What do you see as the most important developments in your field in the past decade or so?
There have been so many exciting developments in the field of genome regulation during the past 10−15 years. In my opinion this has come from the convergence of different fields. Ten to fifteen years ago, many groups, including my own, were studying how enhancers function as individual modules − dissecting the relationship between DNA sequence content and transcription factor occupancy, and the relationship between occupancy and activity, trying to learn rules about motif spacing and orientation in terms of output, such as linear versus non-linear effects. For this, you can study enhancers in isolation; this is actually one of their remarkable features that they can function as individual separate modules [cis-regulatory modules (CRMs)], out of their normal context, to regulate expression in much the same pattern as when in their endogenous location. In parallel, many scientists were working on how chromatin is organized in the nucleus, defining the general properties of heterochromatin and euchromatin, how the genome is folded and if its movement within the nucleus was random or constrained. This was mainly driven by microscopy-based methods. But as more molecular tools became available, many people from this field started moving down the molecular scale towards different cis-regulatory elements including enhancers, as an important potential player for chromatin movement. In parallel, ‘enhancer biologists’ were beginning to look up and ask how enhancers interact with their target gene, and how the activity of multiple enhancers is integrated at a gene’s promoter to regulate gene expression. What was almost two separate fields has now come together where scientists are converging on the same problem from very different angles.
The other very important advancement in the last 5 years, is the development of single-cell regulatory genomes methods, which allow us to look at enhancer usage at a scale that simply wasn’t possible before. This is allowing us to look upstream of RNA, identifying the regulatory elements that are being dynamically used at different stages of embryogenesis. We can basically follow the regulation of a tissue’s development.
What’s exciting in your research area right now?
I’m excited about many things at the moment. The current questions that we are discussing in the lab are how enhancers find their correct target gene. What are the forces that bring them together? What controls the specificity of enhancer−promoter interactions? What are the dynamics of these interactions and how do they relate to transcriptional activity? What are the factors regulating these loops?
The technologies are now quantitative and dynamic enough to be able to measure enhancer−promoter looping. We are studying this in the context of embryonic development, using Drosophila as a model system. We are using genetics and optogenetics to dissect cause from consequence – to establish the order of events.
Zooming out from how enhancers work mechanistically, a long-standing interest of mine is how enhancers regulate large gene regulatory networks that drive embryonic development. Here, single-cell genomics, especially methods that give regulatory information, are very exciting. We are combining those with different mutants, perturbing development, and it’s amazing to see that this combination can phenotype mutants de novo and quantify those phenotypes, as well as identify new subtle phenotypes that were previously missed.
Should biochemists / molecular biologists / cell biologists be interested in research beyond their own area nowadays?
Absolutely: it is not a question of should we – we must! Time and time again, science has shown us that the big discoveries, and the most exciting research, often come from the intersection of different fields. New methods and concepts in one area of biology can really help to illuminate another. The life sciences have also become very interdisciplinary. In my own field, this is very clear from the integration of high-level microscopy and genomics for example, and currently from the integration of AI and deep learning in almost everything. Sitting in your own area with your blinkers on will not help you, and is also a pretty boring way to do science, in my opinion!
Introduction to Eileen Furlong’s work
The Furlong lab dissects fundamental principles of transcriptional regulation, and how it drives cell fate decisions during development, focusing on the organizational and functional properties of the genome. Complex patterns of spatial and temporal gene expression are a hallmark of development, and a central driving force for the progressive restriction of cell fates during embryogenesis. How a single genome can generate such a diversity of cells, and how transcriptional networks control and buffer the process of differentiation, are the two overarching questions in the lab. To tackle these, the group optimizes and pushes genomic methods for use within complex multicellular embryos. They make use of the systematic unbiased nature of genomics, the power of Drosophila genetics, high-resolution imaging and approaches from developmental and evolutionary biology, to understand how the genome is regulated and organised during development.
Lab webpage: http://furlonglab.embl.de/
Two recent/key papers:
Secchia, S. et al. (2022) Simultaneous cellular and molecular phenotyping of embryonic mutants using single-cell regulatory trajectories. Dev. Cell 57, 496-511.e8. https://doi.org/10.1016/j.devcel.2022.01.016
Calderon, D. et al. (2022) The continuum of Drosophila embryonic development at single-cell resolution. Science 377:eabn5800. https://doi.org/10.1126%2Fscience.abn5800
More information on the EMBO Lecture at the FEBS Congress
Eileen Furlong will deliver the EMBO Lecture at the 47th FEBS Congress in Tours, France on Monday 10th July 2023 on ‘Genome regulation during developmental transitions: New views of old questions’: 2023.febscongress.org/