Thesis defense Yike Huang ‘Space odyssey: characterizing transcriptional regulation at a distance’

The DNA, containing the genetic information of our cells, is divided into chunks of information called genes. Gene activation can result in protein production and is termed gene expression. DNA organization, referring to the folding and storage of DNA in the cell nucleus, is one of the processes that affects the expression of genes. Here, a general rule applies: the more loosely folded a DNA region, the more ‘active’ the genes. In her PhD project, Huang investigated DNA organization and gene expression, specifically focusing on the interaction between them.

Creating DNA loops

A specific process of DNA organization that Huang studied is called ‘loop extrusion’. “This involves a protein called cohesin, which can fold the DNA to make loops in it,” Huang explains. To study the effect of this looping, Huang developed a new method, TArgeted Cohesin Loader (TACL), that enables researchers to initiate loop extrusion at specific locations in the DNA. “This method allowed us to measure how loop extrusion influences gene expression. It gives us an idea of how this would influence the cell. We discovered that gene expression is hampered at locations where we induced the formation of loops,” Huang says. With these results, Huang and her colleagues shed new light on one of the mysteries in the field: the interaction between cohesin and the proteins involved in gene expression.

Enhancers and silencers

Apart from DNA organization, other mechanisms also influence gene expression, such as regulatory DNA elements called enhancers and silencers. These regions are located in a part of the DNA that is quite condescendingly referred to as ‘junk DNA’. Although this suggests it to be useless, nothing is further from the truth: enhancers and silencers regulate gene expression and can therefore steer protein production. Their effects on gene expression are as their names suggest: enhancers can stimulate it and silencers repress it. During her PhD, Huang uncovered new roles of enhancers and silencers. “We discovered that enhancers may play a role in recruiting cohesin to the DNA, which in turn makes loops in the DNA and stimulates the expression of specific genes in that DNA area,” she explains. Huang also identified new silencers that are capable of inhibiting the expression of genes across great distances in the DNA. In other words, these regulatory DNA elements are able to inactivate parts of the DNA that are far from their own location, something for which direct evidence had been limited.

The PhD experience

Although it could sometimes be difficult to deal with the stress, Huang also sees many highlights in her PhD. One of those was obtaining a Keystone Symposia scholarship. “This allowed me to attend and present at a conference on chromatin architecture in Canada, which was a great experience,” Huang says. “Another highlight is that some of my former and current lab mates are now my friends outside of work.” Finally, Huang has some advice for students considering to do a PhD: “Take your time to selects topics and projects that you are interested in. It takes a lot of hard work and stress to finish a PhD, so choose the things that you really like.”