Asymmetric distribution of parental H3K9me3 in S phase silences L1 elements

Zhiming Li, Shoufu Duan, Xu Hua, Xiaowei Xu, Yinglu Li, Demis Menolfi, Hui Zhou, Chao Lu, Shan Zha, Stephen P. Goff and Zhiguo Zhang ()
Additional contact information
Zhiming Li: Columbia University Irving Medical Center
Shoufu Duan: Columbia University Irving Medical Center
Xu Hua: Columbia University Irving Medical Center
Xiaowei Xu: Columbia University Irving Medical Center
Yinglu Li: Columbia University Irving Medical Center
Demis Menolfi: Columbia University Irving Medical Center
Hui Zhou: Columbia University Irving Medical Center
Chao Lu: Columbia University Irving Medical Center
Shan Zha: Columbia University Irving Medical Center
Stephen P. Goff: Columbia University Irving Medical Center
Zhiguo Zhang: Columbia University Irving Medical Center

Nature, 2023, vol. 623, issue 7987, 643-651

Abstract: Abstract In eukaryotes, repetitive DNA sequences are transcriptionally silenced through histone H3 lysine 9 trimethylation (H3K9me3). Loss of silencing of the repeat elements leads to genome instability and human diseases, including cancer and ageing1–3. Although the role of H3K9me3 in the establishment and maintenance of heterochromatin silencing has been extensively studied4–6, the pattern and mechanism that underlie the partitioning of parental H3K9me3 at replicating DNA strands are unknown. Here we report that H3K9me3 is preferentially transferred onto the leading strands of replication forks, which occurs predominantly at long interspersed nuclear element (LINE) retrotransposons (also known as LINE-1s or L1s) that are theoretically transcribed in the head-on direction with replication fork movement. Mechanistically, the human silencing hub (HUSH) complex interacts with the leading-strand DNA polymerase Pol ε and contributes to the asymmetric segregation of H3K9me3. Cells deficient in Pol ε subunits (POLE3 and POLE4) or the HUSH complex (MPP8 and TASOR) show compromised H3K9me3 asymmetry and increased LINE expression. Similar results were obtained in cells expressing a MPP8 mutant defective in H3K9me3 binding and in TASOR mutants with reduced interactions with Pol ε. These results reveal an unexpected mechanism whereby the HUSH complex functions with Pol ε to promote asymmetric H3K9me3 distribution at head-on LINEs to suppress their expression in S phase.

Date: 2023
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DOI: 10.1038/s41586-023-06711-3

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