Distinct nuclear compartment-associated genome architecture in the developing mammalian brain

Nat Neurosci. 2021 Sep;24(9):1235-1242. doi: 10.1038/s41593-021-00879-5. | PubMed

Sajad Hamid Ahanger^1,2,3, Ryan N Delgado^1,2,4, Eugene Gil^1,2, Mitchel A Cole^2,5, Jingjing Zhao^6,7, Sung Jun Hong^1,2,8, Arnold R Kriegstein^2,9, Tomasz J Nowakowski^2,4,10, Alex A Pollen^2,9, Daniel A Lim^11,12,13

1. Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA.
2. Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA.
3. San Francisco Veterans Affairs Medical Center, San Francisco, CA, USA.
4. Department of Anatomy, University of California, San Francisco, San Francisco, CA, USA.
5. Medical Scientist Training Program, Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA, USA.
6. Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, USA.
7. Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA.
8. Developmental and Stem Cell Biology Graduate Program, University of California, San Francisco, San Francisco, CA, USA.
9. Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
10. Department of Psychiatry, University of California, San Francisco, San Francisco, CA, USA.
11. Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA. daniel.lim@ucsf.edu.
12. Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA. daniel.lim@ucsf.edu.
13. San Francisco Veterans Affairs Medical Center, San Francisco, CA, USA. daniel.lim@ucsf.edu.

Abstract

Nuclear compartments are thought to play a role in three-dimensional genome organization and gene expression. In mammalian brain, the architecture and dynamics of nuclear compartment-associated genome organization is not known. In this study, we developed Genome Organization using CUT and RUN Technology (GO-CaRT) to map genomic interactions with two nuclear compartments-the nuclear lamina and nuclear speckles-from different regions of the developing mouse, macaque and human brain. Lamina-associated domain (LAD) architecture in cells in vivo is distinct from that of cultured cells, including major differences in LADs previously considered to be cell type invariant. In the mouse and human forebrain, dorsal and ventral neural precursor cells have differences in LAD architecture that correspond to their regional identity. LADs in the human and mouse cortex contain transcriptionally highly active sub-domains characterized by broad depletion of histone-3-lysine-9 dimethylation. Evolutionarily conserved LADs in human, macaque and mouse brain are enriched for transcriptionally active neural genes associated with synapse function. By integrating GO-CaRT maps with genome-wide association study data, we found speckle-associated domains to be enriched for schizophrenia risk loci, indicating a physical relationship between these disease-associated genetic variants and a specific nuclear structure. Our work provides a framework for understanding the relationship between distinct nuclear compartments and genome function in brain development and disease.

Presented By Sajad Hamid Ahanger | ORCID iD