April 19, 2021

The architect of genome folding

The spatial organization of the genome is fundamental for the regulation of our genes and has to be established de novo during early embryogenesis. By combining powerful Drosophila genetics with 3D chromosome modelling, a collaboration between the Giorgetti group at the FMI and the MPI of Immunobiology and Epigenetics in Freiburg revealed a critical role of the epigenetic regulator HP1 in the establishment of 3D genome organization in the early Drosophila embryo. The study was published in Nature.

The human genome is encoded by approximately 3 billion DNA base pairs and packaged into 23 pairs of chromosomes. If all chromosomes could be disentangled and linearly aligned, they would make up a thin thread of about 2 meters. The DNA molecule must therefore be extensively packaged to fit inside the tiny nucleus of each cell in our bodies. The chromatin fiber – made by DNA wounded around histone proteins – is fundamental for further packaging of the genetic material into chromosomes. The degree at which chromatin is packaged and folded in the nucleus also correlates with the timing and type of gene expression, but the molecular machinery that supervises the establishment of 3D chromatin organization remains largely unknown.

Early embryonic development is a particularly interesting time window to study the processes governing the 3D organization of chromatin. At fertilization, sperm and egg fuse, and the resulting zygote will ultimately give rise to all the different cells of the body. Interestingly most of the epigenetic modifications that shape chromatin and control gene activity are erased and have to be established de novo. The 3D structure of the genome also undergoes major restructuring events after fertilization including a clustering of highly compacted regions around the centromere, the folding of chromosome arms, and the segregation of chromosomes into active and inactive compartments.

In this study, using Drosophila as a model organism, the lab of Nicola Iovino at the Max Planck Institute (MPI) in Freiburg, Germany identified heterochromatin protein 1 (HP1) as an important epigenetic regulator necessary to maintain individual chromosome integrity and to establish the global structure of the genome in the early embryo.

3D genome simulation
The MPI researchers then wanted to understand in detail what effect the depletion of HP1 had on chromosome folding and nuclear structure. They reached out to Luca Giorgetti’s team at the FMI for that. Using the data generated at the MPI, PhD student Yinxiu Zhan (now a postdoc) and colleagues applied a genome-wide polymer modelling strategy. This can be considered as if they built a realistic three-dimensional models of chromosomes applying the laws of polymer physics (a chromosome is a polymer).

“The advantage of this approach is that it allows simulating the effects of very large numbers of mutations,” says Giorgetti. “This enables researchers to explore scenarios that are beyond experimental reach such as the simultaneous depletion of many different proteins that would require years of lab work. By comparing simulations with the outcome of experiments, this approach also allows to test alternative hypotheses concerning the mechanisms that lay at the basis of experimental observation.”

Thanks to the polymer models, the FMI researchers could determine the forces that alter the shape of chromosomes when HP1 is removed from its binding sites, and provided further confirmation that HP1 plays a key role in establishing the three-dimensional structure of the genome in the early embryo.