While solos are the key to some of your favorite tunes, a masterpiece as magnificent as chromatin conformation is hardly the work of a one-man band; instead, it takes an orchestra of histone modifications to complement and counterpoint cohesin´s sonorific solos. Now, a duet from the labs of Francois Spitz (Pasteur Institute, France) and Leonid Mirny (MIT) brings music to our ears by communicating the mechanisms of cohesin’s musical mastery.
Chromatin conformation is complicated, to say the least, consisting of distinct regions enriched for chromatin contacts and marked by sharp boundaries known as topologically associating domains (TADs). The chromatin architects cohesin and CTCF are often found at TADs, where a loop extrusion model previously proposed by the Mirny lab proposes that cohesin extrudes chromatin loops until it runs into boundaries created by CTCF. But the complexities of chromatin architecture don’t end there as there are also larger scale chromatin compartments that are either transcriptionally active (A compartment) and inactive (B compartment). However, it has remained a mystery as to whether TADs are the building blocks for the larger scale A/B compartments or a very different, and potentially antagonistic, type of chromatin conformation.
To tackle this question, the talented team turned to a liver-specific and inducible Cre driver to delete Nipbl, a motor protein that loads cohesin onto chromatin. Here’s what their Hi-C maps of purified hepatocytes revealed:
- While hepatocytes lose TADs, the A/B compartments remain
- Some regions previously from the same TAD now split between two compartments
- The A/B compartments become enhanced and better reflect the underlying chromatin states (histone modifications and accessibility) and transcriptional activity of the regions located within
- Thus, TADs serve to bring together sequences with different chromatin states
- Genes that lose distant contacts, which are presumably enhancers, tend to decrease in expression, while the sequences next to these enhancers increase in expression, even if they are not protein coding
Overall, this study demonstrates the existence of two independent forms of chromatin organization; smaller scale TADs that depend on cohesin and larger-scale A/B compartments that do not. The TADs bring enhancers and distant genes together, while the A/B compartments are defined chromatin state. Co-first author Nezar Abdennur concludes, “It’s like two pianists playing on the same piano. They interfere and put constraints on each other, but together they can produce a beautiful piece of music.”