Belokopytova, P. S. | bioRxiv Science

bioRxiv2025

A novel role for the CNTN6 locus in lumenization and radial glial cell fate determination during early human cortical development revealed in cerebral organoids

Neurodevelopmental disorders are a class of heterogeneous diseases with a significant genetic contribution, including pathologies resulting from copy number variations (CNVs). Recent advancements in genetic diagnostic technologies have led to the identification of new genes associated with neurodevelopmental disorders through CNVs. One such gene is CNTN6, whose variants and CNVs are associated with intellectual disability and autism spectrum disorders. Cntn6 encodes a neural cell adhesion molecule involved in rodents in axon and dendrite guidance, synapse formation, and oligodendrocyte differentiation, playing a critical role in brain development. However, in humans, the specific molecular and cellular pathogenetic mechanisms remain elusive. Using various techniques to model human brain development pathologies, such as somatic cell reprogramming, cerebral organoids, and genome editing, we established that the CNTN6 locus is involved in the lumenization and cell identity of radial glial cells, as well as in regulating their proliferation. Furthermore, we found that the CNTN6 locus is involved in the nuclear-cytoplasmic translocation of PAX6 protein, a key regulator of forebrain development. Molecular studies revealed that CNTN6 partially functions through the Notch signaling pathway during the early stages of human brain development. Our findings unveil a novel role of the CNTN6 locus in the early stages of human cortical development.

developmental biology↗

bioRxiv2024

Direction and modality of transcription changes caused by TAD boundary disruption in Slc29a3/Unc5b locus depends on tissue-specific epigenetic context

Topologically associated domains (TADs) are believed to be involved in the regulation of gene expression. While the impact of TAD perturbations is usually studied in developmental genes with highly cell-type-specific expression patterns, this study examines genes with broad expression profiles divided by a strong insulatory boundary. We focused on mouse Slc29a3/Unc5b locus, which encompasses two distinct TADs. Our analysis demonstrates that deletions of CTCF binding sites within this locus lead to alterations in local chromatin architecture, disrupting existing loops and forming novel long-range interactions. We evaluated the transcription changes of Unc5b, Slc29a3, Psap, Vsir, Cdh23, and Sgpl1 genes across various organs, finding that TAD boundary disruption results in variable transcriptional responses, where not only magnitude, but also direction of gene expression changes are tissue-specific. Current models of genome architecture, including enhancer competition and hijacking, only partially account for these transcriptional changes, indicating the need for further investigation into the mechanisms underlying TAD function and gene regulation.

genetics↗