The National Institutes of Health have named Jennifer Phillips-Cremins, an assistant professor in the University of Pennsylvania School of Engineering and Applied Science’s Department of Bioengineering, as a member of its 2015 class of New Innovator awardees.  

As part of the NIH’s “High-Risk, High-Reward Research” program, the New Innovator Award provides Phillips-Cremins $2.4 million for the next five years to advance her work on the dynamics of the “3-D Epigenome,” or how DNA, and consequently the epigenetic modifications on top of the DNA sequence, is folded and coiled in the nucleus of neurons during brain development.

Every cell in the body has essentially the same genetic sequence, so the differences in tissue appearance and function can be traced to the timing and level that genes are transcribed in development. Epigenetic marks are a wide range of chemical modifications on top of the genome’s base pairs that give rise to differences in gene expression. Changes in epigenetic modifications have been implicated in normal brain development as well as in neurological disease.      

“We’re interested in the link between epigenetic modifications and the diversity of cell types in the developing and diseased brain,” Phillips-Cremins said. “We now have a wealth of insight into the mechanisms regulating epigenetic marks on the linear genome, but what hasn't been addressed is how epigenetic modifications work through long-range, 3-D mechanisms and how genome architecture fluctuates over short and long time-scales.“

Classic epigenetic marks are chemical modifications physically attached to the genes they influence. When visualized as a linear gene sequence, these epigenetic marks represent an additional layer of information on top of the long sequence of base-pair letters. Looking at these marks in a linear fashion does not reveal the whole picture, however.   

“Often times one might think that epigenetic marks are unrelated if they are separated by vast distances on the linear genome,” Phillips-Cremins said, “but, if you consider the epigenome in the context of the three-dimensional nucleus, many key regions in the genome are spatially adjacent and thereby functionally linked.”

Studying the three-dimensional shape of a genome is daunting, as existing tools can only analyze large populations of cells. The millions of cells studied at a given snapshot in time might each have a slightly different three-dimensional configuration, but scientists are thus far only able to capture what amounts to an averaged signal. This erases whatever signal might be coming from one particular 3-D pattern and how this changes over time.     

“If we could develop tools to very rapidly synchronize the 3-D epigenome across the population of cells and control the folding over very short time scales, we can start to understand how architecture dynamics are linked to brain cell function,” Phillips-Cremins said.

Her New Innovator Award will fund research on “3-D opto-epigenetic” techniques for achieving architecture synchronization and pulsing. Certain proteins are known to aggregate in response to specific frequencies of light. By genetically engineering cells to express these proteins in their nuclei, entire populations of cells could be coaxed into the same 3-D genome configuration upon light pulsing with a laser.  

“Imagine a ball of string that can be coaxed into new 3-D configurations upon flashes of light; the power in this approach is that one could specifically dictate what pieces of string are touching,,” Phillips-Cremins said.    

The same tools that force a population of cells to exhibit the same three-dimensional state in their nuclei could subsequently be used to better understand epigenetic dynamics. Better understanding of the dynamics of epigenetic regulation could eventually lead to targeted treatments for neurological diseases, such as Alzheimer’s.

“If one could control the dynamics of 3-D genome folding on demand, it could have important clinical applications,” Phillips-Cremins said. “It could bring to light the possibility of noninvasively shining light on specific sections of the brain, precisely controlling the gene expression of only specific cell types across time.”