Alistair Boettiger, PhD,  Assistant Professor in the Department of Developmental Biology at the Stanford University School of Medicine

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Alistair Boettiger, PhD,  Assistant Professor in the Department of Developmental Biology at the Stanford University School of Medicine

February 1, 2023 @ 4:00 pm - 5:00 pm

Biomedical Data Science Seminar Series, BRB Gaulton Auditorium

Title: Untangling genetic puzzles with spatial genome imaging

This week hosted by IBI, invited by Golnaz Vahedi

Abstract

Over the past decade, advances in sequencing based methods have helped advance our understanding of genome organization and function from a 1D view into a new field of 3D genome organization, mapping structural organization genome wide and identifying key regulators. These advances have opened an array of new questions, not easily addressed by the available technologies but central to understanding the results. What physical 3D structures underlie the patterns in frequency-of-contact among genomic loci revealed by sequencing approaches such as Hi-C?  That is to say, what does a “topologically associating domain” (TAD), a “CTCF loop”, or an “architectural stripe” look like under the microscope, and how do such measurements help us understand the transcriptional regulatory potential of such features?

I will describe our work developing single molecule super-resolution methods to image the 3D organization of the genome, and describe how these approaches are helping us to understand both the mechanisms which regulate genome structure and the impact of this regulation on transcriptional control in animal development.  Using an imaging approach we’ve called Optical Reconstruction of Chromatin Architecture (ORCA), I will first show how the microscopy data, averaged across a population of cells, can map de novo these same TADs, loops and stripes, identified by deep Hi-C, helping to validate both methods, while uncovering artifacts in some related sequencing methods. I will then describe how the single-cell nature of the 3D traces uncover the highly heterogeneous, likely dynamic nature of chromatin folding, and exclude some earlier explanations of cis-regulatory specificity based on chromatin globules. Applying ORCA in spatially organized embryonic tissues, combined with multiplexed single molecule RNA analyses, we are able to follow how divergent 3D folding leads to divergent cell-fates during development and how disruption of this 3D structure can produce homeotic fate transformations. Combining ORCA with fast-acting degrons to rapidly deplete architectural proteins, I will show unpublished work on how we have mapped the key proteins CTCF and cohesin organize 3D genome folding in single cells, from the kilobase scale of single genes to the whole chromosomes. These data reveal unexpected roles for CTCF in the bypass of TAD borders and unexpected roles for cohesin in chromosome-scale 3D structure, which we find has an essential noise-damping effect of global transcription regulation.

I will close with a final unpublished example of how imaging 3D chromatin structure has helped us evaluate and understand the potential roles of phase-separation and droplet formation in the function of the epigenetic repressive system of Polycomb factors.

 

Bio

Alistair Boettiger is an Assistant Professor of Developmental Biology at Stanford University, where his lab develops and applies quantitative super-resolution microscopy to study the role of 3D genome organization in transcriptional regulation and differentiation.

Alistair completed his undergraduate training in the Department of Physics at Princeton University, where Stansilav Shvartsman introduced him to quantitative imaging in Drosophila development. He conducted his Ph.D. research in Biophysics under the guidance of Michael Levine at UC Berkeley, a team known for pioneering work understanding cis-regulation, where his work identified several molecular and genetic mechanisms ensuring transcriptional precision and robustness in early Drosophila embryogenesis. His postdoctoral research was conducted in the laboratory of Xiaowei Zhuang at Harvard, known for pioneering work in single-molecule super-resolution. There, he co-led the development of methods for image-based spatial transcriptomics with fellow physicist Jeffrey Moffitt and graduate student Kok-Hao Chen, and adapted super-resolution microscopy approaches to uncover organizational principles of how epigenetic differences affect 3D chromatin folding. Since 2016, his team at Stanford combines the power of both Drosophila genetics and mouse embryonic stem cell genetics with single-molecule and super-resolution imaging to better understand transcriptional regulation during development. His awards include recognition as a ”Dale Frey Award for Breakthrough Scientists”, a “New Innovator” from NIH, a “Packard Foundation Fellow”, a “Beckman Young Investigator”, a “Kavli Fellow” from the National Academy of Sciences, and a “Searle Scholar”.

Details

Date:
February 1, 2023
Time:
4:00 pm - 5:00 pm
Event Category:

Organizer

Jessica Incmikoski
Email
jessicai@pennmedicine.upenn.edu

Venue

Upenn, Biomedical Research Building
421 Curie Boulevard
Philadelphia, PA 19104 United States
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Phone
215-746-4060
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