Erika Larshan’s primary research focus is on understanding the X chromosome and how dose compensation affects sex-specific gene expression.
Image credits:Matt Kalinowski Erin Lemieux, Brown University
I2012, scientist Molecular biologist Erika Larshan said this shortly after establishing her lab at Brown University. Larshan’s early interest in biology led him to focus his research on gene regulation, and he uncovered the role of a family of histone-modifying enzymes in yeast transcriptional activation and the mechanisms of sex chromosome dose compensation in yeast. Drosophila early in her career.
Over the next 14 years, Rashan continued to harness the power of modern technology to unravel the intricacies of gene regulation and the mysteries of the X chromosome. “The development of new technology has really helped us ask deeper questions,” Rashan said. “For example, we used to primarily study genomes in two dimensions, but now we can actually look at 3D genomes and see what’s going on in real time. [and] Let’s look at it at the single cell level. ”
CRISPR revolution, multi-omics, and machine learning
In the early days of Rashan’s lab, she faced her first major challenge. “We spent the first five years in the lab actually knocking out this gene at a very difficult location in the genome, a very compressed and heterochromatic location,” she explained. “We were just banging our heads against the wall.”
When her former colleague Jennifer Doudna, now a biochemist at the University of California, Berkeley, revealed the groundbreaking potential of precision gene editing using CRISPR-Cas9 at an alumni symposium, Larshan had to follow up on the talk, and she quickly realized how much of an impact it would have on her research. “The CRISPR revolution has changed everything in terms of what we can do. I think it’s had the biggest impact of almost any discovery in the past decade,” Rashan said.
Advances in multi-omics have also facilitated the evolution of Larshan’s research. For example, her group developed a web-based tool called TIMEOR (Trajectory Inference and Mechanism Exploration with Omics in R). This tool uses time-series multi-omics data to predict relationships between gene regulatory events and how gene regulation changes over time.1
Larschan’s primary focus over the years has been studying the X chromosome and how dose compensation balances the magnitude of X-linked gene expression. Studying the genome in three dimensions helped Larshan and her team better understand the chromatin structure of the X chromosome and identify how transcription factor binding sites cluster in 3D space.2 “We have made great advances in our understanding of how the X chromosome is specifically specified for gene regulation, and this underlies many of the sex differences we see between men and women,” said Rashan. “I think our biggest accomplishment is actually figuring out in three dimensions how to find the X chromosome and target it for this particular regulation.”
Rashan also uses artificial intelligence in his research, collaborating with computer scientists on joint projects. She and her colleagues will use machine learning to develop a model that can predict factors that differ between the X chromosome and other chromosomes, and will test potential candidates in the lab. Although the team expected many generalizations to be made, the results were surprising. “We found that there are a lot of combinatorial interactions that we didn’t expect, and machine learning can help us parse them out,” she said.
Unexpected discoveries and inspiration for the next generation
Rashan’s efforts to understand the X chromosome led her down an unexpected path. When neuroscientist Kate O’Connor Giles moved her lab to Brown University, she approached Larshan with the idea of studying gene regulation in the brain. Interested, Rashan agreed, and they accepted a joint student, who began working there.
In a recent preprint, the research team demonstrated that two chromatin regulators that Larshan had previously studied in connection with X-chromosome gene expression actually function to coordinate synapse formation in the brain. Disruption of either regulatory factor results in excessive synapse formation, leading to intellectual disability.3 Larshan said the results were highly unexpected, as researchers had thought that these regulators worked in every cell in the body and had no tissue-specific functions. “They turned out to be very important in the brain,” she added.
When evaluating his success, Rashan emphasized the accomplishments of the students he has mentored as well as his own scientific discoveries. “The most important thing we can do is help the next generation,” she said. “Several of the people in my lab have started their own labs and are now able to really go in new directions and expand what we can do. That’s the best part. Our success will be measured by how well they do and how well we can continue these exciting areas of research.”
Looking back on his previous profile articles, Rashan said it helped him boost his confidence at the right time. “At the time I was a young mother with a very small baby. [had] “I was suffering from a lot of impostor syndrome, so it definitely helped me,” she recalled.
