Cerebellar cells show dramatic changes in the 3D structure of their genome throughout the first year of a person’s life, according to new research presented yesterday at Neuroscience 2022 in San Diego, California. The findings, compiled into an atlas of genomic architecture in the brain region over time, could help reveal how neurodevelopmental conditions such as autism alter neuronal function, the researchers say.
The human genome, if stretched into a single strand, would be about 2 meters long. To fit into the 10-micron nucleus of a cell, it must be tightly packed into chromatin, protein bundles, and chromosomes. The resulting physical conformations – through which genes from distant parts of the strand can come into close contact – influence gene expression and cellular function.
This genomic architecture differs by cell type and changes with age in mouse cerebral cortex, according to previous research from the same team. But it wasn’t clear whether that was true for humans and in the cerebellum, an area of the brain that includes different cell types and appears to develop atypically in autism, says Longzhi Tan, a postdoctoral researcher in the lab. by Karl Deisseroth at Stanford University in California. , who presented the work.
The new atlas “could provide unique insights into the molecular mechanism of neurodevelopment and autism, as the cerebellum and chromatin organization have been repeatedly implicated in autism,” Tan says.
JAn and his colleagues assessed the genomic structure of 10,476 cells from cerebellar tissue samples from mice and humans, from birth to adulthood.
The researchers determined the genomic structure of cerebellar cells using their previously developed method, called Dip-C, which cuts out a strand of DNA for sequencing while retaining information about originally neighboring regions. This information makes it possible to reconstruct the physical structure of the genome inside the cell nuclei.
At birth, the outer layer of cerebellar cells, called granule cells, in mice and humans have genomic shapes similar to those seen in cortical cells, Tan and colleagues found, with most interactions occurring between neighboring genes. But in both species, the granule cells end up reconfiguring their genomes in such a way that generally distant genes have an increased amount of contact.
Cerebellar cells take longer to mature and show greater changes in their genomic structure than cells in the cerebral cortex, the team found.
This suggests that the maturation of the cerebellum genome “continues well beyond the maturation of its gross anatomy,” Tan says.
The genomic architecture of granule cells also continues to mature long after birth, and unlike that of cells in the cerebral cortex, it exists in multiple stages of maturation at once rather than maturing synchronously, the team found.
Mutations in the autism-linked genes ARID1B and CHD8, which are known to affect chromatin structure, did not alter the genomic structure of granule cells in a small sample of adult mice, the team found. But it’s possible that other cells or earlier periods of development were affected by the mutations, Tan says. For now, the overall results can serve as a resource for brain cell development and a guide on how to further study genomic structure, he says.
“A cell’s fate changes over time,” says Haruhiko Bito, a professor of neurochemistry at the University of Tokyo in Japan, who was not involved in the work. Genetic changes that lead to conditions such as autism could very well affect a cell’s ability to alter genomic structure, he says, even if those changes aren’t immediately obvious. “That’s why it’s very important that you can test the flexibility and dynamics of these nuclear states during the different stages of life.”
In the future, Tan and his colleagues plan to compare the 3D genomic structures of cells from autistic and non-autistic people and study whether proteins encoded by autism-linked genes affect the genomic architecture of cerebellar cells, says Tan.
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Cite this article: https://doi.org/10.53053/HKEW7747