Dr. Marta Seczynska

Written by Dr. Anna Sherwood

Dr. Marta Seczynska is a postdoctoral researcher with Prof. Lars Steinmetz at the Department of Genetics of Stanford University, USA. She obtained her PhD in Medical Science with Prof. Paul Lehner from University of Cambridge, UK and her MSc and BSc in Biotechnology from Jagiellonian University in Krakow, Poland. Dr. Seczynska is a recipient of the prestigious International Birnstiel Award for Doctoral Research in Molecular Life Sciences as well as a postdoctoral fellowship from the European Molecular Biology Organization (EMBO).

During her doctoral studies, Marta studied how mammalian cells recognize and respond to invading genetic elements such as viruses and transposons. She discovered that the human silencing hub (HUSH), an epigenetic repressor, targets a broad range of invading DNAs for transcriptional repression, even in the absence of prior exposure to those specific DNAs. As other silencing pathways rely on sequence-based memory of previous invasions to recognize their targets, this established a novel paradigm in genome defense. Marta showed that HUSH specifically recognizes nascent RNA from its target loci and identified intronless DNA as a key molecular feature, which allows HUSH to differentiate ‘self’ genomic DNA from ‘non-self’ genetic invaders. Lack of introns is the essential hallmark of genetic elements which replicate through an RNA-intermediate and are reverse transcribed from RNA to DNA prior to genome integration. By silencing intronless DNAs, HUSH controls this unusual, reverse flow of genetic information within mammalian genomes. These findings reveal the existence of a unique genome defense pathway and have important implications for both genome evolution and therapeutic expression from recombinant DNAs.

Dr. Seczynska was especially excited about parts of this project: “HUSH is a truly fascinating complex and although my work provided some important insight into HUSH function, there is still a lot to understand about the mechanism by which it works. My work also raises some important questions. For example, what is the interplay between HUSH and other epigenetic silencing pathways (in particular in the germline), and also how the repression of different RNA-derived elements, including endogenous intronless genes, influences genome evolution.”

She further elaborated on the most thrilling parts of this stimulating project: “The most satisfying moments in this project were when I was going through genome browser and found that HUSH binds and represses some endogenous intronless genomic loci. At that time, we had a hypothesis that HUSH may somehow use introns to distinguish ‘non-self’ invading elements (usually intronless) from ‘self’ host genes (majority have classical intron-exon structure). If that was true, then we would expect intronless endogenous loci (so ‘self’ intronless host genes) to be HUSH repressed too. Realizing this is indeed the case was one of the most exciting and satisfying moments in this project.”

Currently, Dr. Seczynska is enthusiastic about her “early days” (she’s been in the lab for ~6 months) postdoctoral project at Stanford. “I am excited to use genetic screens with targeted single cell transcriptome readouts to identify novel mechanisms by which RNA-binding proteins control tissue-specific gene expression and maintain transcriptional memory. Despite the well-recognized importance of RNA-binding proteins in regulating gene expression and a clear association of RNA-binding proteins dysfunction with numerous diseases, only a small fraction of over 2,000 RNA-binding proteins have known molecular functions. So far, RNA-binding proteins have been mostly characterized through biochemical approaches and I feel this field can greatly benefit from functional genetic approaches.”

“I have always been trying to get inspiration from many different scientists: learn how they approach science and take away the best aspects of it for myself - almost like making a mosaic with different types of tiles in the hope to end up with a comprehensive picture.”

The development of new “functional genetic approaches” is one of the reasons she was drawn to the Steinmetz laboratory at Stanford. “Steinmetz lab develops and applies novel technologies to investigate gene expression mechanisms and the genetic basis of complex phenotypes and diseases. What drew me to this lab was its’ well-recognized expertise in the development and application of technologies that greatly expand the scope of functional genetic screening approaches. I did my PhD with Paul Lehner who is one of the pioneers of forward genetic screening in mammalian cells. During my training, I developed a great appreciation for functional genetic approaches, especially in the context of discovery science. Moving forward, my aim is to leverage the technological expertise of the Steinmetz laboratory to generate insights and hypotheses that I can then mechanistically interrogate using a more reductionist approach. Another reason I decided to join the lab is the incredible atmosphere of collegiality. All lab members get along with each other really well and are eager to frequently and openly discuss science. Also, Lars is very supportive and gives everybody a lot of freedom. This in turn empowers people to take the initiative and really drive their own research. The atmosphere and the overall work environment could be often overlooked when deciding to join a particular laboratory but greatly enhances our satisfaction and scientific output. At the end of the day, I think we all enjoy science the most when we can share our scientific passion with driven and enthusiastic colleagues.”

Expanding further on her scientific career choices, Marta gave the following advice: “Don’t follow ‘scientific fashion’ by focusing on the ‘trendy’ topics, which are often transient. Instead, put your efforts into addressing the important scientific questions. Also, don’t necessarily go for ‘low-hanging fruit’ projects. Although these seem attractive, they may neither lead to any interesting discoveries nor offer room for scientific development. I think that long-term perspective is what matters the most. So take up challenges and invest your time in developing your skills and growing as a scientist and always learn!  Learn how people approach science differently and take away the best aspects of their approaches for yourself. Finally, surround yourself with supportive mentors and people who want to see you succeed. I was privileged to have amazing mentors in my career, and I think that makes all the difference.”

Fortunate to be surrounded by accomplished scientists, Marta specifically mentioned Barbara McClintock as one of her scientific inspirations: “As a scientist interested in mobile genetic elements, I have been always inspired by testimonies describing Barbara McClintock’s life and groundbreaking research. What particularly strikes me is her reputation for having an almost obsessive attention to detail in her experiments and observations, but, at the same time, her ability to take creative leaps to explain those details as well as her extraordinary vision of the implications of her discoveries. It is absolutely remarkable to me that ~70 years ago, she envisioned that ‘the real point of mobile elements is control’! Seeing recent studies describing numerous examples of how transposon-derived regulatory sequences and cellular pathways that control transposon expression orchestrate gene regulation in developing and adult tissues, I think we can all say she couldn’t have been more right!”

When asked about a favorite paper from the RNA journal, Marta mentions a new paper describing extensive structural homology between two distantly-related pseudo-PARP domains found in HUSH complex member TASOR and piRNA-pathway protein TEX15. “I find it interesting that despite the significant evolutionary distance between these two domains, TEX15 pseudo-PARP can functionally substitute for TASOR pseudo-PARP, an essential domain within the HUSH complex, whose function remains unknown.”

You can reach out to Dr. Marta Seczynska on Twitter @seczynska.