About This Project

A large proportion of our genome consists of no more active viral remains (retrotransposons) that integrated in our DNA millions of years ago but their transcription is repressed by the epigenetic machinery. As aging is a degenerative condition that can lead to a progressive impairment of the epigenomic maintenance in cells, we aim at discovering if aging-associated chromatin modifications can induce the re-expression of these dormant viral sequences.

Ask the Scientists

What is the context of this research?

A recent paper "DNMT and HDAC inhibitors induce cryptic transcription start sites encoded in long terminal repeats" (Brocks et al. Nature Genetics 2017) showed that epigenetic drugs affecting DNA-Methylation or Histone modifications can reactivate the transcription of endogenous retroviruses.

Increasing evidence suggests that large part of aging-related changes are indeed epigenetic. Horvath S. generated a machine learning model (‘epigenetic clock’) that can predict the age of an individual starting from DNA-methylation levels. ChIP-Seq data produced by ENCODE suggests that histone modifications also change over time. Thus, aging-associated impairment of the epigenetic machinery may mimic the effect exerted by certain epigenetic drugs.

What is the significance of this project?

If retrotransposons are reactivated during aging and their expression is increased this could lead to two significant discoveries.

First, this could cause an increment of the transcriptional noise in cells. This means a reduction of Signal-to-Noise ratio (SNR) as more and more mRNAs are likely to undergo non-sense mediated decay.

Secondly, this may give origin to alternative TSS with codogenic potential that may alter gene function and regulation. This again may increase transcriptional entropy in the aging cells.

What are the goals of the project?

Our aim is to determine whether retroviral sequences are being re-expressed in the aging human transcriptome and if their re-activiation can lead to the appearance of alternative cryptic Transcription Start Sites (TSS). This research is of particular interest because epigenetic changes are in principle reversible.
Initially, we will identify whether aging can promote the origin of new not-annotated TSS that may be deleterious for the cell. Subsequently, we will determine if specific transcription factors (TFs) are able to bind to these dormant viral sequences and boost their expression. The identification of these TFs would be relevant as their inhibition could repress global retroviral transcription.