Completed Genetics & Molecular Biology Cells, Biochemistry & Physiology

Genome regulation across developmental trajectories

In plain English

AI plain-English summary

Every cell in a worm embryo will have its DNA activity mapped, one cell at a time, from the very first division to the formation of a fully differentiated intestine. The central problem this research tackles is that we still do not understand how a single fertilised egg reliably turns into hundreds of specialised cell types, each with a unique pattern of which genes are switched on or off. Current single-cell techniques can measure gene activity in individual cells, but they cannot easily track how a mother cell’s regulatory state is inherited by its daughters. The nematode *C. elegans* solves this because its cell lineage is fixed and completely known—every cell’s family tree is identical from one worm to the next. By profiling every cell from the zygote to the 26-cell stage, and then following the 20-cell intestine through its entire development, the researchers will map how the genome wakes up after fertilisation, how cells commit to different fates, and how three-dimensional genome structure relates to gene activity. This is fundamental science with no immediate practical application, but understanding the core principles of genome regulation in a simple animal has historically revealed mechanisms—such as programmed cell death and RNA interference—that later proved universal across animals, including humans.

View original technical description
To understand how the genome directs development, we need to know the cell-to-cell changes in genomic activity at individual loci and how changes are regulated. Advances in single-cell profiling provide a new ability to determine the regulatory configuration of individual cells genome-wide through profiling gene expression and chromatin accessibility. However, determining the connections between mother and daughter cells remains difficult. The invariant and known cell lineage of C. elegans solves this problem, making it possible with single-cell profiling to determine locus-specific activity in every cell from the zygote to the differentiated state. In Aim 1 we study the early events of genome quiescence, zygotic genome activation (ZGA), and lineage commitment by profiling all cells from the zygote to the 26-cell stage, and germ cells through their later ZGA. In Aim 2 we use the 20-cell intestine as a paradigm to study progression through a complete developmental trajectory. We will investigate mechanisms of key transitions and further study the relationship of activity patterns to genome 3D structure. In Aim 3, we focus on the impacts and regulation of active and PRC2/Polycomb chromatin domains. Our work will impact understanding of core principles of genome regulation relevant across animals.

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Researchers

Julie Ahringer (EPMC Awardee)

Related Research

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Original classification

Investigator Award in Science

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