The genome-wide multi-layered architecture of chromosome pairing in early Drosophila embryos

Jelena Erceg,Nezar Abdennur,Maxim Imakaev,Anton Goloborodko,Bryan R Lajoie,Jumana Alhaj Abed,T Niroshini Senaratne,Mohammed A Hannan,Son C Nguyen,C.-Ting Wu,Leonid A Mirny,Eric F Joyce,Ruth B Mccole,Wren Saylor,Job Dekker,Geoffrey Fudenberg,Guy Nir

doi:10.1038/s41467-019-12211-8

Abstract

Genome organization involves cis and trans chromosomal interactions, both implicated in gene regulation, development, and disease. Here, we focus on trans interactions in Drosophila, where homologous chromosomes are paired in somatic cells from embryogenesis through adulthood. We first address long-standing questions regarding the structure of embryonic homolog pairing and, to this end, develop a haplotype-resolved Hi-C approach to minimize homolog misassignment and thus robustly distinguish trans-homolog from cis contacts. This computational approach, which we call Ohm, reveals pairing to be surprisingly structured genome-wide, with trans-homolog domains, compartments, and interaction peaks, many coinciding with analogous cis features. We also find a significant genome-wide correlation between pairing, transcription during zygotic genome activation, and binding of the pioneer factor Zelda. Our findings reveal a complex, highly structured organization underlying homolog pairing, first discovered a century ago in Drosophila. Finally, we demonstrate the versatility of our haplotype-resolved approach by applying it to mammalian embryos.

Highlights

Genome organization involves cis and trans chromosomal interactions, both implicated in gene regulation, development, and disease
We reveal the coincidence between trans-homolog features and the positions and sizes of analogous cis features and provide a three-axis framework of precision, proximity, and continuity to accommodate all types of inter-chromosomal interactions, including homolog pairing
We focused our Hi-C analysis on the window of Drosophila embryogenesis extending from 2–4 h after egg laying (AEL), when zygotic gene transcription is activated and the embryo transitions from a syncytial blastoderm into a multicellular state[32]

Summary

Introduction

Genome organization involves cis and trans chromosomal interactions, both implicated in gene regulation, development, and disease. We first address long-standing questions regarding the structure of embryonic homolog pairing and, to this end, develop a haplotype-resolved Hi-C approach to minimize homolog misassignment and robustly distinguish trans-homolog from cis contacts This computational approach, which we call Ohm, reveals pairing to be surprisingly structured genome-wide, with trans-homolog domains, compartments, and interaction peaks, many coinciding with analogous cis features. We reveal the coincidence between trans-homolog features and the positions and sizes of analogous cis features and provide a three-axis framework of precision, proximity, and continuity to accommodate all types of inter-chromosomal interactions, including homolog pairing These findings complement those of our companion study (AlHaj Abed, Erceg, Goloborodko et al.31), which, by generating and using a Drosophila hybrid cell line with a high degree of pairing, enabled a much more indepth analysis of the structure of pairing. We find that pairing correlates with the opening of chromatin mediated by the pioneer factor Zelda during zygotic genome activation

Methods

Results

Conclusion