How does DNA fold? The loop extrusion model

Summary

This study explores how the 2-meter-long human genome folds into the microscopic cell nucleus by forming 10,000 loops, with distant chromosome anchor points coming together. The process is driven by 'Loop Extrusion,' where an extrusion complex expands loops by sliding along the DNA. Specific DNA motifs, such as CTCF, stop the extrusion at certain points, following the 'convergent rule.' This process leads to the formation of loop domains, which segregate genomic regions and prevent entanglement. The findings provide new insights into the 3D architecture of the genome, which aids in understanding how chromosomes organize and behave during cell division.

Takeaways

• 🧬 The human genome, which is 2 meters long, folds into 10,000 loops within the microscopic nucleus of a cell.
• 🔗 Each loop connects two anchor points that are far apart on the chromosome but come close together during folding.
• 📏 The process by which loops are formed is called 'extrusion,' involving two subunits that slide along DNA in opposite directions.
• 🔄 The extrusion complex looks for a specific DNA motif (CTCF) that acts as a stopping point for subunits if it is pointing towards them.
• ↔️ The 'convergent rule' states that CTCF motifs at the ends of a loop must face towards each other for proper loop formation.
• 📊 Loops formed by extrusion lead to the creation of 'loop domains,' areas where parts of the genome inside the same loop interact more frequently.
• 🔍 Extrusion provides insight into how loops and domains form without entanglements, unlike diffusion-based loop formation.
• 🔗 Loops formed by extrusion are unknotted, making it easier to access the genetic information within them.
• 📚 Extrusion also helps in organizing chromosomes into territories, preventing entanglement even when several chromosomes are close together.
• 🔬 The extrusion mechanism offers a richer understanding of the three-dimensional architecture of the human genome, particularly at larger scales beyond the double helix.

Q & A

What is the significance of the human genome folding into loops within the cell nucleus?

The folding of the human genome into loops is significant because it allows distant anchor points along the chromosome to come close together, facilitating interactions and regulation of genetic information.

How many loops does the human genome form when folded inside the cell nucleus?

The human genome forms approximately 10,000 loops when folded inside the cell nucleus.

What is the process called that leads to the formation of these loops?

The process that leads to the formation of these loops is called 'Extrusion'.

How does the Extrusion process operate on a segment of DNA?

The Extrusion process involves an extrusion complex attaching to DNA, forming a small loop, and then sliding along the DNA in opposite directions, causing the loop to grow bigger.

What is a specific motif that the extrusion complex looks for on the DNA?

The extrusion complex looks for a specific motif known as the 'ctcf motif' on the DNA.

How does the direction of the ctcf motif affect the extrusion process?

The direction of the ctcf motif affects the extrusion process because if a subunit encounters a ctcf motif pointing at it, it tends to stop, but if the motif is pointing the other direction, it won't be recognized and appears as if it's backwards.

What is the 'convergent rule' mentioned in the script?

The 'convergent rule' refers to the requirement that the pair of ctcf motifs at the ends of a loop must be pointing towards one another on the DNA.

What are 'loop domains' and how do they form?

Loop domains are spatially segregated areas that form when loops are created by extrusion. If two pieces of the genome are inside the same loop, they tend to interact more frequently.

Why is the extrusion mechanism an exciting model for understanding the genome?

The extrusion mechanism is exciting because it allows for the unobstructed access to genetic information within loops and can lead to the segregation of domains within chromosomes and the formation of chromosome territories.

How does extrusion prevent entanglements when chromosomes are close together?

Extrusion prevents entanglements by naturally segregating chromosomes within the nucleus, forming distinct chromosome territories, thus avoiding the tangling that would occur if loops were formed by diffusion.

What does the structure of the human genome reveal about its three-dimensional architecture?

The structure of the human genome, as revealed by the extrusion model, shows a complex three-dimensional architecture that is crucial for gene regulation and access to genetic information.