The secret double life of MSL: A new facet of the epigenetic regulator MSL1

16 May 2016

Gene expression is the process by which genetic information is used to produce proteins that are essential for cells to function properly. This requires a coordinated interplay among different factors.  In collaboration with scientists at the Max Planck Institute of Immunobiology and Epigenetics in Freiburg, the Crick's Nicholas Luscombe was part of a team that revealed how MSL1, a central component of dosage compensation in flies, interacts with the enzyme CDK7 broader role in the chromosome-wide gene regulation.

Usually we are surprised if we unmask the secret double life of a close friend of who we thought we knew well. Researchers of the Max Planck Institute of Immunobiology and Epigenetics in Freiburg and the Francis Crick Institute have such a special friend. Its name is the "MSL complex" and the scientists recently able to reveal a new exciting facet of its "personality". 

The MSL complex is a particular set of proteins and non-coding RNAs that is already known for mediating dosage compensation in flies. Dosage compensation is a necessary molecular balancing mechanism to guarantee that males (XY) and females (XX) produce the same amount of proteins from the genes encoded on the X chromosome despite the difference in the number of X chomosomes. The Max Planck lab led by Asifa Akhtar is investigating the role of the MSL complex as major player in dosage compensation in Drosophila melanogaster. Here, the daily life of the MSL complex is to upregulate the activity of gene transcription of the single male X chromosome to balance the overall gene expression between the sexes. 

The Crick's Nicholas Luscombe, head of the Bioinformatics and Computational Biology Laboratory, was part of the team in an international, collaborative research effort to reveal the secret second life of MSL1, which is one of the five proteins comprising the MSL complex. Previous studies provided some hints that MSL1 may also have a broader role in chromosome-wide gene regulation in addition to its canonical role in X chromosome dosage compensation. It was already known that MSL1 is not only found on the X chromosome but also on other chromosomes which suggested a potential contribution of MSL1 to the general transcription machinery. 

By using a combination of ChIP experiments, genetic and biochemical approaches the team found that MSL1 interacts with CDK7. This enzyme is important in the early steps of gene expression. The results show that MSL1 depletion leads to a less efficient phosphorylation of RNA polymerase which is mediated by the enzyme CDK7, thereby regulating the transcriptional output of MSL1 bound genes. 

"Revealing that MSL1 has a global effect on phosphorylation status of RNA polymerase II was very exciting as it hinted at more general function of this protein that we had not anticipated before," said Akhtar. By further investigating the different facet of the 2 protein in the general transcription regulation the scientists found that MSL1 does not only interacts with CDK7 but that CDK7 can also phosphorylate MSL1. The team has now evidence that CDK7 is required for MSL's function in dosage compensation. 

"Learning about the CDK7 connection also changed our view on MSL1," said joint co-first author, Maria Samata. 

he MSL1 Frog Prince is waiting patiently for a CDK7 enzyme princess to transform him into a prince.

Fig. 1: The secret double life of the Frog Prince: The MSL1 Frog Prince is waiting patiently for a CDK7 enzyme princess to transform him into a prince. The power of the phosphorylating kiss of the CDK7 princess transforms the MSL1 prince into a different form that gives him broader abilities in chromosome-wide gene regulation.

 

"It seems that the two facets of MSL1 are interconnected. We speculate that the interaction of the two proteins is dynamic: On the one hand the daily life of MSL1 in dosage compensation needs the involvement of CDK7; on the other hand MSL1 is involved in the recruitment of CDK7 on common gene targets beyond X chromosome regulation," explained Sarantis Chlamydas and Herbert Holz joint authors of the paper. 

Both the day job of MSL1 in dosage compensation and the former secret life of MSL1 in general gene expression need further investigation. The team now wants to study the common parameters to get more insight in the interaction of the proteins. It truly turns out that to reveal the new facet of a close friend is not just surprising but in cases like MSL1 also very exciting.   

Functional interplay between MSL1 and CDK7 controls RNA polymerase II Ser5 phosphorylation is published in Nature Structural & Molecular Biology, 16 May 2016 (AOP).DOI: 10.1038/nsmb.3233