LncRNA Gas5 directs SUV39H2 to establish heterochromatin and maintain genome stability
image: Toward the goal of elucidating the targeting mechanism of SUV39H2, this study demonstrates that RNA-binding is required for its chromatin recruitment. The lncRNA Gas5 was identified to direct SUV39H2 to genomic targets in ESCs, and the SUV39H2-Gas5 interaction is critical for heterochromatin maintenance and genome stability.
Credit: HIGHER EDUCATION PRESS
This work was funded by Key Research and Development Program, Ministry of Science and Technology of China (2022YFA1103103), National Natural Science Foundation of China (32488101, 32330030, 32370870, and 32170801), Fundamental Research Funds for the Central Universities (22120250336), and Fundamental and Interdisciplinary Disciplines Breakthrough Plan of the Ministry of Education of China (JYB2025XDXM508). The authors thank the Peak Disciplines (Type IV) of Institutions of Higher Learning in Shanghai, and the Frontier Science Research Center for Stem Cells, Ministry of Education for their support.; 4) Method of Research: experimental study; 5) Subject of Research: cell.
Constitutive heterochromatin, characterized by trimethylation of lysine 9 of histone H3 (H3K9me3), is essential for genome stability, pluripotency, and developmental fidelity. While the SUV39H histone methyltransferases catalyze H3K9me3 deposition, their locus-specific targeting mechanisms remain unclear.
This study demonstrate that RNA binding is required for the recruitment of SUV39H2 to chromatin in mouse embryonic stem cells (ESCs). Specifically, researchers identified the long non-coding RNA (lncRNA) Gas5 as a critical partner for SUV39H2 function and H3K9me3 maintenance.
Key findings of this study include:
RNA-binding is required for SUV39H2 recruitment to chromatin: Utilizing RNA-dependent chromatin immunoprecipitation sequencing (rChIP-seq), researchers found that RNase A treatment caused a substantial loss of SUV39H2 from chromatin. Treatment with actinomycin D further confirmed the requirement of nascent RNA for SUV39H2 chromatin occupancy. Moreover, mutating the RNA-binding domain of SUV39H2 also disrupted its chromatin recruitment and impaired the self-renewal capacity of the ESCs.
Gas5 acts as a key partner for SUV39H2 function and H3K9me3 maintenance: By analyzing RNA immunoprecipitation sequencing (RIP-seq) and RNA-seq datasets, researchers identified Gas5 as the specific transcript directs SUV39H2 to genomic target sites. Deletion of Gas5 or disruption its interaction with SUV39H2 led to abnormal clonal morphology, S-phase cell cycle arrest and impaired proliferation in ESCs. This deficiency also caused a genome-wide reduction in H3K9me3 levels, resulting in abnormal transcriptional activation of repetitive elements.
SUV39H2-Gas5 interaction is required for faithful mitosis and genome instability: By mining the interactome of SUV39H2 and Gas5, researchers uncovered the RNA dependence of SUV39H2's interaction with its partners, and demonstrated a Gas5-dependent interaction between SUV39H2 and LRWD1. Depletion of either Gas5 or LRWD1 elevated the frequency of chromosome segregation errors during mitosis, indicating the important role of Gas5 for genome stability.
In summary, this study reveals a lncRNA-mediated mechanism governing the SUV39H2-H3K9me3 axis, linking metabolism to the preservation of ESC identity and genome stability. The RNA dependence of epigenetic enzymes opens intriguing possibilities for site-specific regulation. Future research deciphering the RNA-guided targeting code that dictates the genomic binding sites of epigenetic modifiers will be crucial for understanding developmental programming and epigenetic diseases pathogenesis. The work entitled “LncRNA Gas5 directs SUV39H2 to establish heterochromatin and maintain genome stability” was published on Protein & Cell.