Epigenetics to Epigenomics: How We Understand the Brain

A blog on brain exploration

In his blog posted on March 17, National Institutes of Health Director Francis Collins asks a provocative question: “What Makes Our Brains Human?” He then provides at least a partial answer to that question with the help of some new science out of Yale (Reilly et al, Science, 2015). 

For starters, there are 16 billion neurons neatly packed into our cerebral cortex. That part of the human brain, the center of our speech and abstract thinking, represents four-fifths of our total brain mass and, as such, is larger and more complex in Homo sapiens than in any other species.

When trying to figure out how our cerebral cortex evolved to this point, many scientists—including Alzheimer’s researchers—have looked to genes that code for diversified proteins underlying the cerebral cortex’s sophisticated functions. However, that’s only part of the answer, says Collins. He describes how the Yale research, rather than focusing on protein-coding DNA, instead tracked the activity of two types of gene regulators: “promoters, which are DNA signals that generally lie just upstream of protein-coding genes; and enhancers, which are DNA regions that can be located some distance away, but modulate a gene’s output, rather like the dimmer function on a light switch.”

Using epigenetic techniques, they were able to identify 22,139 promoters and 52,317 enhancers active in human embryonic brain tissue between 7 to 12 weeks following conception—a critical start-up period for the human cerebral cortex. When this genetic map was compared to those from the rhesus monkey and mouse, nearly 12,000 regulatory elements stood out as being more active in humans than in the other mammals.

The same researchers next overlaid their human-specific list of regulatory elements and target genes onto the BrainSpan atlas, an NIH-supported effort that “maps” gene expression in the human brain from early development to adulthood. After combining both data sets in this fashion, they were able to narrow their list of promoters and enhancers down to ones that regulate genes playing pivotal roles in human brain development. Remarkably, they identified 17 common biological processes and pathways—including cortical patterning, renewal of progenitor cells, and migration of neurons—as being crucial for the development of the human cortex.

In the director’s words: “This work demonstrates the power of comparing maps of regulatory elements with maps of gene expression. Not only does this ‘epigenomic’ approach enable scientists to look more systematically at biological processes in the brain, it may prove valuable in studying other organ systems as well.”

Their accomplishment also lends insight into the sophistication of Alzheimer’s research which, rather than being focused on the developing brain, is focused on the role of gene expression and regulation in the deteriorating hippocampus—the brain’s chief “indexer” or “card catalog” that provides access to stored memories. In our quest for “cure in mind”—one part of our three-fold mission to find new treatments and cures for Alzheimer’s disease, macular degeneration, and glaucoma—BrightFocus is funding numerous investigations to uncover the genetic trail behind memory loss and cognitive dysfunction. To describe the work in more poetic terms, our researchers are attempting to write the saga of the imperiled hippocampus as it comes under attack during the decades-long course of Alzheimer’s disease.

It’s fitting that the pioneers behind this research call it their attempt to “map” the brain. Similar to their layering of genetic discoveries, Carolus Linnaeus once organized life on this planet into kingdoms and species (with a few levels in between), work illuminated by Darwin’s unifying theory of evolution. Before that, Copernicus, Magellan, and others overlaid star maps with physical data to achieve the breakthrough realization that our planet orbits around the sun, rather than vice versa, and is itself a round orb that is perpetually spinning. The past century’s expansion of knowledge makes the inner world of the brain seem as complicated as the outer world of the planets and universe. Still, it’s all part of the same tradition, and eventually we’ll be able to navigate this universe and fix more of the problems that lie within, including Alzheimer’s.