Our research provided ground breaking information on each of the aims of the project. The main discoveries from the 3DEpi project are as follows:
Aim 1a). The Drosophila fruit fly can carry transgenerational epigenetic inheritance (TEI) of chromatin states thanks to the modulation of its three-dimensional (3D) nuclear organization. In the past, we had exploited a system of transgenic flies that can lead to TEI. In the 3DEpi project, we mutated transcription factor binding sites within the Fab-7 element. The data demonstrate the importance of two DNA binding proteins in the establishment and maintenance of TEI. This work has been published recently (see paper 1).
Aim 1b). In a second endeavour, we investigated whether memory of chromatin states can be perturbed by transient impairment of Polycomb function. Thanks to the 3DEpi project, we could show that epithelial cells with an identical genome could be committed to a tumor phenotype by transiently reducing the activity of the PRC1 complex during development. These tumors are therefore completely epigenetic in nature (see paper 2).
Aim 2a). In order to directly address whether 3D genome organization changes can lead to TEI, we have designed a synthetic biological system called “Three-Dimensional Contact Induction System” or “3D-CIS”. This system can artificially induce chromatin contacts. Our results showed that the activation of the 3D-CIS system was able to establish TEI. These results demonstrate that chromatin contacts alone, in the absence of any genetic perturbation, are sufficient to induce TEI in Drosophila (see paper 1).
Aim 2b). In parallel, we used super-resolution microscopy in order to understand the physical nature of chromatin domains in single cells and to understand whether challenges to mammalian cells can translate into modification of this physical state. Our analysis provided fundamental information for the folding of individual chromosomes at the nanoscale (see paper 3) and it is being used as a basis for further studies aimed at understanding the role or 3D architecture in epigenetic inheritance.
Aim 3). Here, we explored whether TEI could play a more general role in natural populations and conditions. We concentrated on the Waddington assimilation of an acquired character experiment (see PMID: 13666847). We could demonstrate that the assimilation of this trait is driven by the selection of regulatory alleles already present in the ancestral populations, rather than stress-induced genetic or epigenetic variation, drives the evolution of ectopic veins in natural fly populations (see paper 4).
1) Fitz-James, M. H., Sabaris, G., Sarkies, P., Bantignies, F. & Cavalli, G. Interchromosomal contacts between regulatory regions trigger stable transgenerational epigenetic inheritance in Drosophila. Molecular Cell (2024), DOI: 10.1016/j.molcel.2024.11.021.
2) Parreno, V. et al. Transient loss of Polycomb components induces an epigenetic cancer fate. Nature 629, 688-696 (2024). https://doi.org:10.1038/s41586-024-07328-w.
3) Szabo, Q. et al. Regulation of single-cell genome organization into TADs and chromatin nanodomains. Nature Genetics 52, 1151-1157 (2020).
4) Sabaris, G. et al. A mechanistic basis of genetic assimilation in natural fly populations. Proc Natl Acad Sci U S A in press, (2025).
