CLICK ON weeks 0 - 40 and follow along every 2 weeks of fetal development
Epigenetic mistakes can be passed on for generations
During development of an embryo and in tumor formation, cell divisions are particularly sensitive. At either time, mistakes made in how chromosomes are divided can be passed on to the next generation - and maybe many generations thereafter.
Scientists at the Centre for Genomic Regulation (CRG) collaborating with Josep Carreras Leukaemia Research Institute (IJC) and the Institute for Health Science Research Germans Trias i Pujol (IGTP) have found DNA replication gone wrong can cause long lasting epigenetic changes. The research is published in Science Advances, August 16, 2017.
They performed their research on worms — a model animal system called Caenorhabditis elegans, or C elegans. C. elegans is primarily used to study neural development, and since 1974 has been used as a model organism for gene study. It is also the first multicellular organism to have its whole genome sequenced, and as of 2012 is the only organism to have its neuronal "wiring diagram" completed.
The research suggests that genome-wide epigenetic alterations establish new ways for gene expression (or how genes function) that may be inherited for up-to five generations.
This is a striking example of trans-generational or how repeated inheritance of epigenetic change occurs. It emphasises how gene expression due to the stress experienced by our ancestors can be inherited by us and our future generations. Research led by Ben Lehner, ICREA research professor and group leader at the CRG, also identified the mechanisms causing these epigenetic changes.
Explains Tanya Vavouri CRG alumna currently group leader at IJC and IGTP and coauthor of this study"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 are tightly packed forms of DNA and prevent genes from becoming active when they should not be. Initially, we noticed that a gene artificially inserted into the worm genome, and normally silenced by heterochromatin, was activated in animals that carried mutations in proteins involved in copying DNA."
Vavouri continues: "We found that this was caused by loss of heterochromatin and that other genes also silenced by heterochromatin were activated too. Unexpectedly, the gene was inappropriately activated for five generations in animals that did not carry the mutation in DNA replication but had ancestors that did."
"Our results show that impaired DNA replication not only causes genetic alterations but also genome-wide epigenetic changes that can be stably inherited," says Ben Lehner, senior author of the paper.
An important question in epigenetics is the extent to which epigenetic states are transmitted between generations. Lehner and collaborators address this and other genetic questions from many different angles. They previously reported that some temperature-induced gene expression changes can also be inherited between generations. "We hope that our work will change the way people think about the impact of replication stress during tumorigenesis and embryonic development as well as about inter-generational inheritance," he concludes.
Impaired DNA replication is a hallmark of cancer and a cause of genomic instability. We report that, in addition to causing genetic change, impaired DNA replication during embryonic development can have major epigenetic consequences for a genome. In a genome-wide screen, we identified impaired DNA replication as a cause of increased expression from a repressed transgene in Caenorhabditis elegans. The acquired expression state behaved as an “epiallele,” being inherited for multiple generations before fully resetting. Derepression was not restricted to the transgene but was caused by a global reduction in heterochromatin-associated histone modifications due to the impaired retention of modified histones on DNA during replication in the early embryo. Impaired DNA replication during development can therefore globally derepress chromatin, creating new intergenerationally inherited epigenetic expression states.
All authors: Adam Klosin, Kadri Reis, Cristina Hidalgo-Carcedo, Eduard Casas, Tanya Vavouri, and Ben Lehner.
Return to top of page
Adult C. elegans worms can be seen with embryos (green) inside them. Image credit: Adam Klosin, CRG