A new study led by MCO graduate student Daniel Loftus of the Whipple Lab has found that differences in maternal and paternal genomes in embryonic stem cells shape gene expression in neurons. The study, which appears in the latest issue of the journal Genes & Development, delves into the 3D structure of a genome region called Peg13-Kcnk9, which contains the gene for the long non-coding RNA Peg13 and the protein-coding gene Kcnk9, among others. The Peg13-Kcnk9 region is known to be imprinted in the brain, meaning that the maternal and paternal copies of the gene are expressed differently. However, relatively little is known about how the parent-specific expression patterns of these genes occur in the brain.
Loftus and his colleagues used a technique called “Hi-C” to look into how the DNA in the Peg13-Kcnk9 is folded in mouse brain tissue and found major differences in the 3D folding of the paternal allele compared to the maternal allele. The maternal allele’s folding made enhancer regions that promote expression of the Kcnk9 gene more accessible, while the paternal allele included binding sites for a protein called CTCF, which can tie the DNA in loops and thus prevent gene expression. While these differences in DNA structure are established early in development, they don’t lead to imprinted gene expression until neurogenesis, demonstrating that chromatin state prior to differentiation can determine developmental gene expression patterns.
The findings show that the changes to how the DNA is folded precede the tissue-specific difference in gene expression. The Peg13-Kcnk9 region is present in the human genome, as well as the mouse genome, meaning that this imprinting mechanism likely occurs in humans. The Whipple team adds that this paper provides an important case study for understanding the mechanisms underpinning genomic imprinting.