2017 August 21

Link between defects in DNA replication and loss of heterochromatin.

Tanya Vavouri from Institut de Recerca contra la Leucèmia Josep Carreras (IJC) and Institut de Recerca Germans Trias i Pujol (IGTP) and Eduard Casas from IGTP, working together with Ben Lehner and his team from the Centre for Genomic Regulation (CRG) in Barcelona, Spain, have discovered that a fault in the process that copies DNA between cell divisions can cause genes that are normally silent to become active, not only in the same animals when they become adults, but also in their offspring for five generations. The findings were published on the 16th of August in the journal Science Advances.
For the correct function of cells and ultimately the health of the organism, it is important to keep certain genes active and others silenced. Inside cells, there are DNA-protein complexes called heterochromatin that prevent genes from becoming activated when they should not be. Initially, the researchers noticed that a gene artificially inserted into the genome of the model organism C. elegans and normally silenced by being packaged into heterochromatin was activated in animals that carried mutations in proteins involved in copying of DNA. Vavouri, Lehner and their team members found that this was caused by loss of heterochromatin and that other genes also silenced by heterochromatin were activated too. Unexpectedly, the transgene was inappropriately activated for five generations in animals that did not carry the mutation in the DNA replication machinery but had ancestors that did. 
Abnormal DNA replication occurs in tumors in humans. This means that problems with DNA replication may not only contribute to cancer formation by promoting new mutations but also by de-silencing certain genes.
This publication follows up from the work recently reported in the journal Science, by the same authors, which showed that environmental change can have an impact on gene activity in worms for 14 generations.
A. Klosin, K. Reis, C. Hidalgo-Carcedo, E. Casas, T. Vavouri, B. Lehner, Impaired DNA replication derepresses chromatin and generates a transgenerational inherited epigenetic memory. Science Advances. 3, e1701143 (2017).
A. Klosin, E. Casas, C. Hidalgo-Carceldo, T. Vavouri, B. Lehner, Transgenerational transmission of environmental information in C. elegans. Science. 356(6335):320-323. (2017).