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Study Links Regulatory Changes during Development to Human Cerebral Cortex Evolution

NEW YORK (GenomeWeb) — By comparing the epigenetic profiles of human, rhesus macaque, and mouse cerebral cortices during development, researchers from Yale School of Medicine and elsewhere uncovered enhancers and promoters that have increased activity in humans.

As they reported in Science today, researchers led by Yale's Kevin Noonan found that these activity gains commonly occurred in modules of genes that are co-expressed in the cerebral cortex, the region of the brain involved in conscious thought and language. These gene modules were linked to neuronal proliferation, cortical patterning, and the extracellular matrix, suggesting to the investigators that regulatory changes might have provided the foundation for the evolution of the human cortex.

"Building a more complex cortex likely involves several things: making more cells, modifying the functions of cortical areas, and changing the connections neurons make with each other. And the regulatory changes we found in humans are associated with those processes," Noonan said in a statement. "This likely involves evolutionary modifications to cellular proliferation, cortical patterning, and other developmental processes that are generally well conserved across many species."

Noonan and his colleagues profiled the chromatin marks H3K27ac and H3K4me2 during three stages of corticogenesis in human, rhesus macaque, and mouse genomes to identify more than 22,000 promoters and 52,000 enhancers active in the human cortex during at least one of the stages examined. They also found 74,000 promoters and enhancers active in the rhesus macaque and nearly 75,000 promoters and enhancers active in the mouse genome.

By comparing across the species, the researchers found 8,996 enhancers and 2,855 promoters with epigenetic gains in humans.

Noonan and his colleagues integrated their epigenetic findings with publicly available RNA sequencing data from BrainSpan on developing neocortical regions to develop a co-expression network. This network included 96 modules, each containing a set of genes with highly correlated expression in a number of neocotical regions over time.

Using this, Noonan and his colleagues found 17 modules enriched for gains in at least one developmental stage. A gene ontology analysis, they noted, found that these modules were enriched for activity in neuronal differentiation and neuron fate commitment.

For instance, module 15 is enriched for promoter gains and is associated with cortical-patterning ontologies like regionalization and forebrain development, while module 10 is strongly enriched for both promoter and enhancer gains and has activity in extracellular matrix, the researchers reported.

They also noted that the expression of these gain-enriched modules were more highly correlated with one another than with other modules in the network, and that gain-associated genes in enriched modules tended to have related biological functions like cortical patterning, extracellular matrix signaling, and cell cycle and cell proliferation.

The investigators additionally found that enhancers and promoters in these modules also contained similar transcription factor motifs, indicating that there is regulatory cross talk among these enriched modules. This, the researchers added, likely contributes to their highly correlated expression.

Noonan and his colleagues also found that these epigenetic changes tended to occur at sequences that had ancestral regulatory activity.

"While we often think of the human brain as a highly innovative structure, it's been surprising that so many of these regulatory elements seem to play a role in ancient processes important for building the cortex in all mammals," first author Steven Reilly from Yale added. "However, this is often a hallmark of evolution, tinkering with the tools available to produce new features and functions."

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