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Nuclear exosome targeting complex safeguards hematopoietic stem cell self-renewal and genomic integrity through resolving R loops

ABSTRACT: Pervasive transcription of the mammalian genome produces a vast repertoire of non-functional nascent transcripts, generating R loops and R-loop-induced DNA breaks. Such a coupling between continual transcription and a burst of R-loop formation, however, presents a challenge for hematopoietic stem cells (HSCs) to maintain their genome integrity. Here, we show that the nuclear exosome targeting (NEXT) complex, an RNA adaptor that targets non-functional nascent transcripts to the RNA exosome for decay, plays a pivotal role in overcoming this challenge. Hematopoietic-specific deletion of ZCCHC8, a core subunit of NEXT, not only leads to impaired HSC self-renewal but also causes elevated DNA lesions and upregulated DNA repair pathways in HSCs due to accumulated R loops. Moreover, dysregulation of ZCCHC8 occurs frequently in diffuse large B cell lymphoma (DLBCL) and is associated with poor clinical outcomes. Collectively, our findings highlight NEXT as a novel protector of HSCs and position it as a potential therapeutic target for DLBCL.

ORGANISM(S): Mus musculus

PROVIDER: GSE281554 | GEO | 2025/12/16

REPOSITORIES: GEO

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The NEXT complex regulates H3K27me3 levels to affect cancer progression by degrading G4/U-Rich lncRNAs

Project description:Polycomb repressive complex 2 (PRC2) is responsible for depositing H3K27me3 and plays essential roles in gene silencing during development and cancer. Meanwhile, the nuclear exosome targeting (NEXT) complex facilitates the degradation of numerous non-coding RNAs in the nucleoplasm. Here find that the functional deficiency of the NEXT complex leads to an overall decrease in H3K27me3 levels. Specifically, ZCCHC8 depletion results in significant upregulation of nascent lncRNAs containing G-quadruplex and U-Rich motifs (G4/U-Rich lncRNAs). The G-quadruplex motif binds to EZH2, blocking the chromatin recruitment of PRC2, while the U-Rich motif is specifically recognized by the NEXT complex for RNA exosome-mediated degradation. In tumor tissues with high ZCCHC8 expression in clear cell renal cell carcinoma (ccRCC) and lung adenocarcinoma (LUAD) patients, the NEXT complex excessively degrades nascent G4/U-Rich lncRNAs. Consequently, PRC2 core subunits are released and recruited to neighboring genomic loci, resulting in increased H3K27me3 levels and downregulation of adjacent genes, including tumor suppressors like SEMA5A and ARID1A. Notably, the EZH2 inhibitor Tazemetostat (EPZ-6438) exhibits greater sensitivity in cells with higher ZCCHC8 expression. Altogether, our findings demonstrate a novel mechanism that the NEXT complex regulates H3K27me3 levels by degrading G4/U-Rich lncRNAs in cancer cells.

2025-02-24 | GSE284433 | GEO

A functional connection between the Microprocessor and a variant NEXT complex

Project description:In mammalian cells, primary miRNAs are cleaved at their hairpin structures by the Microprocessor complex, whose core is composed of DROSHA and DGCR8. Here, we show that 5’flanking regions, resulting from Microprocessor cleavage, are targeted by the RNA exosome in mouse embryonic stem cells (mESCs). This is facilitated by a physical link between DGCR8 and the nuclear exosome targeting (NEXT) component ZCCHC8. Surprisingly, however, both biochemical and mutagenesis studies demonstrate that a variant NEXT complex, containing the RNA helicase MTR4 but devoid of the RNA-binding protein RBM7, is the active entity. This Microprocessor-NEXT variant also targets stem-loop containing RNAs expressed from other genomic regions, such as enhancers. In contrast, Microprocessor does not contribute to the turnover of less structured NEXT substrates. Our results therefore demonstrate that MTR4-ZCCHC8 can link to either RBM7 or DGCR8/DROSHA to target different RNA substrates depending on their structural context.

