Studies Reveal How 3D Genome Folding Shapes Early Human Development and Meiosis

Two studies from researchers at the MRC Laboratory of Medical Sciences (LMS) and Imperial College London reveal how the genome’s three-dimensional architecture pre-arranges gene activity during early human development. One study, published in Cell Reports, shows that enhancers form physical contacts with their future target genes long before those genes are switched on, helping pre-select them for rapid activation. The other, published in Nature Structural & Molecular Biology, finds that embryonic germ cells uniquely reorganize their chromosomes before meiosis, a step that may be critical for creating functional sperm and eggs in the laboratory.

Every cell in the body contains the same set of genes. Regions of DNA called enhancers act as “molecular switches” that turn genes on and off in the correct cell type and conditions. Because enhancers are often far away on the DNA thread from the genes they control, they need to come into proximity through DNA looping within the 3D space of the nucleus. Using a high-resolution technique called Capture Hi-C, the team mapped enhancer chromosomal contacts in human pluripotent stem cells transitioning from the naïve to the primed state, a critical window in early human embryogenesis when cells undergo crucial changes in gene expression, chromatin state and developmental potential. During this time, many enhancers controlling genes responsible for embryonic development acquire an intermediate, ‘poised’ chromatin state between ‘on’ and ‘off’ and make physical connections with their future target genes.

The results show that many enhancers form chromosomal contacts with genes long before these genes are turned on, and these pre-formed contacts are often retained until genes must activate later. To test the functional importance of this pre-wiring, the team artificially switched on a poised enhancer using CRISPR targeting. This activated a gene already connected to the enhancer in 3D, but not a gene located closer along the chromosome that lacked such contact. The study’s senior author said: “Even before any gene expression has happened, the genome is already set up to enable the right enhancers to activate. This is a fundamental process that helps define cell identity across the life course.” The work complements another recent study from the institute demonstrating the 3D genomic blueprint of the first steps of embryo development in Drosophila.

In the second study, researchers focused on germ cells — the embryonic precursors of egg and sperm cells. Before these cells can develop into gametes, they undergo epigenetic reprogramming, wiping and rebuilding chemical marks on DNA and reorganizing how DNA is packaged inside the cell. This reset prepares cells for meiosis. By studying mouse germ cells under a microscope, the team found that around 14.5 days after fertilization, the constricted region of the chromosomes — the centromere — becomes tethered to the edge of the nucleus. The same phenomenon was visible in early germ cells in human embryos at 14 weeks post conception. Hi-C analysis revealed that at this transitional point the genome’s three-dimensional organization becomes less structured and chromosomes become more separated inside the nucleus. According to the first author, this is the first time anyone has seen this change in chromosome conformation at this crucial developmental stage, right before meiosis begins.

The finding may help explain a major challenge in reproductive biology: recreating meiosis in the laboratory. Lab-generated primordial germ cell–like cells (PGCLCs) often fail to complete all steps of meiosis. The team studied lab-generated mouse PGCLCs and did not see the same centromere migration, suggesting this structural change could be required for meiosis to proceed properly. The senior author said: “Our study has uncovered a previously unknown and frankly very surprising restructuring of genome architecture that occurs in developing germ cells, which we believe is critical for a successful execution of meiosis.” The findings provide a new framework for improving in vitro gametogenesis, which could lead to new treatments for infertility.

The Cell Reports study was funded by the Medical Research Council, the Biotechnology and Biological Sciences Research Council and the Wellcome Trust. The Nature Structural & Molecular Biology study was funded by the Medical Research Council, the European Research Council, the Academy of Medical Sciences and the Department of Business, Energy and Industrial Strategy.