Investigating the role of the long noncoding transcriptome in chromatin replication

Project Information

NonChroRep

Grant agreement ID: 771425

DOI

10.3030/771425

Project closed

EC signature date 7 February 2018

Start date 1 April 2018

End date 31 March 2024

Funded under

• EXCELLENT SCIENCE - European Research Council (ERC)

Total cost

€ 2 000 000,00

EU contribution

€ 2 000 000,00

Coordinated by

FUNDACION PARA LA INVESTIGACION MEDICA APLICADA FIMA
Spain

Periodic Reporting for period 4 - NonChroRep (Investigating the role of the long noncoding transcriptome in chromatin replication)

Reporting period: 2022-10-01 to 2024-03-31

Summary of the context and overall objectives of the project

The human genome contains thousands of unconventional genes that do not code for proteins, but are transcribed, producing long RNA molecules named lncRNAs. LncRNAs have been recently found, and despite their abundance, their functions are very poorly understood. During their life cycle, cells need to copy their DNA to produce an exact copy that will be carried by the daughter cell. This is a tightly regulated process because mistakes in DNA replication can lead to mutations that cause cancer or even be lethal for the cells. In this project, we investigated how lncRNAs influence DNA replication. We found that lncRNAs and other RNAs interact with the cellular machinery that initiates the replication of the DNA, helping its correct function. In addition, we found that under stress causing stalled replication, specific lncRNAs are recruited to the chromatin. One of them, named lncREST, is needed for the assembly of factors that participate in stress signaling, which is required for the normal resumption of stalled replication. We observed that as a consequence, the activity of lncRNAs directly relates to genomic instability, a characteristic of colorectal tumors, and may be therapeutically targeted. Our work sheds new light on the process of DNA replication and the preservation of genomic stability, considering noncoding RNAs as key factors in play.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

We have started to uncover the roles of lncRNAs in DNA replication. In particular we have found that the human protein ORC1, which determines in what positions of the genome the process of copying the DNA starts, has the property to bind to molecules of RNA (some of which are lncRNAs). Thse RNAs are for the initiation of the replication, and as consequence, for the normal cell division.
We have also found that lncRNAs are involved with the response to the replicative stress, acting on the chromatin. We are currently studying their mechanisms.
As result of our investigation of the roles of lncRNAs in the chromatin regulation, and their alterations in cancer, we have published the following papers.
• Grossi E, Raimondi I, Goñi E, González J, Marchese FP, Chapaprieta V, Martín-Subero JI, Guo S, Huarte M. (2020) A lncRNA-SWI/SNF complex crosstalk controls transcriptional activation at specific promoter regions. Nat Commun. Feb 18, 11(1):936.
• Athie A, Marchese FP, González J, Lozano T, Raimondi I, Juvvuna PK, Abad A, Marin-Bejar O, Serizay J, Martínez D, Ajona D, Pajares MJ, Sandoval J, Montuenga LM, Kanduri C, Lasarte JJ, Huarte M. (2020). Analysis of copy number alterations reveals the lncRNA ALAL-1 as a regulator of lung cancer immune evasion. JCB Sep 7;219(9). (highlighted with commentary)
• Saeinasab M, Bahrami AR, González J, Marchese FP, Martinez D, Mowla SJ, Matin MM, Huarte M. SNHG15 is a bifunctional MYC-regulated noncoding locus encoding a lncRNA that promotes cell proliferation, invasion and drug resistance in colorectal cancer by interacting with AIF (2019) J Exp Clin Cancer Res. Apr 24;38(1):172
Review article:
• Statello L, Guo CJ, Chen LL, Huarte M. Gene regulation by long noncoding RNAs and its biological functions. Nature Reviews Molecular Cell Biology. doi: 10.1038/s41580-020-00315-9. (In press)

Commentaries:
• Mas AM, Huarte M (2020). EMBO Rep. Mar 4;21(3):e50107
• Marchese FP, Huarte M (2018). Cell. May 31; 173(6) 1318-1319.
• Grossi E, Huarte M (2018). Nat Cell Biol. Apr; 20(4):371-371.
And have filed a patent for the therapeutic targeting of a lncRNA in lung cancer.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

The project is now finalized, having achieved several findings that increase our understanding of long noncoding RNA functions. Namely, we have found that specific long non-coding RNAs are required for the normal progression of DNA replication, and their functions are linked to their specific expression during the cell cycle and specific RNA sequences and interactions with proteins. We have also found that RNAs that reside in the nucleus help shaping up the replication initiation landscape. These are exciting findings with many implications for genomic instability, which we will keep investigating in future projects