Epigenetic regulators partition the genome by evolutionary and developmental constraint
- 1Max Planck Institute of Molecular Genetics
Abstract
Many epigenetic regulators play essential roles in animal development, but precisely how they function across different cell types without clear sequence preferences remains a foundational challenge. Here, we employed single-cell RNA sequencing to survey the mutant phenotypes of 30 essential regulatory pathways across over 450 gastrulation stage mouse embryo replicates, including essential factors associated with repressive chromatin states, RNA surveillance/processing, and other genomic roles. We then use this integrated manifold to partition mutant responses into a developmentally-resolved interaction network, revealing a hierarchy of heterochromatin-associated interactions that act orthogonally to Polycomb Repressive Complex-mediated control of embryo patterning. Compared to the embryo proper, we find that the developing placenta and yolk sac can accommodate broad swings in repetitive element expression, a resilience in keeping with the relative evolutionary recency and phenotypic plasticity of these tissues. Dense temporal sampling of Human Silencing Hub (HUSH) mutant embryogenesis further supports the notion that the gastrulating embryo is particularly constrained and depends on multiple layers of insulation, including the need to suppress evolutionarily young genetic elements to stably license highly conserved, phylotypic programs. In combination, our work highlights the power of single cell-resolved developmental genetics to contextualize the roles of epigenetic regulators, which restrict genomic action to support robust cellular identities and embryological forms.
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BibTeX
@misc{kijima2026epigenetic,
title = {{Epigenetic regulators partition the genome by evolutionary and developmental constraint}},
author = {Y. Kijima and J. Villagrana and M. Wang and R. Tornisiello and N. Dias and J. T.-C. Hou and K. Tse and J. Wang and H. Kretzmer and K. Sumigray and T. Aktas and Z. Smith},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.01.755350},
url = {https://www.biorxiv.org/content/10.64898/2026.10.01.755350v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - Epigenetic regulators partition the genome by evolutionary and developmental constraint
AU - Y. Kijima
AU - J. Villagrana
AU - M. Wang
AU - R. Tornisiello
AU - N. Dias
AU - J. T.-C. Hou
AU - K. Tse
AU - J. Wang
AU - H. Kretzmer
AU - K. Sumigray
AU - T. Aktas
AU - Z. Smith
PY - 2026
DA - 2026/10/01
PB - bioRxiv
DO - 10.64898/2026.10.01.755350
UR - https://www.biorxiv.org/content/10.64898/2026.10.01.755350v1
AB - Many epigenetic regulators play essential roles in animal development, but precisely how they function across different cell types without clear sequence preferences remains a foundational challenge. Here, we employed single-cell RNA sequencing to survey the mutant phenotypes of 30 essential regulatory pathways across over 450 gastrulation stage mouse embryo replicates, including essential factors associated with repressive chromatin states, RNA surveillance/processing, and other genomic roles. We then use this integrated manifold to partition mutant responses into a developmentally-resolved interaction network, revealing a hierarchy of heterochromatin-associated interactions that act orthogonally to Polycomb Repressive Complex-mediated control of embryo patterning. Compared to the embryo proper, we find that the developing placenta and yolk sac can accommodate broad swings in repetitive element expression, a resilience in keeping with the relative evolutionary recency and phenotypic plasticity of these tissues. Dense temporal sampling of Human Silencing Hub (HUSH) mutant embryogenesis further supports the notion that the gastrulating embryo is particularly constrained and depends on multiple layers of insulation, including the need to suppress evolutionarily young genetic elements to stably license highly conserved, phylotypic programs. In combination, our work highlights the power of single cell-resolved developmental genetics to contextualize the roles of epigenetic regulators, which restrict genomic action to support robust cellular identities and embryological forms.
ER -