Conserved and species-specific chromatin remodeling and regulatory dynamics during mouse and chicken limb bud development

Shalu Jhanwar,Olga Romashkina,Jonas Malkmus,Rolf Zeller,Aimée Zuniga,Jens Stolte

doi:10.1038/s41467-021-25935-3

Abstract

Chromatin remodeling and genomic alterations impact spatio-temporal regulation of gene expression, which is central to embryonic development. The analysis of mouse and chicken limb development provides important insights into the morphoregulatory mechanisms, however little is known about the regulatory differences underlying their morphological divergence. Here, we identify the underlying shared and species-specific epigenomic and genomic variations. In mouse forelimb buds, we observe striking synchrony between the temporal dynamics of chromatin accessibility and gene expression, while their divergence in chicken wing buds uncovers species-specific regulatory heterochrony. In silico mapping of transcription factor binding sites and computational footprinting establishes the developmental time-restricted transcription factor-DNA interactions. Finally, the construction of target gene networks for HAND2 and GLI3 transcriptional regulators reveals both conserved and species-specific interactions. Our analysis reveals the impact of genome evolution on the regulatory interactions orchestrating vertebrate limb bud morphogenesis and provides a molecular framework for comparative Evo-Devo studies.

Highlights

Chromatin remodeling and genomic alterations impact spatio-temporal regulation of gene expression, which is central to embryonic development
Genes belonging to E9.75hi and E11.5lo Differentially expressed genes (DEGs) modules show the highest expression at E9.75 and their expression decreases during limb bud outgrowth, these two modules are distinct due to their significantly different expression levels at the transition point (E10.5, top and bottom panels in Fig. 1d; box plots in Supplementary Fig. 1c)
Developmental stage-specific transcriptome profiling identified DEG modules characterized by distinct expression trajectories, which reveals the temporal gene expression dynamics during limb bud development

Summary

Introduction

Chromatin remodeling and genomic alterations impact spatio-temporal regulation of gene expression, which is central to embryonic development. In mouse forelimb buds, we observe striking synchrony between the temporal dynamics of chromatin accessibility and gene expression, while their divergence in chicken wing buds uncovers species-specific regulatory heterochrony. Comparative analysis of mouse and pig limb buds identified variations in cis-regulatory landscapes that likely participate in the functional emergence of Artiodactyl limb traits[9,10] Another mechanism contributing to functional divergence of gene regulation is the excessive number of base substitutions that accumulated in a species within otherwise conserved vertebrate CREs. Many of the accelerated regions[11] are developmental enhancers with divergent spatiotemporal activities. Our analysis reveals the striking synchrony between temporal dynamics of chromatin accessibility and gene expression in mouse forelimb buds in contrast to stage-specific divergence in chicken wing buds. Our study reveals the impact of genome evolution on the conserved and diversified gene regulatory trajectories underlying mouse forelimb and chicken wing bud development

Methods

Results

Conclusion