Researcher of the Month: Yin Shen, PhD

Posted: May 20, 2019
By Shelley Wong

Although it only costs a thousand dollars to sequence a human genome, our ability to interpret DNA function is quite limited. Only about one to two percent of DNA is coded for protein, with the rest being what Yin Shen, PhD calls “the dark matter of the genome.” Shen, an assistant professor in the Department of Neurology and the Institute for Human Genetics, and her functional genomics lab are investigating non-coding DNA elements and the fundamental mechanisms of transcriptional control underlying cellular function.

“Every single cell in an individual’s body has almost the same genetic blueprint. It is fascinating that each cell knows to express specific genes to achieve highly specialized functions, such as enabling the muscles with contraction, eyes with vision, and the brain with learning and memory abilities. These functional specificities are achieved by the precise control of genes by the 98% of the genome that’s non-coding. The non-coding regions of the genome are like an instructional manual to control the cell to turn genes on and off. The manual is there, but we don’t know how to read it yet,” says Shen. “It’s similar to readers each having a different impression of the same book.”

Her lab is specifically interested in interpreting DNA function related to brain development and how DNA sequences go awry in neuropsychiatric disorders, including autism spectrum disorders (ASD), Alzheimer’s disease (AD), and Parkinson’s disease (PD).

“A lot of common complex disorders don’t have a clear coding mutation. Instead of coding mutation(s), it is the non-coding DNA, which regulates the coding genes, that is altered and contributes to an individual’s altered susceptibility to these complex diseases,” says Shen.

Our work is like creating a GPS for the genome, so that we can link distal non-coding regulatory DNA sequences to their cognate genes in biologically relevant cell types.

Yin Shen, PhD

Assistant Professor of Neurology

It is not straightforward to investigate the function of the “dark matter” part of the genome. Regulatory DNA can control target gene expression from a distance in a cell type-specific manner and such regulation is thought to be achieved by chromatin looping. To better interpret non-coding DNA function, Shen is studying the three-dimensional (3-D) chromatin folding in various cell types. Her lab studies regulatory looping structures of the chromatin in order to know if a piece of non-coding DNA is in contact with gene promoters and whether such looping is critical for transcriptional control.

“It is like creating a GPS for the genome, so that we can link distal non-coding regulatory DNA sequences to their cognate genes in biologically relevant cell types. We then can perturb these sequences to check the biological consequences in corresponding cell types,” Shen says.  

Most recently, Shen has been conducting research to understand how non-coding DNA contributes to human brain development and neurological diseases. “Studying the 3-D epigenome of cells in the nervous system is difficult. The material is scarce and isolating individual cell-types is technically challenging. Every cell type has a distinct 3-D epigenome. We therefore would like to create the GPS in a cell type-specific manner so that we have the resolution to know how non-coding genetic variants contribute to disease in different ways in each cell type,” she says.

To achieve those goals, the Shen lab uses two different but complementary cellular systems. The first system uses induced pluripotent stem cells (iPSC) and differentiates them into different kinds of neural cell types that are impractical to isolate in humans. Her lab is using the iPSC differentiation system to study the 3-D chromatin interactions. Studies adopting this iPSC system in the Shen lab involve collaborations with labs locally at UCSF (Bruce Conklin's and Faranak Fattahi's labs) and across the nation (Li Gan’s lab at Cornell University, and Hongjun Song’s lab at University of Pennsylvania).

“The iPSC system is a beautiful system that allows us to generate the 3-D epigenomic maps of different kinds of neurons, including those nearly equivalent to the excitatory neurons in the cortex, hippocampal dentate gyrus granule cells in the hippocampus, dopamine neurons in the midbrain, lower motor neurons in the spinal cord, and enteric neurons in the gut,” she says.

Their second system uses developing human brain tissues. Together with Arnold Kriegstein's lab at UCSF, they are able to isolate distinct cell populations during human corticogeneisis, including radial glial cells, intermediate progenitor cells, newborn excitatory neurons and interneurons.

Shen says, “Generating the genomic GPS in a cell type-specific manner will enable us to interpret variants related to many neuropsychiatric diseases, link distal variants to target genes, and help us prioritize variants for functional studies. The results from our study suggest that more than half of the variants don’t regulate their neighboring gene(s), but regulate something else in the genome. You won't be able to know this information until you start to investigate the DNA in 3-D conformation. We are continuing with CRISPR tools to demonstrate that perturbing distal regulatory DNA sequence, which is far away from its corresponding target gene, can affect target gene expression and ultimately contribute to diseases.” Her research has the potential to predict the risk of complex diseases, especially neurodegenerative diseases, which would result in earlier diagnosis and interventions. Currently, patients with AD and PD often seek clinical care too late for treatment, because they are diagnosed at a late stage.

These two systems of investigations have a direct link to disease. The Shen lab additionally focuses on the basic research of functional annotation of the mammalian genome. Shen says, “We are performing large-scale CRISPR screenings of non-coding sequences across many regions. We hope by collecting enough functional data for non-coding DNA, we will be able to learn the regulatory logic of transcriptional control and help to understand the genetic basis of complex diseases.”

Shen is currently leading one of the largest functional characterization centers for the Encyclopedia of DNA Elements (ENCODE) project, a National Human Genome Research Institute-funded public research consortium aimed at identifying all functional elements in the human and mouse genomes. Shen strives to achieve the broadest possible reach of this knowledge. “My goal is to be able to tell people which of their variants confer altered risks of diseases. For example, if people know they have a genetic variant associated with an elevated diabetes risk, they will be able to make early lifestyle adjustments,” she says.

Shen grew up in China, earned her PhD at UCLA, and finished her postdoctoral training at the Ludwig Institute for Cancer Research at UC San Diego. Since joining UCSF in 2015, she has been embraced with supportive colleagues and a highly collaborative environment. She is thrilled to be in the Bay Area, where technology innovation is paramount.

As a junior faculty member, Shen is finding success and receiving robust investment in her work. She was ranked as one of the top 2% of funded medical school investigators nationwide by the NIH in 2018. Her guiding light is her commitment to her work: “I believe that persistence is the key to success. Going through grad school and postdoc training is a long journey and there are a lot of distractions along the way. If you can stay focused, you will become the best, eventually.”