CORDIS - Resultados de investigaciones de la UE

Characterization of the role of histone H1 and its post-translational modifications in the functional regulation of chromatin

Final Activity Report Summary - HISTONE H1 FUNCTION (Characterization of the role of histone H1 and its post-translational modifications in the functional regulation of chromatin)

In eukaryotic cells, the DNA has to be compacted into chromatin to allow an efficient and accurate regulation of all cellular processes related to DNA. For that purpose, DNA is packed together with specific proteins called histones into chromatin. The basic unit of this chromatin is the nucleosome, formed by an octamer of the so-called 'core' histones (histones H2A, H2B, H3 and H4) wrapped by around 146 bp of DNA. There are different degrees or orders of compaction of chromatin that are very tightly regulated and allow that the nuclear DNA can organize efficiently in a relatively small space such is the nucleus of the cell. There is actually another non-'core' histone, the histone H1, that seems to be key for the proper establishment of these successive orders of chromatin compaction. Until recently, it was assumed that histones in general had only a structural role. However, with the identification and characterization of chemical modifications in histones, the post-translational marks such as acetylation, methylation, phosophorylation, and others, it has been shown that they actually are more important for the proper functionality of the genome that was previously assumed.

In fact, what we know today is that in addition to the information encoded in the DNA itself there is very important information or epigenetic 'memory' stored in the form of these modifications and that its perturbation has important consequences in the expression of genes, the progression through the cell cycle, the structure and organization of the genome and many key cellular events. In fact, today we know that the onset of many human pathologies are directly related to the alteration of this epigenetic memory, such as cancer, neurodegenerative diseases, etc... Therefore, understanding the role of histones and what is the nature of this epigenetic information that they contain is key to understand these pathologies in a more global and efficient way.

In the case of histone H1, many different studies have been done in vitro to characterize their functions, but in vivo studies have been impossible until very recently, given that in mammals there are seven different isoforms or 'types' of histone H1, and any attempt to work with any of them was blocked by the fact that these seven isoforms show a high degree of redundancy. This means that when one of them is not present the others can cover up for the loss and therefore no clear role can be associated to the specific loss of one of these isoforms.

This project aimed to determine the function of histone H1 in vivo. The main original aspect of this work is to use Drosophila melanogaster as experimental model for our in vivo and in vitro studies, since it has only one isoform in contrast to higher organisms. Drosophila is a very interesting model of study, since is a multicellular organism, offers obvious technical advantages from a biochemical and genetic point of view, and undergoes all basic processes as mammals in regard the basic organization of chromatin regulation and epigenetic processes. Our studies have demonstrated that loss of Drosophila H1 correlates with a general loss of compaction and organization of the Drosophila genome, clearly establishing that H1 is directly involved in the control of the organization of chromatin.

We have also studied the epigenetic information associated to Drosophila histone H1 and we have identified different modifications. One of them has been fully characterized; dimethylation in lysine 27 of histone H1, a modification that associates to compacted structures and might have a key role on the organization of the chromosomes. These findings should be key for understanding how histone H1 and the epigenetic information associated to this histone contribute to the proper maintenance and management of the genome and the implications of the alteration of this information in human pathologies.