Mammalian genomes encode multiple transposable element (TE) silencing pathways that distinguish their targets through different molecular features, with KRAB zinc finger proteins recognizing DNA sequence, the HUSH complex sensing intronless transcripts, and the PIWI–piRNA pathway using small RNA guides. How chromatin state itself contributes to TE recognition remains less defined. Here we identify Spindlin1 (SPIN1), a three-Tudor-domain histone reader implicated in germline piRNA-directed DNA methylation, as a transcriptional repressor of evolutionarily young TEs in mouse embryonic stem cells. SPIN1 selectively binds LINE and ERV loci carrying H3K4me3 and H3K9me3, a chromatin signature enriched at young, transcription-permissive elements, and recognition of these marks by Tudor domains 1 and 2 is required for TE targeting. SPIN1 engages SPINDOC as a Tudor 1 and 3-dependent cofactor whose loss phenocopies SPIN1 depletion, and associates with the H3K9 methyltransferases SETDB1 and G9a. SPIN1 loss reduces H3K9me3 and is accompanied by increased chromatin accessibility, without altering DNA methylation. Thus, SPIN1 uses a histone-state-based mechanism to identify and repress young TEs in pluripotent cells, mechanistically distinct from its germline mode in which SPIN1 cooperates with the PIWI–piRNA pathway to promote DNA methylation, illustrating how a single histone reader engages distinct silencing machineries across cellular contexts.
The piRNA pathway maintains genome integrity by silencing transposons cotranscriptionally in the nucleus through recognition of nascent transposon RNAs and recruitment of endogenous transcriptional and chromatin-level repressive mechanisms to transposon loci. However, the molecular link between the SFiNX complex, which recognizes nascent transposon RNA, and downstream effector complexes has remained elusive. Here, we demonstrate that the Small ovary (Sov) protein mediates this connection. By mapping the functional activities of its structural elements, we reveal that Sov contributes to transposon silencing through two distinct molecular mechanisms. First, Sov specifically directs nascent transposon transcripts toward nuclear RNA exosome-mediated degradation by physically interacting with the RNA decay factor TEsup1. Second, Sov directly binds the heterochromatin protein HP1a via multiple conserved motifs and undergoes phase separation, facilitating heterochromatin formation and genome-wide gene repression. Genetic analyzes of sov mutants reveal that these functions are separable: RNA-mediated transcriptional silencing is essential for piRNA pathway activity, while phase separation-dependent heterochromatin regulation is critical for stable transposon repression. We propose that Sov acts as a molecular scaffold in piRNA-guided transposon silencing, integrating transposon recognition with cotranscriptional RNA decay and chromatin-based regulatory pathways.
Z. Földi, Melinda Bence, Zsanett Takács et al.· bioRxiv· 0 citations
Silencing complexes formed by PIWI-clade Argonaute (Ago) proteins and PIWI-interacting RNAs (piRNAs) are essential guardians of genome integrity, restricting the activities of transposable elements (TEs) in the animal germline. However, our understanding of PIWI-piRNA-directed TE silencing remains incomplete. Here, we systemically characterize the proximity proteome of the PIWI members Piwi, Aubergine (Aub), and Ago3 in the germline of Drosophila ovaries. Functional screening identifies previously uncharacterized factors involved in TE silencing, including the H3K4me3 writer and transcriptional coactivator Set1. Transcriptome analysis reveals that Set1 acts as an indispensable repressor of TEs, particularly of those at telomeres. Set1 is required for the production of antisense, TE-targeting piRNAs. Genome-wide chromatin profiling by CUT&Tag demonstrates that Set1 preferentially associates with TE sequences, including their 3'UTRs, and is localized at subtelomeric piRNA-producing loci. It also controls the accumulation of Rhino, a key activator of piRNA precursor transcription, at these sites. Notably, the catalytic activity of Set1 is dispensable. Our findings uncover a noncanonical function of Set1 in Piwi-mediated TE silencing in germline nuclei.
Wakana Isshiki, H. Kozuka-Hata, M. Oyama et al.· EMBO Reports· 0 citations
Histone post-translational modifications (hPTMs) are key regulators of chromatin states1,2, influencing gene expression, epigenetic memory, and transposable element repression across eukaryotic genomes. While many hPTMs are evolutionarily conserved3, the extent to which the chromatin states they define are similarly preserved remains unclear. Here, we developed a combinatorial indexing ChIP-seq method to simultaneously profile specific hPTMs across diverse eukaryotic lineages4, including amoebozoans, rhizarians, discobans, and cryptomonads. Our analyses revealed highly conserved euchromatin states at active gene promoters and gene bodies. In contrast, we observed diverse configurations of repressive heterochromatin states associated with silenced genes and transposable elements, characterized by various combinations of hPTMs such as H3K9me3, H3K27me3 and/or different H3K79 methylations. These findings suggest that while core hPTMs are ancient and broadly conserved, their functional readout has diversified throughout eukaryotic evolution, shaping lineage-specific chromatin landscapes.
Cristina Navarrete, Sean A. Montgomery, Julen Mendieta et al.· bioRxiv· 11 citations· ⚡4
It is concluded that the exosome couples RNA decay to epigenetic state across the lifespan, positioning RNA surveillance as an emerging therapeutic target.
SunTag-NOVA robustly installed DNA methylation and repressed transcription at the endogenous FWA, FT and TMM genes with minimal genome-wide off-target consequences, and establishes SunTag-NOVA as a specific epigenome-editing platform for plants.
Yan He, Ming Wang, T. J. Buckley et al.· bioRxiv· 0 citations
Transposable elements (TEs) account for nearly half of the human genome and shape chromatin organization, gene regulation, and genome evolution. However, their contributions to human physiology and disease remain incompletely understood. The most active elements in humans, LINE-1 (L1), Alu, and SVA, retain some copies with the ability to evade epigenetic repression and mobilize via target-primed reverse transcription (TPRT), whereas copies become inactive through various fragmentations and mutations. TE activity contributes to genomic instability and has been implicated in aging, cancer, neurological disorders, chromatin organization, and epigenetic regulation. Studying TE is challenging due to their repetitive and polymorphic nature. Recent advances in sequencing technologies and short- and long-read sequencing platforms, combined with specialized bioinformatic pipelines, currently enable more comprehensive characterization of TE insertions, deletions, expression, and epigenetic status. Computational approaches vary in sensitivity, specificity, and resource requirements, and their performance is influenced by sequencing modality, coverage, and the reference genome used. Assembly-based and read-based methods, as well as integrating methylation data or single-cell data, provide complementary insights into TE biology. This review summarizes the biology of active human TE, surveys state-of-the-art short- and long-read pipelines for TE analysis, and highlights their applications in studies of aging, cancer, and other complex diseases. We also provide practical guidance for selecting appropriate sequencing strategies and tools for TE-focused projects, and discuss emerging approaches and open questions in the field.
Dániel Vörösvácki, Nikolett Szakállas, Alexandra Kalmár et al.· Biomolecules· 0 citations
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