Researchers at the Institute of Biomedical Research of Bellvitge (IDIBELL) in Catalonia, led by Alex Vaquero, have explored the role of HP1 isoforms in relation to chromatin structure and genome stability, distinguishing differentiated effects depending on the presence of different variants this protein. The work, published in Cell Reports, had the collaboration of other research groups in Europe and the US.

Our genetic material is organized in the cell nucleus in the form of chromatin, a structure mainly made of DNA molecules associated with histones and other proteins. Chromatin is found in two clearly different forms when the cell is not dividing: euchromatin (less condensed) and heterochromatin (more condensed).

The heterochromatin protein 1 (HP1) is a structural component of heterochromatin exists in three different variants or isoforms: HP1α, HP1β and HP1γ. Much of the activity of these isoforms appears to be redundant, regardless of the variant.

In a earlier work published earlier this year at the journal Epigenetics, Vaquero’s team showed that unlike previously thought, under conditions of oxidative stress (involved in diseases such as cancer, Parkinson’s and Alzheimer’s, as well as in aging), the three variants of HP1 play different roles in maintaining stability and establishing different levels of chromatin compaction.

Specifically, the three variants establish differential functional relationships with Suv39h1 methyltransferase, a key enzyme in the genome epigenetic control. In this new study, the team of researchers elaborates on the regulatory role of HP1α, HP1β and HP1γ regarding pericentric heterochromatin, i.e. which delimits the centromere or junction between sister chromatids in a chromosome.

These regions have a key structural role in the genome, and its alteration is associated with genomic instability, chromosomal aberrations and human diseases such as cancer. In a series of experiments with mouse embryonic fibroblasts (MEFs), the researchers show that the specific loss of HP1α leads to a greater presence of epigenetic marks H4K20me3 and H3K27me3, directly linked to chromatin hiper-compaction. On the contrary, HP1β loss results in an increase of CTCF, a key transcription factor in the regulation of chromatin architecture.

Increased knowledge of different diseases

The different variants of HP1 could play a key role in the organization of chromatin domains. In the words of Vaquero, “HP1α would mantain, along with CTCF, the internal structure of the peripheral heterochromatin by controlling the distribution of H4K20me3 and H3K27me3. This finding expands our knowledge of the genome organization, contributing with a new perspective on the role HP1 isoforms and their functional relationship with the heterochromatin structure and its stability“.

Given that alterations in pericentric heterochromatin have been linked to defects in the cell cycle, DNA damage, chromosomal aberrations, cell death, cancer and aging, both studies open the way to basic research toward better understanding these processes linked to numerous diseases.

 

Source: SINC