Kavli Affiliate: Arnold R. Kriegstein
| Authors: Chujing Zhang, Eugene Gil, Sajad Hamid Ahanger, Mingcong Li, Li Wang, Jingjing Li, Arnold Kriegstein and Daniel Lim
| Summary:
Approximately 30-40% of the human genome is anchored to the nuclear lamina through variably sized (10 kb–10 Mb) lamina-associated domains (LADs). Previous work in cultured murine and human cell lines indicate that LADs are not homogenous but can be classified into two subtypes (T1 and T2) based on levels of lamina-association. Due in part to technical limitations, the LAD substructure of neurons maturing in vivo is poorly understood. Here, we developed Genome Organization with CUT and Tag (GO-CaT) to map LAD substructure in neurons isolated from the midgestational human cortex and adult human brain. GO-CaT with LaminB1 antibodies mapped LADs with high efficiency as compared to other methods, and in prenatal neurons, we distinguished T1- and T2-LADs based on levels of LaminB1 enrichment. While T1-LADs had the transcriptional and epigenomic characteristics of cell type-invariant LADs including strong transcriptional repression, T2-LADs had a distinct epigenomic state that included enrichment of promoter-enhancer DNA interactions and intermediate levels of gene expression. In prenatal neurons, T2-LADs defined genomic regions that play key roles in neuronal development and were enriched for neurological GWAS phenotypes including those of human cognitive disorders. In a population of adult brain neurons, most prenatal T2-LADs were repositioned to either inter-LAD regions or further sequestered into T1-LADs, perhaps representing the completed, life-long spatial genome architecture of human neurons. These studies highlight the utility of GO-CaT for LAD subdomain mapping in cells isolated from human tissues and illustrate how the substructure of LADs may contribute to neural development, neuronal maturation, and human brain disease.