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Dev Cell. 2015 Sep 14;34(5):592-607. doi: 10.1016/j.devcel.2015.07.014. Epub 2015 Aug 27.

The Regulatory Landscape of Lineage Differentiation in a Metazoan Embryo.

Author information

1
Sloan Kettering Institute, 1275 York Avenue, New York, NY 10065, USA. Electronic address: zdu@genetics.ac.cn.
2
Sloan Kettering Institute, 1275 York Avenue, New York, NY 10065, USA.
3
Sloan Kettering Institute, 1275 York Avenue, New York, NY 10065, USA. Electronic address: baoz@mskcc.org.

Abstract

Elucidating the mechanism of cell lineage differentiation is critical for our understanding of development and fate manipulation. Here we combined systematic perturbation and direct lineaging to map the regulatory landscape of lineage differentiation in early C. elegans embryogenesis. High-dimensional phenotypic analysis of 204 essential genes in 1,368 embryos revealed that cell lineage differentiation follows a canalized landscape with barriers shaped by lineage distance and genetic robustness. We assigned function to 201 genes in regulating lineage differentiation, including 175 switches of binary fate choices. We generated a multiscale model that connects gene networks and cells to the experimentally mapped landscape. Simulations showed that the landscape topology determines the propensity of differentiation and regulatory complexity. Furthermore, the model allowed us to identify the chromatin assembly complex CAF-1 as a context-specific repressor of Notch signaling. Our study presents a systematic survey of the regulatory landscape of lineage differentiation of a metazoan embryo.

PMID:
26321128
PMCID:
PMC4573902
DOI:
10.1016/j.devcel.2015.07.014
[Indexed for MEDLINE]
Free PMC Article

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