The clustering of pericentromeric heterochromatin and the folding of chromosome arms lead to a highly regular Rabl configuration during zygotic genome activation (ZGA) 3, 4. In metazoans, fertilization triggers global de novo chromatin reorganization into heterochromatin and euchromatin. Our work identifies HP1a as an epigenetic regulator that is involved in establishing the global structure of the genome in the early embryo. However, depletion of HP1a does not affect the A-compartment, which suggests that a different molecular mechanism segregates active chromosome regions. Moreover, HP1a binding within chromosome arms is responsible for overall chromosome folding and has an important role in the formation of B-compartment regions. The binding of HP1a at pericentromeric heterochromatin is required to establish clustering of pericentromeric regions. Here, by combining chromosome conformation capture (Hi-C), chromatin immunoprecipitation with high-throughput sequencing (ChIP–seq), 3D DNA fluorescence in situ hybridization (3D DNA FISH) and polymer simulations, we show that heterochromatin protein 1a (HP1a) is essential for de novo 3D genome organization during Drosophila early development. However, the molecular mechanisms that drive de novo organization remain unknown 1, 2. Fundamental features of 3D genome organization are established de novo in the early embryo, including clustering of pericentromeric regions, the folding of chromosome arms and the segregation of chromosomes into active (A-) and inactive (B-) compartments.

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