NCBP2-mediated apoptosis contributes to developmental defects of the schizophrenia-associated 3q29 deletion

Singh, M. D.; Jensen, M.; Lasser, M.; Huber, E.; Yusuff, T.; Pizzo, L.; Lifschutz, B.; Desai, I.; Kubina, A.; Yennawar, S.; Kim, S.; Iyer, J.; Rincon-Limas, D. E.; Lowery, L. A.; Girirajan, S.

doi:10.1101/614750

bioRxiv · 10.1101/614750

NCBP2-mediated apoptosis contributes to developmental defects of the schizophrenia-associated 3q29 deletion

Singh, M. D.·Jensen, M.·Lasser, M.·Huber, E.·Yusuff, T.·Pizzo, L.·Lifschutz, B.·Desai, I.·Kubina, A.·Yennawar, S.·Kim, S.·Iyer, J.·Rincon-Limas, D. E.·Lowery, L. A.·Girirajan, S.

View original source ↗Export metadata ↓

Abstract

The 1.6 Mbp deletion on chromosome 3q29 is associated with a range of neurodevelopmental disorders, including schizophrenia, autism, microcephaly, and intellectual disability. Despite its importance towards neurodevelopment, the role of individual genes, genetic interactions, and disrupted biological mechanisms underlying the deletion have not been thoroughly characterized. Here, we used quantitative methods to assay Drosophila melanogaster and Xenopus laevis models with tissue-specific individual and pairwise knockdown of 14 homologs of genes within the 3q29 region. We identified developmental, cellular, and neuronal phenotypes for multiple homologs of 3q29 genes, potentially due to altered apoptosis and cell cycle mechanisms during development. Using the fly eye, we screened for 314 pairwise knockdowns of homologs of 3q29 genes and identified 44 interactions between pairs of homologs and 34 interactions with other neurodevelopmental genes. Interestingly, NCBP2 homologs in Drosophila (Cbp20) and X. laevis (ncbp2) enhanced the phenotypes of homologs of the other 3q29 genes, leading to significant increases in apoptosis that disrupted cellular organization and brain morphology. These cellular and neuronal defects were rescued with overexpression of the apoptosis inhibitors Diap1 and xiap in both models, suggesting that apoptosis is one of several potential biological mechanisms disrupted by the deletion. NCBP2 was also highly connected to other 3q29 genes in a human brain-specific interaction network, providing support for the relevance of our results towards the human deletion. Overall, our study suggests that NCBP2-mediated genetic interactions within the 3q29 region disrupt apoptosis and cell cycle mechanisms during development. AUTHOR SUMMARYRare copy-number variants, or large deletions and duplications in the genome, are associated with a wide range of neurodevelopmental disorders. The 3q29 deletion confers an increased risk for schizophrenia, autism, and microcephaly. To understand the conserved biological mechanisms that are disrupted by this deletion, we systematically tested 14 individual homologs and 314 pairwise interactions of 3q29 genes for neuronal, cellular, and developmental phenotypes in Drosophila melanogaster and Xenopus laevis models. We found that multiple homologs of genes within the deletion region contribute towards developmental defects, such as larval lethality and disrupted cellular organization. Interestingly, we found that NCBP2 acts as a key modifier gene within the region, enhancing the developmental phenotypes of each of the homologs for other 3q29 genes and leading to disruptions in apoptosis and cell cycle pathways. Our results suggest that multiple genes within the 3q29 region interact with each other through shared mechanisms and jointly contribute to neurodevelopmental defects.

