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bioRxiv · 10.1101/2024.11.27.625786

Genome Organization with CUT and Tag (GO-CaT) identifies substructure and maturation of lamina-associated domains in neurons of the developing human brain

Zhang, C.·Gil, E.·Ahanger, S. H.·Li, M.·Wang, L.·Li, J.·Kriegstein, A.·Lim, D.
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Abstract

Approximately 30-40% of the human genome is anchored to the nuclear lamina (NL) through variably sized (10 kb-10 Mb) lamina-associated domains (LADs), which can be classified into two subtypes (T1 and T2) based on their level of lamina-association. The dynamics of LAD substructure in cells that remain postmitotic for long periods of time are poorly understood. Here, we developed Genome Organization with CUT and Tag (GO-CaT) to determine the T1- and T2-LAD substructure of postmitotic excitatory neurons isolated from the prenatal and adult human cortex. While T1-LADs exhibited epigenomic features characteristic of stable, cell type-invariant LADs including strong transcriptional repression, in prenatal neurons, T2-LADs were enriched for promoter-enhancer DNA interactions, intermediate levels of gene expression, and genetic risk associated with neurodevelopmental and cognitive disorders. In adult cortical neurons, T1-LADs were expanded in size and genomic coverage, incorporating the majority of the prenatal T2-LADs, sequestering genes involved in neurodevelopment. In contrast, the minority of prenatal T2-LADs that relocated to inter-LAD regions in adult neurons were enriched for processes related to synaptic function. Overall, these data provide evidence that LADs "mature" in postmitotic neurons, remodeling from a genomic architecture that is more permissive for the dynamics of transcription of development to one that is more restricted and focused on the decades-long transcriptional needs of adult brain neurons.

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Zhang, C., Gil, E., Ahanger, S. H., Li, M., Wang, L., Li, J., Kriegstein, A., Lim, D.. 2024-11-28. Genome Organization with CUT and Tag (GO-CaT) identifies substructure and maturation of lamina-associated domains in neurons of the developing human brain. https://doi.org/10.1101/2024.11.27.625786

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