2025-04-01 | GSE271796 | GEO

Identification of a nuclear exosome decay pathway for processed transcripts

Project description:The RNA exosome is fundamental for the degradation of RNA in eukaryotic nuclei. Substrate targeting is facilitated by its co-factor Mtr4p/hMTR4, which links to RNA-binding protein adaptors. One such activity is the human Nuclear EXosome Targeting (NEXT) complex, composed of hMTR4, the Zn-finger protein ZCCHC8 and the RNA-binding factor RBM7. NEXT primarily targets early and unprocessed transcripts, demanding a rationale for how the nuclear exosome recognizes processed RNAs. Here, we describe the PolyA tail eXosome Targeting (PAXT) connection, comprising the hitherto uncharacterized ZFC3H1 Zn-knuckle protein as a central link between hMTR4 and the nuclear polyA binding protein PABPN1. Individual depletion of ZFC3H1 and PABPN1 results in the accumulation of common transcripts, that are generally both longer and more 3’polyadenylated than NEXT substrates. Importantly, ZFC3H1/PABPN1 and ZCCHC8/RBM7 contact hMTR4 in a mutually exclusive manner, revealing that the exosome targets nuclear transcripts of different maturation status by substituting its hMTR4-associating adaptors.

2016-11-03 | GSE84172 | GEO

Structural basis for RNA capture and surveillance by the human Nuclear Exosome Targeting (NEXT) complex

Project description:Abstract: RNA quality control relies on co-factors and adaptors to identify and prepare substrates for degradation by ribonucleases such as the 3′ to 5′ ribonucleolytic RNA exosome. Here, we determined cryo-electron microscopy structures of human Nuclear Exosome Targeting (NEXT) complexes bound to RNA, that reveal mechanistic insights to substrate recognition and early steps that precede RNA handover to the exosome. The structures illuminate ZCCHC8 as a scaffold, mediating homodimerization while embracing the MTR4 helicase and flexibly anchoring RBM7 to the helicase core. All three subunits collaborate to bind the RNA, with RBM7 and ZCCHC8 engaging sequences upstream of the 3′ end that is bound by MTR4. ZCCHC8 obscures MTR4 surfaces that are important for RNA binding and extrusion as well as surfaces important for MPP6-dependent recruitment and docking onto the RNA exosome core, features of which might contribute to coordinating RNA translocation and extrusion from the helicase to exosome recruitment and decay.

2022-06-09 | GSE185374 | GEO

Nuclear exosome targeting complex core factor Zcchc8 regulates the degradation of LINE1 RNA in early embryos and embryonic stem cells

Project description:The nuclear exosome targeting (NEXT) complex is responsible for recruiting RNA exosomes to degrade specific nuclear RNAs in mammalian cells. However, its function in mammalian development remains unknown. Here, we found that the depletion of a central factor of the NEXT complex, Zcchc8, resulted in mouse developmental defects, a shortened life span and infertility. Zcchc8-deficient embryonic stem cells (ESCs) exhibited proliferation abnormalities and reduced developmental potencies. Interestingly, we found that retrotransposon elements, especially LINE1 RNAs, are targeted and degraded by Zcchc8 in ESCs. We subsequently demonstrated that Zcchc8-depleted oocytes show defects in meiotic maturation and early embryo development. Moreover, the sustained expression of higher levels of LINE1 RNA was also detected in maternal Zcchc8-depleted oocytes and Zcchc8-deficient embryos, which can further increase chromatin accessibility. Collectively, our study uncovers the important role of Zcchc8 in the degradation of LINE1 transcripts in early embryos and ESCs at the posttranscriptional level.

2019-11-07 | GSE127790 | GEO

PAXT/NEXT targeting of RNA exosome regulates antisense transcripts through cohesin-mediated long-range contacts [ChIP-seq]

Project description:Here, we mapped the binding sites of PAXT/ZFC3H1, NEXT/ZCCHC8 and their shared MTR4 helicase subunit. Our data highlight a key interplay between cohesin-mediated long-range interactions in 3D and ncRNA regulation by MTR4 helicase and nuclear RNA exosome.

