Conformational acrobatics of entire chromosomes during development

Ahilya Sawh, PhD
Postdoctoral fellow
Biozentrum
University of Basel
Basel, Switzerland

This conference is part of the the IRCM Early-Career Scientist Seminar Series (ECS³), a groundbreaking initiative whose mission is to showcase early career scientists. This is a great opportunity to discover the exciting projects of these researchers in training in front of a multidisciplinary audience.

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Zoom Link: https://zoom.us/j/95269762104
ID: 952 6976 2104
Code: 476372

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About the conference: 
Genome organization is ordered and multi-layered, from the nucleosome to chromosomal scales. Defects in organization are implicated in aberrant developmental and diseased states, but the mechanisms of action are not well understood, nor is it clear what conformations are prevalent in vivo and how they are formed. In my research program, I study the forms and functions of genome organization at the single-cell level with high spatiotemporal resolution, using novel super-resolution imaging and computational approaches. I developed high-throughput, multiplexed DNA FISH to trace the contours of chromosomes (‘chromosome tracing’) and probe conformational dynamics during C. elegans development. Chromosome tracing enables the simultaneous localization of thousands of fluorescently-labeled targets to directly map chromosome architecture. I found that early embryonic chromosomes form unexpected barbell-like configurations, where epigenetically similar domains are segregated. The barbell is remodeled at the onset of gastrulation and the zygotic genome activation to group inactive genomic regions in space over large distances. Using unsupervised single-chromosome clustering, I uncovered sub-populations of chromosomes defined by differing lamina association, biophysical folding, and compartment strength and positioning, suggesting highly divergent epigenetic profiles and transcriptional outputs. Moreover, I found that the lamina plays a novel topological role in systemically stretching chromosomes, increasing structural heterogeneity, and weakening compartments. My studies reveal an unexpected push and pull between epigenetic state and lamina tethering in chromosome conformation, and lay the foundation for the future functional dissection of the 3D genome in development and disease.

About Ahilya Sawh : 
Dr. Ahilya Sawh holds a PhD in Biochemistry from McGill University and currently pursues postdoctoral training in the lab of Dr. Susan Mango, which relocated in 2019 from Harvard University to the University of Basel Biozentrum, in Switzerland. Her research focuses on spatial omics and aims to characterize nuclear organisation and chromatin biology in the context of development and disease. The work of Dr. Sawh is funded by a SPARK Project Grant from the Swiss National Science Foundation and by an Excellent Junior Researcher Grant from the University of Basel. Her discoveries have published in several high-calibre journals such as Molecular Cell, Cell Reports, and Nature Ecology and Evolution. Dr. Sawh is involved in countless spheres of the scientific world, as a speaker, teacher, reviewer, mentor, event organizer, and society member.

Please tell us about your career path, leading up to your application to the ECS3 program:
During my postdoctoral studies in the Mango lab (Harvard University/University of Basel), I have developed new high-throughput single-molecule tools and applied them to make biological discoveries that challenge previous theories about the 3D organization of the genome. The 3D organization of chromosomes can be a key contributor of essential genomic functions, but many gaps remain in our knowledge regarding the forms and functions of nuclear organization in vivo. I discovered the developmental milestone for chromosome compartmentalization in embryogenesis and a remarkable heterogeneity of co-existing chromosome compartment structures. I also discovered a surprising role for the nuclear lamina in stretching entire chromosomes, promoting heterogeneity, and inhibiting compartmentalization. My work was the first to directly demonstrate such higher-order structural variability, and challenges the original concept of chromosome compartments as static entities.

During my PhD studies in the Duchaine lab (McGill University), I studied the mechanisms of multiple RNA interference pathways. RNAi mechanisms orchestrate gene silencing through overlapping pathways in a multitude of organisms, but how the RNAi machinery itself is regulated is not well understood. I discovered and characterized novel proteoforms of the highly conserved RNase III enzyme Dicer, and investigated the molecular mechanisms of nuclear RNAi pathways.

In the future, I will launch an interdisciplinary program to delve deeper into the principles of genome organization and answer fundamental questions that were previously untenable. I will combine the novel super-resolution imaging (spatial genomics) and computational biology approaches I have developed as a postdoctoral fellow with my expertise in biochemistry, genetics, and genome engineering (HBSc Biochemistry & Biomedical Sciences, summa cum laude McMaster University; PhD Biochemistry McGill University).

Please tell us about your passion for research. What motivates you most about your work?
What motivates me the most in research is a passion for discovery. Peering “under the hood” at miraculous and complex biological processes, which answers some questions and simultaneously generates many newer questions, is a joy.

Please tell us about the next steps of your career. How will participating in the ECS3 program help you progress as a researcher?
This great opportunity to participate in the ECS3 program will allow me to communicate my research vision, and discuss diverse topics with the stellar researchers in the IRCM community. I hope to create my own research group, and bring my expertise, technology, and knowledge back home to Canada. The ECS3 program will provide visibility and networking opportunities to help me achieve this goal.

Please tell us about your professional goals. What do you hope to accomplish as a scientist?
The aim of my research is to understand the fundamental principles of nuclear organization and its role in cell fate decisions, at the single-cell level and across biological scales. My work will uncover the genetic and molecular determinants of chromosome conformations to shape our understanding of how 3D genome features are established and maintained. Ultimately, I aspire to elucidate both the forms and functions of nuclear organization during animal development, and deepen our understanding of how nuclear organization impacts pathological cell states.

As a scientist, I am also committed to broader academic goals. I believe that a diversity of perspectives creates an academic environment that is creative, innovative, productive, and fair. Thus, I hope to foster equitable and inclusive excellence in academia through both personal and institutional efforts in mentoring, teaching, and outreach.