The HP1 box of KAP1 organizes HP1α for silencing of endogenous retroviral elements in embryonic stem cells

Nitika Gaurav, Ryan O’Hara, Usman Hyder, Weihua Qin, Cheenou Her, Hector Romero, Amarjeet Kumar, Maria J. Marcaida, Rohit K. Singh, Ruud Hovius, Karthik Selvam, Jiuyang Liu, Sara Martire, Yuhang Yao, Ashwini Challa, Matteo Dal Peraro, Beat Fierz, Hidetoshi Kono, M. Cristina Cardoso, Galia T. Debelouchina, Heinrich Leonhardt, Iván D’Orso (), Laura A. Banaszynski () and Tatiana G. Kutateladze ()
Additional contact information
Nitika Gaurav: University of Colorado School of Medicine
Ryan O’Hara: The University of Texas Southwestern Medical Center
Usman Hyder: The University of Texas Southwestern Medical Center
Weihua Qin: Ludwig-Maximilians-Universität München
Cheenou Her: University of California San Diego
Hector Romero: Technical University of Darmstadt
Amarjeet Kumar: National Institutes for Quantum Science and Technology
Maria J. Marcaida: Ecole Polytechnique Fédérale de Lausanne
Rohit K. Singh: University of Colorado School of Medicine
Ruud Hovius: Ecole Polytechnique Fédérale de Lausanne
Karthik Selvam: University of Colorado School of Medicine
Jiuyang Liu: University of Colorado School of Medicine
Sara Martire: The University of Texas Southwestern Medical Center
Yuhang Yao: The University of Texas Southwestern Medical Center
Ashwini Challa: The University of Texas Southwestern Medical Center
Matteo Dal Peraro: Ecole Polytechnique Fédérale de Lausanne
Beat Fierz: Ecole Polytechnique Fédérale de Lausanne
Hidetoshi Kono: National Institutes for Quantum Science and Technology
M. Cristina Cardoso: Technical University of Darmstadt
Galia T. Debelouchina: University of California San Diego
Heinrich Leonhardt: Ludwig-Maximilians-Universität München
Iván D’Orso: The University of Texas Southwestern Medical Center
Laura A. Banaszynski: The University of Texas Southwestern Medical Center
Tatiana G. Kutateladze: University of Colorado School of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract Repression of endogenous retroviral elements (ERVs) is facilitated by KAP1 (KRAB-associated protein 1)-containing complexes, however the underlying mechanism remains unclear. Here, we show that binding of KAP1 to the major component of the heterochromatin spreading and maintenance network, HP1α, plays a critical role in silencing of repetitive elements. Structural, biochemical and mutagenesis studies demonstrate that the association of the HP1 box of KAP1 (KAP1Hbox) with the chromoshadow domain of HP1α (HP1αCSD) leads to a symmetrical arrangement of HP1αCSD and multimerization that may promote the closed state of chromatin. The formation of the KAP1Hbox-HP1αCSD complex enhances charge driven DNA binding and phase separation activities of HP1α. ChIP-seq and ATAC-seq analyses using KAP1 knock out mouse embryonic stem cells expressing wild type KAP1 or HP1-deficient KAP1 mutant show that in vivo, KAP1 engagement with HP1 is required for maintaining inaccessible chromatin at ERVs. Our findings provide mechanistic and functional insights that further our understanding of how ERVs are silenced.

Date: 2025
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DOI: 10.1038/s41467-025-60279-2

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