Explore related subjects

genomics Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Singh, M. D., Jensen, M., Lasser, M., Huber, E., Yusuff, T., Pizzo, L., Lifschutz, B., Desai, I., Kubina, A., Yennawar, S., Kim, S., Iyer, J., Rincon-Limas, D. E., Lowery, L. A., Girirajan, S.. 2019-04-22. NCBP2-mediated apoptosis contributes to developmental defects of the schizophrenia-associated 3q29 deletion. https://doi.org/10.1101/614750

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Long-read DNA sequencing reveals global hypomethylation and focal hypermethylation in SDHx-deficient pheochromocytoma and paraganglioma

Pheochromocytomas and paragangliomas (PPGL) are highly heritable neuroendocrine tumors of the autonomic ganglia. Genomic DNA in most cancer cells is hypomethylated. However, DNA in PPGLs secondary to mutations in succinate dehydrogenase complex (SDHx) genes is reportedly hypermethylated due to succinate-mediated inhibition of DNA demethylases. We used nanopore long-read sequencing to characterize the methylome of tumor and white blood cell DNA from SDHx and non-SDHx PPGL patients, alongside normal adrenal medulla. We find that both SDHx and non-SDHx PPGLs are globally hypomethylated, particularly at centromeres. In normal adrenal medulla, CpG islands marked by H3K4 methylation are hypomethylated, whereas CpG islands lacking H3K4 methylation are hypermethylated. In SDHx-related PPGL, some H3K4me-marked CpG islands are hypermethylated, but most are not. We propose that DNA methylation in SDHx-related PPGL reflects the global hypomethylation generally observed in tumors, partly offset by succinate-mediated inhibition of TET DNA demethylases. Opposing effects of succinate may alter the balance between DNA methylation (indirect inhibition of the DNMT3A/B DNA methylases via inhibition of H3K4me demethylases) and DNA demethylation (inhibition of TET DNA demethylases) at active CpG islands.

genomics↗

bioRxiv2026

High piRNA abundance is a hallmark of evolutionarily persistent piRNA-producing loci.

PIWI-interacting RNAs (piRNAs) silence transposons in the germline, and the loci that produce them diverge rapidly between species. Yet, some loci retain both their genomic location and their piRNA production across large evolutionary distances, and the basis for this conservation is unclear. To identify the features that distinguish these persistent loci, we compared piRNA production at orthologous loci in three closely related mouse species, contrasting loci that produce piRNAs in all three species with those that do so in only one. Transposon content and UTR features, often linked to piRNA production, did not distinguish the two groups. Transcription extending beyond gene ends (readthrough) was more frequent at conserved loci, but did not explain conservation once the amount of piRNAs produced was taken into account. Instead, we found that the conserved loci are those that produce the most piRNAs. The same association holds true in human and two other primate species. We speculate that most piRNAs expressed in testis are tolerated molecular noise, and that only the highly expressed minority are likely to be functional.

genomics↗

bioRxiv2026

Epigenome-informed Polymer Modeling Reveals Chromosome Folding Landscapes across Distinct Genetic and Epigenetic Contexts

Three-dimensional (3D) genome organization is critical for gene regulation, enabling long-range interactions between genes and distal regulatory elements. Genomic structural variations and epigenetic differences can perturb this organization, contributing to phenotypic variation and tissue-specific gene regulation. Prior studies have assessed the impact of these genetic and epigenetic changes on 3D genome folding, primarily using population-averaged features such as topologically associating domains and loops. However, growing evidence from single-cell and live-imaging studies indicates that chromosomes are highly dynamic and exist as heterogeneous ensembles of conformations. Here, we applied an epigenetic-state-informed polymer modeling framework to generate chromosomal conformational ensembles directly from cell- and tissue-specific epigenomic data. The resulting ensembles reproduced experimental Hi-C maps across cell lines and tissue types. Comparison of these conformational ensembles revealed that, although polymer dynamics were conserved across cell lines, their folding landscapes diverged. These differences arose primarily from cell-line-specific chromatin-state interaction networks and were concentrated in rare, long-lived contacts. Furthermore, modeling a TAD-boundary-disrupting deletion without re-optimizing the model parameters indicated a shift in the chromatin conformational ensemble from predominantly insulated to predominantly fused states. The modeled deletion also selectively strengthened active chromatin contacts and differentially disrupted enhancer contacts involving neighboring genes. Finally, comparison of two tissue types from the same donor revealed epigenetically driven rewiring of chromatin-state interaction networks. These findings establish chromosomal conformational ensembles as a sensitive readout of genome reorganization across distinct genetic and epigenetic contexts.

genomics↗