NonChroRep: Investigating the role of the long non-coding transcriptome in chromatin replication.

Project information

There has been a significant shift in our conception of genome regulation in recent years. It is now obvious that most cellular transcripts do not encode proteins, and that a significant subset of them are long RNAs (lncRNAs).

Dr. Maite Huarte's lab at Cima, and others, have shown that lncRNAs regulate genome function and gene expression and that alterations in lncRNAs are inherent to diseases, including cancer. However, our understanding of the functions of lncRNAs and their underlying molecular mechanisms is still extremely poor. Among all the reported mechanisms, the obvious connection between lncRNAs and chromatin places them at the center of cell biology. During their cycle, cells must undergo faithful DNA replication to ensure that an exact copy of their genetic content is passed on to their daughters. Throughout this tightly regulated process, chromatin must be disordered and reconstituted and determines where and when replication takes place. If replication is deregulated, cells can proliferate out of control and suffer loss of genome integrity.

Our recent findings implicate lncRNAs in the DNA replication process, representing a novel aspect of genome regulation that places lncRNAs at the crux of cancer biology. To further explore these findings the project proposes:

1. Identify the role of lncRNAs in chromatin replication.
2. To dissect the molecular mechanism by which lncRNAs function in this process.
3. Explore the role of these lncRNAs as cancer drivers and their potential as therapeutic targets.

In this research, we will apply tools that we have generated in recent years, as well as new ones, including approaches to identify lncRNAs associated with replicating chromatin, new CRISPR applications tailored to lncRNAs, and the latest methodology for the functional study and targeting of long non-coding transcriptomes in cancer. I am confident that we are uniquely positioned to address these essential life-critical and still outstanding questions, laying the groundwork for future lncRNA-based therapies.

• Reference: ERC-2017-COG
• Start date: April 1, 2018
• End date: March 31, 2023
• Funder: Comisión Europea
• Grant: 2.000.000 €
• Nature of project: European
• Award year 2018