Epigenetic reader ZMYND11 noncanonical function restricts HNRNPA1-mediated stress granule formation and oncogenic activity
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1150951 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR30338303_1.fastq.gz | Fastqsanger.gz | |||
| SRR30338303_2.fastq.gz | Fastqsanger.gz | |||
| SRR30338304_1.fastq.gz | Fastqsanger.gz | |||
| SRR30338304_2.fastq.gz | Fastqsanger.gz | |||
| SRR30338305_1.fastq.gz | Fastqsanger.gz |
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Project description:Epigenetic reader ZMYND11 noncanonical function restricts HNRNPA1-mediated stress granule formation and oncogenic activity, PPI of ZMYND11 in LNCap
2024-08-28 | PXD055421 |
Project description:Epigenetic reader ZMYND11 noncanonical function restricts HNRNPA1-mediated stress granule formation and oncogenic activity, To investigate the function of ZMYND11 in prostate cancer, We performed Co-IP and mass-spectometry (MS) analysis of ZMYND11.
2024-08-27 | PXD055219 |
Project description:To investigate the function of ZMYND11 in prostate cancer, we knockdown ZMYND11 in 22Rv1 cells and do RNA-seq.
2024-08-26 | GSE275451 | GEO
Project description:Epigenetic readers frequently affect gene regulation, correlate with disease prognosis, and hold significant potential as therapeutic targets for cancer. Zinc finger MYND-type containing 11 (ZMYND11) is notably recognized for reading the epigenetic marker H3.3K36me3; however, its broader functions and mechanisms of action in cancer remain underexplored. Here, we report that ZMYND11 downregulation is prevalent across various cancers and profoundly correlates with poorer outcomes in prostate cancer patients. Depletion of ZMYND11 promotes tumor cell growth, migration, and invasion in vitro, as well as tumor formation and metastasis in vivo. Mechanistically, we discover that ZMYND11 exhibits tumor suppressive roles by recognizing arginine-194-methylated HNRNPA1 dependent on its MYND domain, thereby retaining HNRNPA1 in the nucleus and preventing the formation of stress granules in the cytoplasm. Furthermore, ZMYND11 counteracts the HNRNPA1-driven increase in the PKM2/PKM1 ratio, thus mitigating the aggressive tumor phenotype promoted by PKM2. Remarkably, ZMYND11 recognition of HNRNPA1 can be disrupted by pharmaceutical inhibition of the arginine methyltransferase PRMT5. Tumors with low ZMYND11 expression show sensitivity to PRMT5 inhibitors. Taken together, our findings uncover a previously unexplored noncanonical role of ZMYND11 as a nonhistone methylation reader and underscore the critical importance of arginine methylation in the ZMYND11-HNRNPA1 interaction for restraining tumor progression, thereby proposing novel therapeutic targets and potential biomarkers for cancer treatment.
| S-EPMC11438962 | biostudies-literature
Project description:Recognition of modified histones by “reader” proteins plays a critical role in the regulation of transcription1. H3K36 trimethylation (H3K36me3) is deposited onto the nucleosomes in the transcribed regions following RNA polymerase II (Pol II) elongation. In yeast, this mark in turn recruits epigenetic regulators to reset the chromatin at an appropriate state to suppress cryptic transcription2,3. However, much less is known about the role of H3K36me3 in transcription regulation in mammals. This is further complicated by the transcription-coupled incorporation of the histone variant H3.3 in gene bodies4. Here we show that the candidate tumor suppressor ZMYND11 specifically recognizes H3K36me3 on H3.3 (H3.3K36me3) and regulates Pol II elongation. Structural studies reveal that in addition to the trimethyl-lysine binding by an aromatic cage within the PWWP domain, the H3.3-dependent recognition is mediated by the encapsulation of the H3.3-specific “Ser31” residue in a composite pocket formed by the tandem bromo-PWWP domains of ZMYND11. ChIP-sequencing analysis reveal a genome-wide colocalization of ZMYND11 with H3K36me3 and H3.3 in gene bodies, and its occupancy requires the pre-deposition of H3.3K36me3. Although ZMYND11 is associated with highly expressed genes, it functions as an unconventional transcription corepressor via modulating the transition of the promoter-proximal paused Pol II to elongation. ZMYND11 is critical for the repression of a transcriptional program that is essential for tumor cell growth; higher expression of ZMYND11 is observed in triple-negative breast cancer patients with better prognosis. Consistently, overexpression of ZMYND11 suppresses cancer cell growth and tumor formation in mice. Together, this study identifies ZMYND11 as an H3.3-specific reader of H3K36me3 that links the histone variant-mediated transcription elongation control to tumor suppression. ChIP-seq analysis of ZMYND11, H3K36me3 in U2OS cells and ZMYND11 knockdown cells; ChIP-seq of H3.3 in Flag-H3.3 stable U2OS cells; RNA-seq of ZNYMD11 depleted U2OS cells.
2014-02-24 | E-GEOD-48423 | biostudies-arrayexpress
Project description:ZMYND11 is a ‘reader’ protein, which specifically recognizes H3.3K36me3 and regulate RNA polymerase II elongation. Our RNA-seq data showed that 93 ISGs were up regulated, 47 ISGs were down regulated and 48 ISGs were not changed in ZMYND11 KO.