2025-11-20 | GSE154083 | GEO

PAXT/NEXT targeting of RNA exosome regulates antisense transcripts through cohesin-mediated long-range contacts [RNA-seq]

2025-11-20 | GSE154099 | GEO

Nuclear exosome targeting complexes modulate 3D chromatin interactions genome-wide

Project description:Three-dimensional chromatin contacts are thought to be largely determined by loop exclusion driven by CTCF and the cohesin complex. Recent evidence also suggests a role for RNA in shaping genome architecture. Nuclear RNA exosome, together with targeting complexes, PAXT and NEXT, control the decay of noncoding RNAs (ncRNAs), notably enhancer-associated RNAs (eRNAs) and promoter upstream transcripts (PROMPTs). We mapped the chromatin recruitment sites of ZCCHC8 (NEXT), ZFC3H1 (PAXT) and MTR4 helicase, as well as the ncRNAs accumulating upon their depletion. While NEXT and PAXT map to both TSSs and enhancers, MTR4 was associated with enhancers that show preferential long-range contacts with promoters. Loss of MTR4 or ZFC3H1 led to the accumulation of cohesin at target enhancers and TSSs. Chromatin conformation capture analysis revealed that MTR4 modulates the 3D genome landscape. Contacts at anchor points were increased while intraloop contacts were decreased following loss of MTR4 suggesting that MTR4 facilitates loop extrusion. These data highlight a key interplay between cohesin-mediated enhancer-promoter interactions and the regulation of ncRNAs by nuclear RNA exosome that is consistent with a role for RNA in genome folding.

2025-11-20 | GSE283061 | GEO

ZCCHC8 is required for the degradation of pervasive transcripts originating from multiple genomic regulatory features

Project description:The vast majority of mammalian genomes are transcribed as non-coding RNA in what is referred to as “pervasive transcription.” Recent studies have uncovered various families of non-coding RNA transcribed upstream of transcription start sites. In particular, highly unstable promoter upstream transcripts known as PROMPTs have been shown to be targeted for exosomal degradation by the nuclear exosome targeting complex (NEXT) consisting of the RNA helicase MTR4, the zinc-knuckle scaffold ZCCHC8, and the RNA binding protein RBM7. Here, we report that in addition to its known RNA substrates, ZCCHC8 is required for the targeted degradation of pervasive transcripts produced at CTCF binding sites, open chromatin regions, promoters, promoter flanking regions, and transcription factor binding sites. Additionally, we report that a significant number of RIKEN cDNAs and predicted genes display the hallmarks of PROMPTs and are also substrates for ZCCHC8 and/or NEXT complex regulation suggesting these are unlikely to be functional genes. Our results suggest that ZCCHC8 and/or the NEXT complex may play a larger role in the global regulation of pervasive transcription than previously reported.

2021-01-29 | GSE165689 | GEO

Chromatin modifier HUSH co-operates with RNA decay factor NEXT to restrict transposable element expression

Project description:Transposable elements (TEs) are widespread genetic parasites known to be kept under tight transcriptional control. Here, we describe a functional connection between the mouse-orthologous ‘nuclear exosome targeting (NEXT)’ and ‘human silencing hub (HUSH)’ complexes, involved in nuclear RNA decay and the epigenetic silencing of TEs, respectively. Knocking out the NEXT component ZCCHC8 in embryonic stem cells results in elevated TE RNA levels. We identify a physical interaction between ZCCHC8 and the MPP8 protein of HUSH and establish that HUSH recruits NEXT to chromatin at TE loci. However, while NEXT and HUSH both dampen TE RNA expression, their activities predominantly affect shorter non-polyadenylated and full-length polyadenylated transcripts, respectively. Indeed, our data suggest that the repressive action of HUSH promotes a condition, favouring NEXT RNA decay activity. In this way, transcriptional and post-transcriptional machineries synergise to suppress the genotoxic potential of TE RNAs.

2022-03-28 | GSE178550 | GEO

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