Beyond loops: cohesin plays central role in linking DNA architecture and epigenetics
The structural organisation of DNA is important for regulating gene activity and ensuring proper cell function. The protein complex cohesin has a key role in this structural organisation by folding DNA into loops. Jan-Michael Peters’ lab at the IMP now discovered that cohesin not only shapes DNA into loops but also positions the epigenetic reader Phf2 within the genome. Their findings, published in EMBO Journal, reveal an unexpected role of cohesin in bridging genome architecture and epigenetics.
A single human cell stores about two meters of DNA, tightly packaged to fit into a nucleus smaller than the width of a human hair. The cell accomplishes this feat by wrapping the long thread of DNA around histone proteins to form nucleosomes, which then organise into chromatin fibres.
These fibres are further shaped by cohesin, a key protein complex that organises chromatin into loops, complementing the ‘beads on a string’ compaction.
At this level, chromatin is governed by two interwoven layers of regulation: spatial organisation and epigenetic control. Spatially, cohesin acts like a molecular motor, extruding DNA into loops that bring distant regions of the genome closer together. This looping plays a vital role in coordinating gene expression and ensuring efficient DNA replication.
Epigenetically, chemical modifications to histones—added by specialised enzymes—serve as markers that influence whether genes are active or silenced. These chemical tags are recognised by epigenetic readers, proteins that interpret the modifications and further refine chromatin structure, fine-tuning gene expression.
Epigenetic and architectural mechanisms are crucial for controlling genomic accessibility and influence every aspect of cell function. However, scientists still don’t understand how histones and cohesin work together in regulating the genome—or in fact, whether they do at all.
Using a combination of biochemistry, microscopy, and genomic tools, researchers in the lab of Jan-Michael Peters found an unexpected link between architectural and epigenetic mechanisms of genome regulation. Their findings, now published in the EMBO Journal, show that cohesin interacts with the epigenetic reader Phf2, positioning it at specific DNA sites by transporting it along chromatin.
Cohesin’s dual role: a bridge between genome architecture and epigenetics
To identify potential cohesin interactors, the scientists used quantitative mass spectrometry—a technique that identifies and measures proteins by analysing their unique molecular fingerprints. Their investigation revealed an intriguing finding: cohesin, directly interacts with Phf2, an epigenetic reader that recognises chemical tags on histones.Using fluorescence microscopy, the team observed Phf2 clustering with cohesin in structures called vermicelli—thin, thread-like chromosomal regions where cohesin can accumulate, making this connection evident. The partnership persisted at thousands of cohesin binding sites across the genome, suggesting a frequent and widespread interaction. The researchers further obtained evidence that cohesin actively positions Phf2 at specific genomic sites, with changes in cohesin’s loop extrusion activity directly influencing Phf2’s location in the genome.
“This is one of the first reported cases of epigenetic and architectural mechanisms of genome regulation working together,” says Wen Tang, research assistant in the Peters lab and first author of the study.
“We were surprised to discover that cohesin can function much like motor proteins, such as kinesin and dynein, which transport cargo along microtubules,” says Lorenzo Costantino, research associate in the Peters lab and co-first author of the study. “These molecular motors use energy from ATP to carry vesicles or proteins across the cell. Similarly, cohesin appears to act as a motor on DNA, transporting Phf2 during its loop extrusion activity and positioning it at specific genomic sites.”
The findings reveal that cohesin’s loop extrusion activity may serve a dual role: not only forming chromatin loops, but also transporting epigenetic regulators such as Phf2—and potentially other genome-regulating proteins—along the DNA.
“We’re excited to explore whether cohesin shuttles other molecules around the genome through loop extrusion,” says Jan-Michael Peters. “And we are eager to dive deeper and test this idea further—it could open up entirely new ways of understanding genome organisation.”
Original Publication
Wen Tang *, Lorenzo Costantino *, Roman Stocsits, Gordana Wutz, Rene Ladurner, Otto Hudecz, Karl Mechtler, and Jan-Michael Peters #: “The epigenetic reader Phf2 is positioned in the genome by cohesin.” EMBO Journal (2024), DOI: 10.1038/s44318-024-00348-2.
*co-first authors, #corresponding author
Further reading