Cold Spring Harbor Researchers Identify Worm Biological Clock

COLD SPRING HARBOR, NEW YORK — Researchers at Cold Spring Harbor Laboratory identified a non-repeating biological clock mechanism that schedules gene expression pulses in the worm C. elegans. This feedback circuit is composed of the proteins MYRF-1 and LIN-42, and it dictates the start and duration of these pulses.

The MYRF-1 and LIN-42 circuit operates in every cell to coordinate a sequential series of gene expression pulses that must occur once for proper development. Protein MYRF-1 initiates each developmental stage in C. elegans and is required for the developmental checkpoint at the end of each stage. MYRF-1 also activates protein LIN-42 after a gene expression pulse begins.

Professor Christopher Hammell of the laboratory said, "This is the central clock for all cells in the worm. It is responsible for coordinating a finite series of sequential pulses of gene expression that must occur only once, and in order, for proper developmental progression. It turns genes on and off multiple times during development, but ultimately, it is only going in one direction."

Protein LIN-42 regulates the intensity and duration of each gene expression pulse. Blocking MYRF-1 disrupts the entire developmental cycle in the worm. Hammell said, "We have never seen anything like this before. MYRF-1 is part of this master regulatory clock for all cells, but it is also acting as a key maker and the master key for each stage of growth. Without the right key for each stage, development hits a wall and cannot progress."

The research team identified this developmental clock mechanism using classical molecular experiments, DNA sequencing, protein sequencing, and the AI tool AlphaFold. Leemor Joshua-Tor serves as Director of Research at the laboratory and is a member of the research team.

Researchers plan to investigate the physical interaction between MYRF-1 and LIN-42. They are also investigating whether independent cellular clocks communicate with each other during development. Hammell said, "The MYRF-1/LIN-42 circuit runs in all cells. And every one of these independent cellular clocks appears to be in sync when you watch normal development. But are they communicating with each other?"