Single-nucleus Hi-C reveals unique chromatin reorganization at oocyte-to-zygote transition

Abstract

Chromatin is reprogrammed after fertilization to produce a totipotent zygote with the potential to generate a new organism1. The maternal genome inherited through the oocyte and the paternal genome provided by sperm coexist as separate haploid nuclei in the zygote. How these two epigenetically distinct genomes are spatially organized is poorly understood. Existing chromosome conformation capture-based methods2–5 are inapplicable to oocytes and zygotes due to a paucity of material. To study the 3D chromatin organization in rare cell types, we developed a single-nucleus Hi-C (snHi-C) protocol that provides >10-fold more contacts per cell than the previous method2. Here we show that chromatin architecture is uniquely reorganized during the mouse oocyte-to-zygote transition and is distinct in paternal and maternal nuclei within single-cell zygotes. Features of genomic organization including compartments, topologically associating domains (TADs) and loops are present in individual oocytes when averaged over the genome; each feature at a locus is variable between cells. At the sub-megabase level, we observe stochastic clusters of contacts that violate TAD boundaries but average into TADs. Strikingly, we found that TADs and loops but not compartments are present in zygotic maternal chromatin, suggesting that these are generated by different mechanisms. Our results demonstrate that the global chromatin organization of zygote nuclei is fundamentally different from other interphase cells. An understanding of this zygotic chromatin “ground state” has the potential to provide insights into reprogramming to totipotency.

Ice-sheet history revealed by fossils

“…As such, they could arise from weak preferences summed across many cells, with real contacts in individual cells frequently crossing TAD boundaries. Single-cell Hi-C (which does measure contacts in individual cells) has not yet given a definitive answer: the current study provides evidence that TADs do indeed exist in individual cells, whereas other recent analyses 12,13 have reached the opposite conclusion.…”

RotoStep: A Chromosome Dynamics Simulator Reveals Mechanisms of Loop Extrusion

“…This unstable positive-feedback loop may contribute to condensin's enrichment at the pericentromere and nucleolus in vivo. Such a transient, positive feedback may explain the existence of TADs in population studies, but not in single cells (Flyamer et al 2017). In essence, the organization of the DNA biases the occasional enrichment of condensin based on the presence of a tether causing a loop.…”

Two independent modes of chromatin organization revealed by cohesin removal

“…This compartmentalization is however blurred by the action of a second, cohesin-dependent, mechanism that compacts chromatin locally, independently of its status. Noteworthy, the independence of the two mechanisms is supported the absence of compartments, despite of the existence of TADs, in maternal zygotic pronuclei 39 .…”