shanghai Normal University; Hao Wu, Emory University; Bo Wen, Fudan University
• Language: English
• Date: 2018-02-01
• Publisher: Cold Spring Harbor Laboratory Press
• Publication Version: Final Published Version
• Copyright Statement: © 2018 Fan et al.; Published by Cold Spring Harbor Laboratory Press
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1101/gr.224576.117
• Title of Journal or Parent Work: Genome Research
• ISSN: 1088-9051
• Volume: 28
• Issue: 2
• Start Page: 192
• End Page: 202
• Grant/Funding Information: This study was supported by the National Basic Research Program of China (2015CB943000 to B.W.) and the National Natural Science Foundation of China (31371296 to B.W.).
• Keywords: CHROMOSOMAL DOMAIN ARCHITECTURE; Science & Technology; Life Sciences & Biomedicine; GENE-EXPRESSION; Genetics & Heredity; SAF-A; CTCF; HI-C; IN-VIVO; Biotechnology & Applied Microbiology; SPATIAL-ORGANIZATION; U/SAF-A; ORDER CHROMATIN-STRUCTURE; XIST RNA; Biochemistry & Molecular Biology
• Research Categories: Biology, Biostatistics; Biology, Molecular

Abstract

Eukaryotic chromosomes are folded into higher-order conformations to coordinate genome functions. In addition to longrange chromatin loops, recent chromosome conformation capture (3C)-based studies have indicated higher levels of chromatin structures including compartments and topologically associating domains (TADs), which may serve as units of genome organization and functions. However, the molecular machinery underlying these hierarchically three-dimensional (3D) chromatin architectures remains poorly understood. Via high-throughput assays, including in situ Hi-C, DamID, ChIP-seq, and RNA-seq, we investigated roles of the Heterogeneous Nuclear Ribonucleoprotein U (HNRNPU), a nuclear matrix (NM)-associated protein, in 3D genome organization. Upon the depletion of HNRNPU in mouse hepatocytes, the coverage of lamina-associated domains (LADs) in the genome increases from 53.1% to 68.6%, and a global condensation of chromatin was observed. Furthermore, disruption of HNRNPU leads to compartment switching on 7.5% of the genome, decreases TAD boundary strengths at borders between A (active) and B (inactive) compartments, and reduces chromatin loop intensities. Long-range chromatin interactions between and within compartments orTADs are also significantly remodeled upon HNRNPU depletion. Intriguingly, HNRNPU mainly associates with active chromatin, and 80% of HNRNPU peaks coincide with the binding of CTCFor RAD21. Collectively, wedemonstrated that HNRNPU functionsas amajor factor maintaining 3D chromatin architecture, suggesting important roles of NM-associated proteins in genome organization.