The nuclear matrix protein HNRNPU maintains 3D genome architecture globally in mouse hepatocytes
- Hui Fan1,6,
- Pin Lv1,6,
- Xiangru Huo1,
- Jicheng Wu1,
- Qianfeng Wang1,
- Lu Cheng1,
- Yun Liu1,
- Qi-Qun Tang1,
- Ling Zhang2,
- Feng Zhang2,3,
- Xiaoqi Zheng4,
- Hao Wu5 and
- Bo Wen1,3
- 1MOE Key Laboratory of Metabolism and Molecular Medicine, Institutes of Biomedical Sciences, and Department of Biochemistry and Molecular Biology, Fudan University Shanghai Medical College, Shanghai 200032, China;
- 2Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200011, China;
- 3State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, Fudan University, Shanghai 200438, China;
- 4Department of Mathematics, Shanghai Normal University, Shanghai 200234, China;
- 5Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, Georgia 30322, USA
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↵6 These authors contributed equally to this work.
Abstract
Eukaryotic chromosomes are folded into higher-order conformations to coordinate genome functions. In addition to long-range 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 or TADs are also significantly remodeled upon HNRNPU depletion. Intriguingly, HNRNPU mainly associates with active chromatin, and 80% of HNRNPU peaks coincide with the binding of CTCF or RAD21. Collectively, we demonstrated that HNRNPU functions as a major factor maintaining 3D chromatin architecture, suggesting important roles of NM-associated proteins in genome organization.
Footnotes
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.224576.117.
- Received May 1, 2017.
- Accepted December 20, 2017.
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