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Unveiling the role of histone H1 protein as a genome stabilizer

Scientists at the Barcelona Molecular Biology Institute of the CSIC research to unveil the secrets of heterochromatin, the most silenced part of the human genome. Factors related to its regulation or misregulation can be involved in growing, development and diseases. Two recent works unveil the essential role of one of these factors, the intriguing histone H1.

Drosophila polytene chromosome. In the yellow circle, the chromocenter region where heterochromatin is accumulated. Image: Jordi Bernués, IBMB-CSICScientists at the Molecular Biology Institute of Barcelona (IBMB-CSIC) research to unveil the secrets of heterochromatin, the most silenced part of the human genome. Factors related to its regulation or misregulation can be involved in growing, development and diseases. Two studies unveil the essential role of one of these factors, the intriguing histone H1 protein.

“Only about 2% of the human genome are sequences which encode proteins”, explains Albert Jordan, scientists at the IBMB-CSIC. “The other part is non-coding DNA, what means that it doesn’t encode any gene or protein,  but has a structural role in the genome”.

Part of this non-coding DNA is in the heterochromatin, the most packed and with less genes region of the genome. It is also the most silenced part: its genes and sequences are not either expressed or expected to express. Heterochromatin has a structural role in the genome, as far as it is known. How heterochromatin is regulated? Part of the answer can be found in the histones, intriguing proteins whose role are not totally understood yet.

Now, two studies by scientists at the IBMB-CSIC and IRB Barcelona give new clues about the role of the H1, the most unknown of the five existing histones. And both studies point out the role of H1 to prevent genomic instability.

H1 represses non-coding sequences

In one of the studies, the team led by Albert Jordan demonstrates that depletion of histone H1 in human cells triggers a strong interferon response. Interferon is the molecule synthesized by cells when a pathogenic infection is detected.  The work has been published in the Nucleic Acids Research magazine.

The experiment, which has been performed with human breast-cancer cells, shows that depletion of each of the H1 isoforms (somatic cells of mammals have seven sub-types or isoforms) disrupts the expression of a sub-group of genes as well as the cellular proliferation. The most deleterious disruption happens when two isoforms of H1 (the H1.2 and H1.4) are simultaneously suppressed: it triggers the interferon response and cellular death.

As Albert Jordan explains, this happens because when both isoforms are eliminated, a part of the non-coding DNA, the “satellites” and endogenous retroviruses, are expressed.

“Satellites” are DNA repetitive sequences that can be found up to millions of times in the genome and endogenous retroviruses are virus which were inserted into the genome at some point of evolution, milions of years ago.

In normal conditions, these sequences have a structural role and are silenced by H1. But when H1 is depleted, and satellites and retrovirus star to express, the organism doesn’t recognize the new sequences and then it triggers the defense response.

The experiment demonstrates the essential role of H1, specially H1.2 y H1.4, for maintaining the cellular homeostasis and silencing these non-coding sequences.

We used breast tumoral cells, says Jordan, because they are easy to grow in the laboratory.  ‘Now we want to extend our studies to other cell types, tumoral or not, in order to confirm the result.

H1 prevents genomic instability

In the other study, led by CSIC scientists Ferran Azorín and Jordi Bernués and published in Nature  Communications, the role of H1 has been studied using Drosophila melanogaster fly, a usual laboratory model. The advantage of the fly is that it only has one H1 isoform, contrarily to the seven somatic isoforms in mammals.

Using genetic manipulation techniques, scientists obtained flies without H1 in the whole body. As a result, the flies couldn’t survive, which confirms that, whatever the function of H1 is, it is essential for life. The next step was obtaining flies without H1 just in one organ (the wing). As a result, there were malformations and a general damage in the organ. Later, a cellular analysis unveiled a general cellular death (apoptosis) in the organ without H1.

As the scientists explain, “depletion of H1 produces a severe genomic damage in the form of many DNA double-strand breaks, which generate genomic instability”. Further analysis demonstrated that the damage was not happening everywhere but especially in a region of the genome: the heterochromatine, and that this damage was accompanied by the expression of genes and retrotransposons, elements which usually are silenced.

“For the first time”, explains Bernués, “ we have seen that this damage is due to the formation of RNA-DNA hybrids, the called R-loops: structures formed when a newly synthesized RNA base-pairs with the transcribed DNA strand, leaving the other DNA strand, the non-transcribed one, loose”.

“Our results demonstrate that damage in the DNA, genomic instability and cellular death induced by the lack of H1, are directly related with these hybrid formation”, say the authors of the study.

Nevertheless, when scientists  altered the expression of heterochromatine using other techniques but H1 was still in the cells,  there was not damage. What makes the scientists think that the role of H1 is something else than silencing heterochromatin.

“We think that H1 protein either must trigger a protective mechanism or it is an essential piece of this mechanism”. The RNA:DNA hybrids appear naturally sometimes. But its uncontrolled formation, as it happens when H1 is missing, is a cause of strong genomic instability and it is, actually, a typical marker of tumours.

Although these are preliminary and basic research, the studies give new clues about the mechanisms involved in genomic instability and hyperrecombination in some type of cancers.

Treballs de referència:

Izquierdo-Bouldstridge A*, Bustillos A*, Bonet-Costa C, Aribau P, Garcia D, Dabad M, Esteve-Codina A, Pascual L, Peiro S, Esteller M, Murtha M, Millán-Ariño Ll, Jordan A (2017) Histone H1 depletion triggers an interferon response in cancer cells via activation of heterochromatic repeats. Nucleic Acids Research. doi.org/10.1093/nar/gkx746.


Aleix Bayona-Feliu, Anna Casas-Lamesa, Oscar Reina, Jordi Bernués and Fernando Azorín (2017) Linker histone H1 prevents R-loop accumulation and genome instability in heterochromatin.  Nature Communications. 8; 283 doi: 10.1038/s41467-017-00338-5