Eukaryotic genomes are organized in 3D in a multiscale manner, and different mechanisms acting at each of these scales can contribute to transcriptional regulation. However, the large single-cell variability in 3D chromatin structures represents a challenge to understand how transcription may be differentially regulated between cell types in a robust and efficient manner. Here, we describe the different mechanisms by which 3D chromatin structure was shown to contribute to cell-type-specific transcriptional regulation. Excitingly, several novel methodologies able to measure 3D chromatin conformation and transcription in single cells in their native tissue context, or to detect the dynamics of cis-regulatory interactions, are starting to allow quantitative dissection of chromatin structure noise and relate it to how transcription may be regulated between different cell types and cell states.
Section snippetsNoise in 3D genome structureEukaryotic chromosomes are compacted into several levels, including chromosome territories [1], active and repressive (A/B) compartments [2], lamina-associated domains (LADs) [3], topologically associating domains (TADs) 4, 5, 6, and loops formed by CCCTC-binding factor (CTCF) binding sites predominantly located at TAD borders [7]. This multiscale organization provides the means to regulate transcription at multiple levels 8, 9, including by histone modifications, by chromatin opening, by
How does 3D genome structure change between cell types?Comparative studies of embryonic stem cells (ESC) and ES-derived cell lineages reported extensive changes in A/B compartments 32, 33. Earlier studies reported that TADs are conserved between cell types and across species [4], and remain stable during differentiation [32]. However, a higher-resolution work showed that TADs can change between mouse ESC and differentiated culture cells 33, 34, 35. We note that evolutionary conservation of TADs does not necessarily reflect structural stability (see
Visualizing chromatin organization in single cellsImaging-based methods have been used for many decades to investigate chromosome organization, with fluorescence in situ hybridization (FISH) being arguably the most popular. A critical limitation of conventional FISH labeling approaches was uplifted by Oligopaint [65], which enables flexible, rapid, and efficient design and synthesis of FISH probesets. This technology, combined with microfluidics and with innovative oligonucleotide designs, enabled the simultaneous imaging of multiple genomic
Conclusions and future perspectivesOver the last two decades, multiple lines of evidence independently established that 3D chromatin organization can drastically change between single cells of the same specimen (chromatin structure noise). In the last few years, the advent of multiplexed imaging, time-lapse microscopy, and single-cell sequencing methods has enabled the dissection of single-cell variability in genome organization at multiple genomic and physical scales, and showed that this noise is present at all levels of
CRediT authorship contribution statementMarie Schaeffer: Conceptualization, Writing – original draft, Writing – review & editing, writing — figures. Marcelo Nollmann: Conceptualization, Funding acquisition, Writing – review & editing.
Conflict of interest statementWe wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome.
AcknowledgementsWe acknowledge funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (Grant Agreement No 724429).
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