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Image: Structure of histone H1 from Drosophila (Prediction from the AI program, AlphaFold).

Research sheds more light on the H1 protein, the ‘guardian’ of genome stability

Researchers from the Institute of Molecular Biology of Barcelona (IBMB-CSIC) describe the link between histone H1 and chromatin RNA and two proteins that transport and protect the RNA.  This finding will help to understand how gene expression is controlled and its implication in the development of cancerous processes. The work, published open acces in Cell Reports, involves the Centre for Genomic Regulation (CRG) and the Institute for Research in Biomedicine (IRB Barcelona).

Histones are proteins that regulate the organisation of DNA throughout the cell cycle. Their modifications determine the degree of the genetics’ material compression as well as how genes are expressed.

The histone H1 protein is considered the guardian of genome stability because it ensures that regions of the genome that should not be expressed are silenced. Seven years ago, a team from the Institute of Molecular Biology of Barcelona (IBMB-CSIC) discovered this regulatory role of H1 in heterochromatin, which is found in the cells’ nucleus. What they didn’t know at the time was how this regulatory mechanism developed.

Part of the answer to that is what they now reveal in a new scientific research, published in Cell Reports a few days ago, and led by Jordi Bernués and Fernando Azorín, both scientists at IBMB-CSIC, based in the Barcelona Science Park . The results show that histone H1 deletion leads to several effects on chromatin, including increased chromatin accessibility, an increase in chromatin RNA (cRNA) and the disappearance of two proteins, hrp36 and hrp48. Under normal conditions these proteins cover cRNA and prevent the formation of RNA:DNA hybrids (R-loops).

H1 maintains genome stability

Chromatin is the form DNA is packaged inside cells’ nucleus and consists of two parts: euchromatin (the one accessible and containing the genes that are normally expressed) and heterochromatin.

‘Heterochromatin,’ researchers explain, ‘is the most compacted part of the DNA, the least gene-rich and the most silenced and least accessible: in general, its genes are not expressed and are not expected to be expressed.’

As the same IBMB-CSIC team revealed in previous work, when they reduced in half the H1 content, heterochromatin triggered intense genomic damage as well as the expression of genes and retrotransposons (viral DNA sequences) that, under normal conditions, should not be expressed.

This led to genomic instability, and compromised the survival of the organism: Drosophila fly embryos with 50% of H1 in all their cells failed to survive. When H1 depletion occurred only in one organ (wings), malformations and general degeneration of the organ appeared.

As they observed then, DNA damage, genomic instability and cell death induced by the absence of H1 were directly related to the formation of RNA:DNA hybrids, called R-loops. These are structures that form when a newly synthesized RNA strand re-hybridizes to the template DNA strand, leaving the non-transcribed DNA strand loose and unhybridized. Although they occur naturally in cells under normal conditions, an excess of R-loops is very damaging

Two RNA-protecting proteins

Results now published in Cell Reports reveal that H1 deletion leads to an increase in chromatin accessibility, RNA polymerase II and transcription, as well as the disappearance of at least the two major proteins, hrp36 and hrp48, which under normal conditions cover chromatin RNA (cRNA).

Proteins hrp36 and hrp38, among others, are responsible for protecting and transporting the nascent RNA. Without them, RNA is exposed and accessible, which facilitates the formation of RNA:DNA hybrids, destabilises the heterochromatin structure and increases the expression of sequences that should not be expressed.

The finding could help understand the mechanisms involved in genomic instability and hyperrecombination in some types of cancer. In fact, it had been observed years ago that in some cancer cell lines there is a decrease in H1.

It will also help understand how gene expression is controlled, in this case, how H1 represses non-coding regions. As a matter of fact, there is a large portion of the DNA of eukaryotic living organisms, including humans, that does not encode for any gene: almost all of this non-coding DNA is in heterochromatin, the most compacted and gene-poor part but, paradoxically, highly conserved, and whose stability depends largely on histone H1.

The work, recently published open acces in Cell Reports, involves researchers from the Centre for Genomic Regulation (CRG) and the IRB Barcelona.

» Reference article: Paula Bujosa, Oscar Reina, Adrià Caballé, Anna Casas-Lamesa, Mònica Torras-Llort, Juan Pérez-Roldán, Ana Silvina Nacht, Guillermo P. Vicent, Jordi Bernués, and Fernando Azorín. Linker histone H1 regulates homeostasis of heterochromatin-associated cRNAs. Cell Reports 2024;43(5):114137. doi: 10.1016/j.celrep.2024.114137

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