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ZMYND11 Functions in Bimodal Regulation of Latent Genes and Brain-like Splicing to Safeguard Corticogenesis [CUT&RUN]

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE279068 | GEO | 2025/08/21

REPOSITORIES: GEO

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Project description:Autism spectrum disorder (ASD) is a common, highly heritable neurodevelopmental condition characterized by marked genetic heterogeneity. Thus, a fundamental question is whether autism represents an aetiologically heterogeneous disorder in which the myriad genetic or environmental risk factors perturb common underlying molecular pathways in the brain. Here, we demonstrate consistent differences in transcriptome organization between autistic and normal brain by gene co-expression network analysis. Remarkably, regional patterns of gene expression that typically distinguish frontal and temporal cortex are significantly attenuated in the ASD brain, suggesting abnormalities in cortical patterning. We further identify discrete modules of co-expressed genes associated with autism: a neuronal module enriched for known autism susceptibility genes, including the neuronal specific splicing factor A2BP1 (also known as FOX1), and a module enriched for immune genes and glial markers. Using high-throughput RNA sequencing we demonstrate dysregulated splicing of A2BP1-dependent alternative exons in the ASD brain. Moreover, using a published autism genome-wide association study (GWAS) data set, we show that the neuronal module is enriched for genetically associated variants, providing independent support for the causal involvement of these genes in autism. In contrast, the immune-glial module showed no enrichment for autism GWAS signals, indicating a non-genetic aetiology for this process. Collectively, our results provide strong evidence for convergent molecular abnormalities in ASD, and implicate transcriptional and splicing dysregulation as underlying mechanisms of neuronal dysfunction in this disorder. To identify potential A2BP1-dependent differential splicing events in ASD brain, we performed high-throughput RNA sequencing (RNA-Seq) on three autism samples with significant downregulation of A2BP1 (average fold change by quantitative RT-PCR = 5.9) and three control samples with average A2BP1 levels. The list of potential A2BP1-depending differential splicing events in ASD is given in the Supplementary file linked at the foot of this record.

Project description:Tuberous sclerosis complex (TSC) is an inherited neurodevelopmental (ND) disorder with frequent manifestations of epilepsy and autism spectrum disorder (ASD) caused by mutations in TSC1 or TSC2 genes. TSC1 and TSC2 form a complex inhibiting mechanistic target of rapamycin complex-1 (mTORC1) signaling, leading to hyperactive mTORC1 signaling upon TSC1/2 loss of function. Although rapalogs, which are FDA-approved allosteric mTORC1-selective inhibitors, are used to treat TSC-associated hamartomas, they are not effective for treating ND manifestations. mTORC1 signaling controls protein synthesis by regulating formation of the eIF4F complex, whose activity is further modulated by the MNK1/2 kinases via phosphorylation of the eIF4F subunit eIF4E. While both these pathways modulate translation in transcript-selective fashion depending on features in target mRNAs’ 5’ untranslated regions (5’UTRs), their effect on transcriptome-wide patterns of mRNA translation has not been compared. Here, employing CRISPR-modified, isogenic TSC2 patient-derived neural progenitor cells (NPCs), we examined how loss of TSC2 affects gene expression via changes in mRNA abundance and translation at a transcriptome-wide scale. This revealed abundant mRNA translation alterations in TSC2-Null NPCs overlapping with those we previously observed in TSC1-Null NPCs. Surprisingly, numerous non-monogenic ASD- and NDD-associated genes, identified in patients harboring putative loss-of-function mutations, were selectively translationally suppressed in TSC2-Null NPCs consistent with their distinct repertoire of 5’UTR features. Importantly, translation of these ASD- and NDD-associated genes was reversed upon inhibition of either mTORC1 or MNK1/2 signaling using RMC-6272 or eFT-508, respectively. This study thereby establishes mTORC1-eIF4F and MNK-eIF4E-sensitive mRNA translation as key components in TSC, ASD and other neurodevelopmental disorders; and lay the groundwork for evaluating drugs in clinical development that target these pathways as a treatment strategy for TSC as well as ASD/NDD.

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ZMYND11 Functions in Bimodal Regulation of Latent Genes and Brain-like Splicing to Safeguard Corticogenesis [CUT&RUN]

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