Lethal Lesions

Scientists headed by Ferran Azorín at the Institute for Research in Biomedicine (IRB Barcelona) have discovered why histone 1 is a major protection factor against genomic instability and a vital protein. Their study of the function of histone 1, the least known of the five histones, has been published in the journal Nature Communications.

“Although histone 1 is key component of chromatin, the form in which DNA is packaged inside the cell nucleus through the action of histones, there are still many questions regarding this molecule,” says Ferran Azorín. “Regarding the other histones, which are major proteins in the regulation of , we know which enzymes modify them, their functions, and how they are regulated. But for some reason, the functions of histone 1 have not been addressed,” he says.

The study explains for the first time that the suppression of histone 1 causes cell damage and DNA damage. The deregulation of a commonly suppressed region of chromatin, called heterochromatin, leads to defects in information transcription, which in turn gives rise to the accumulation of DNA and RNA hybrids, the so-called R-loops, which are lethal.

“The deregulation of heterochromatin has disastrous consequences,” says Jordi Bernués, associate researcher in Azorín’s group and co-leader of the study. The team also observed that in the presence of histone 1, these problems did not arise in spite of heterochromatin expression. “Histone 1 not only serves as a repressor but also actively contributes to the removal of R-loops.” However, the researchers do not know how this function arises. “The mechanism is what we want to study, how histone 1 prevents the mechanism from causing damage,” explains IRB Barcelona PhD student Anna Casas-Lamesa, co-author of the article together with Aleix Bayona-Feliu.

The fruit fly Drosophila melanogaster is crucial in unraveling this function. First, only one variant of this histone is present in the fly, while humans have up to seven, so the research is simplified. Second, the fly allows scientists to remove a protein from a specific place and at a specific time. They removed histone 1 from the precursor structure of wings. They observed that the fly was born alive but without wings; thus, the removal of this molecule caused the death of all cell precursors of this tissue—if histone 1 is completely removed, the embryo dies.

Image credit: S. Flores and P. Mena

Histone 1 and Cancer

A statistical analysis of gene expression allowed the scientists to reject a longstanding hypothesis, namely that histone 1 is a global repressor of expression. “The effect of removing histone 1 on gene expression is very weak,” says Bernués. Its expression alters that of only 5 percent of genes. “It is not a transcriptional regulator,” says Azorín.

Heterochromatin contains genetic information that is not translated for proteins but that comprises repetitive sequences that the cell silences and that is tightly regulated. “Both R-loops and the information held in heterochromatin have natural functions, but when they are deregulated, they are lethal. “We have now been able to associate genomic instability with the uncontrolled formation of R-loops caused by the lack of histone 1 and this is completely new,” says Bernués.

Preliminary experiments in cultured tumour cells confirm that the genomic instability present in these  is partly caused by histone 1 deficiency. “But we have to further study the functions of this histone, identify the other proteins with which it is associated, and determine the enzymes that modify it and why, and the cell signaling pathways involved,” says Bernués.

In addition to exploring the mechanisms through which histone 1 keeps  in check and prevents R-loop formation, Anna Casas-Lamesa is also addressing the involvement of this molecule in cancer. “Our preliminary studies are promising,” explains Azorín. “But we are still a long way off proposing  1 as a target.”
This article was provided by the Institute for Research in Biomedicine (IRB Barcelona). Materials may have been edited for clarity and brevity.