Scientists from the Institute for Research in Biomedicine (IRB Barcelona) at the Barcelona Science Park, headed by Ferran Azorín, have discovered why histone 1 is a major protection factor against genomic instability and a vital protein for the organism. Genomic instability is the main risk factor for tumour development in humans. Therefore understanding its origin and exploring therapeutic targets is paramount.

The study, published in Nature Communications, reveals that the Histone 1 –  the least known of the five histones– silences a region of the genome that causes irreparable DNA damage when translated and is lethal for the organism.

“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 open regarding this molecule,” says Ferran Azorín, head of the Chromatin Structure and Function group at IRB Barcelona and CSIC research professor.  “Regarding the other histones, which are major proteins in the regulation of gene expression, 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 adds. 

The study explains for the first time that the suppression of histone 1 causes cell damage and genomic instability (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,” explains Jordi Bernués, associate researcher in Azorín’s group and coleader of the study.  Furthermore, 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 comes about. “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-first author of the article together with Aleix Bayona-Feliu.

In addition to exploring the mechanisms through which histone 1 keeps heterochromatin in check and prevents R-loop formation, Anna Casas-Lamesa is also addressing the involvement of this molecule in cancer. Preliminary experiments in cultured tumour cells confirm that the genomic instability present in these cells 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 signalling pathways involved,” explain the scientists.

► For further information: IRB website [+]

► Reference article:

Aleix Bayona-Feliu, Anna Casas-Lamesa, Oscar Reina, Jordi Bernués and Fernando Azorín. “Linker histone H1 prevents R-loop accumulation and genome instability in heterochromatin“. Nature Communications (2017). doi: 10.1038/s41467-017-00338-5