It is concluded that the exosome couples RNA decay to epigenetic state across the lifespan, positioning RNA surveillance as an emerging therapeutic target.
Abstract
The nuclear RNA exosome, a conserved 3′→5′ ribonuclease complex, degrades the vast majority of RNA polymerase II output, including promoter upstream transcripts, enhancer RNAs, antisense transcripts, and retrotransposon-derived RNAs. Beyond this housekeeping role, the exosome acts as an epigenetic effector, and its dysfunction underlies a growing spectrum of human disease. Here we integrate recent structural, genomic, and disease-focused studies into a unified model of the exosome as a guardian of the epigenome. We describe how MTR4-containing adaptor complexes TRAMP, NEXT, and PAXT confer substrate selectivity, and how the exosome enforces heterochromatic silencing in concert with HP1 proteins and the Human Silencing Hub (HUSH) complex and preserves three-dimensional genome architecture at insulators and enhancers, such as the protocadherin locus where RNA surveillance, CTCF insulation, and heterochromatin converge. We then examine the consequences of failure: exosomopathies such as pontocerebellar hypoplasia, loss of DIS3- and PAXT-mediated tumor suppression in cancer, and age-related erosion of surveillance that permits transposable element de-repression, RIG-1/MDA5 and cGAS-STING-driven inflammation, cellular senescence, and neurodegeneration. We conclude that the exosome couples RNA decay to epigenetic state across the lifespan, positioning RNA surveillance as an emerging therapeutic target.
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.
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
Abstract Nucleases are specialized enzymes known for degrading nucleic acids in diverse cellular processes. Among them, EXD2 contributes to genome maintenance by digesting a broad range of nucleic acid substrates, including non-canonical RNA–DNA hybrids (RDHs). However, the molecular mechanism underlying the interplay of EXD2 with these hybrid structures has remained elusive. Here, using an optical tweezers-based single-molecule approach, we unveil that EXD2 cooperatively binds to and slowly digests mechanically tensioned RDHs. On the other hand, the cooperative binding of a high amount of EXD2 onto a relaxed RDH drives their co-condensation. Moreover, EXD2 is capable of recognizing damage sites along RDHs and inducing damaged RDH condensation even at low protein concentrations. Surprisingly, this co-condensation, in contrast, protects RDHs from timely degradation by other nucleases. Consistently, we unveil that overexpressed EXD2 colocalizes with mitochondrial RDHs and, rather than cleavage, prevents them from fast degradation. Therefore, EXD2 is a promiscuous moonlighting enzyme that can exert opposing activities toward RDHs. Our findings provide a mechanistic understanding of the functional roles of EXD2 in cells.
Meng Hu, Yinghong Chen, Yanan Li et al.· Nucleic Acids Research· 0 citations
This study uncovers a therapeutic vulnerable lncRNA-centric circuitry and provides compelling preclinical evidence for the development and application of a novel RNA targeting-LNP based therapy for treatment of myeloid leukemia.
Zhenggen Jin, Brendan D. Ma, Karen Y. T. Chan et al.· bioRxiv· 0 citations
A mechanism-driven approach is adopted to systematically examine SNHG1 dysregulation and its roles in cancer, which complements existing literature and provides a clear framework for future SNHG1 research.
Hao Zhou, Jian-Lin Zhou, Lin Zhou· Biocell (Mendoza)· 0 citations
These findings call for a revised molecular dogma in which the noncoding genome is recognized as a major regulator of cellular function, oncogenic transformation, and immune surveillance.
Maria Lteif, Assia Hijazi, E. Morgand et al.· Oncoimmunology· 0 citations
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