2019-12-31 | GSE97275 | GEO
Project description:Recognition of modified histones by “reader” proteins plays a critical role in the regulation of transcription1. H3K36 trimethylation (H3K36me3) is deposited onto the nucleosomes in the transcribed regions following RNA polymerase II (Pol II) elongation. In yeast, this mark in turn recruits epigenetic regulators to reset the chromatin at an appropriate state to suppress cryptic transcription2,3. However, much less is known about the role of H3K36me3 in transcription regulation in mammals. This is further complicated by the transcription-coupled incorporation of the histone variant H3.3 in gene bodies4. Here we show that the candidate tumor suppressor ZMYND11 specifically recognizes H3K36me3 on H3.3 (H3.3K36me3) and regulates Pol II elongation. Structural studies reveal that in addition to the trimethyl-lysine binding by an aromatic cage within the PWWP domain, the H3.3-dependent recognition is mediated by the encapsulation of the H3.3-specific “Ser31” residue in a composite pocket formed by the tandem bromo-PWWP domains of ZMYND11. ChIP-sequencing analysis reveal a genome-wide colocalization of ZMYND11 with H3K36me3 and H3.3 in gene bodies, and its occupancy requires the pre-deposition of H3.3K36me3. Although ZMYND11 is associated with highly expressed genes, it functions as an unconventional transcription corepressor via modulating the transition of the promoter-proximal paused Pol II to elongation. ZMYND11 is critical for the repression of a transcriptional program that is essential for tumor cell growth; higher expression of ZMYND11 is observed in triple-negative breast cancer patients with better prognosis. Consistently, overexpression of ZMYND11 suppresses cancer cell growth and tumor formation in mice. Together, this study identifies ZMYND11 as an H3.3-specific reader of H3K36me3 that links the histone variant-mediated transcription elongation control to tumor suppression.
2014-02-24 | GSE48423 | GEO
Project description:SPOP is known to bind to serine/theronine-rich degrons on substrate proteins. We identified two degron sequences within the PWWP and MYND domain of ZMYND11, a novel SPOP substrate, and investigated whether ZMYND11 may contribute to the transcriptional output of mutant SPOP in VCaP cancer cells. Hence, we performed over-expression of degron-deficient ZMYND11 and degron-deficient ZMYND11 with W294A mutation in VCaP cells. While WT ZMYND11 constructs can be robustly over-expressed at the mRNA level, only the degron-deficient variants yielded a robost increase in ZMYND11 protein expression. Degron mutant-induced transcriptional perturbations partially mimicked SPOP mutant-induced gene expression changes, suggesting that ZMYND11 is sufficient to recapitulate certain features of mutant SPOP.
2020-12-16 | E-MTAB-7173 | biostudies-arrayexpress
Project description:While the identification of pathogenic variants linked to neurodevelopmental (NDD) and autism spectrum disorders (ASD) has advanced rapidly, the mechanisms underlying these genetic risks remain unclear. Here, we leveraged a human pluripotent stem cell model to uncover the neurodevelopmental consequences of mutations in ZMYND11, a newly implicated risk gene. ZMYND11, known for its tumor suppressor function, encodes a histone-reader that recognizes sites of transcriptional elongation and acts as a co-repressor. Our findings reveal that ZMYND11 deficient cortical neural stem cells exhibit upregulation expression of latent developmental pathways, leading to impaired production of secondary neural progenitors and neurons. In addition to its chromatin-related functions, we found ZMYND11 orchestrates a brain specific isoform switch that affects migration and proliferation of cortical neural stem cells. We further demonstrated that brain specificity is likely to involve the activity of the splicing regulator RBFOX2. Finally, we extended our findings to 10 additional lines with different chromatin-related NDD/ASD risk factors and identified a subset displaying similar activation of developmental pathways and splicing dysregulation, which could partially be rescued by leveraging the transcriptional repression and splicing coordination of ZMYND11. Collectively, our work highlights the critical role of ZMYND11 in regulating developmental signals and alternative splicing, offering novel insights into the molecular pathology of ZMYND11-associated NDDs. Moreover, these findings suggest broader convergence with other genetic risk factors for NDD/ASD, presenting potential therapeutic avenues for intervention.
2025-08-21 | GSE279072 | GEO
Project description:While the identification of pathogenic variants linked to neurodevelopmental (NDD) and autism spectrum disorders (ASD) has advanced rapidly, the mechanisms underlying these genetic risks remain unclear. Here, we leveraged a human pluripotent stem cell model to uncover the neurodevelopmental consequences of mutations in ZMYND11, a newly implicated risk gene. ZMYND11, known for its tumor suppressor function, encodes a histone-reader that recognizes sites of transcriptional elongation and acts as a co-repressor. Our findings reveal that ZMYND11 deficient cortical neural stem cells exhibit upregulation expression of latent developmental pathways, leading to impaired production of secondary neural progenitors and neurons. In addition to its chromatin-related functions, we found ZMYND11 orchestrates a brain specific isoform switch that affects migration and proliferation of cortical neural stem cells. We further demonstrated that brain specificity is likely to involve the activity of the splicing regulator RBFOX2. Finally, we extended our findings to 10 additional lines with different chromatin-related NDD/ASD risk factors and identified a subset displaying similar activation of developmental pathways and splicing dysregulation, which could partially be rescued by leveraging the transcriptional repression and splicing coordination of ZMYND11. Collectively, our work highlights the critical role of ZMYND11 in regulating developmental signals and alternative splicing, offering novel insights into the molecular pathology of ZMYND11-associated NDDs. Moreover, these findings suggest broader convergence with other genetic risk factors for NDD/ASD, presenting potential therapeutic avenues for intervention.
2025-08-21 | GSE279068 | GEO