Javier Caceres Research Group

Section Head: Genome Regulation

Research in a Nutshell 

The flow of genetic information from DNA to RNA to protein involves complex mechanisms of regulation, most of which act downstream of the process of transcription, which produces RNA molecules from a DNA template. RNA splicing is a process that eliminates non-coding intervening sequences from precursor RNAs and that joins together coding sequences to form the mature mRNA that is exported from the nucleus for translation to produce proteins in the cell.  Sometimes, a series of different mRNA molecules can be produced from the same precursor RNA, in a process termed alternative splicing. This allows a single gene to increase its coding capacity, leading to the synthesis of structurally and functionally distinct forms of a protein that influence different cellular processes. We study the regulation of alternative splicing and how its misregulation can lead to human disease. We are also focusing on a surveillance mechanism, termed Nonsense-mediated decay or NMD, that eliminates mRNAs with premature termination codons that would otherwise give rise to truncated proteins that are potentially harmful for the cell. This is important since the NMD response affects the severity of up to one third of all human genetic diseases. We expect to facilitate a greater understanding of how the production of cellular RNAs is controlled, and how its dysregulation contributes to human disease. This research will illustrate how alterations in RNA binding proteins-mediated gene regulation can contribute to human disease.

Research Programme

Contact

Javier.Caceres@ed.ac.uk

Publications

1. Hug N, Aitken S, Longman D, Raab M, Armes H, Mann AR, Rio-Machin A, Fitzgibbon J, Rouault-Pierre K, Cáceres JF (2022) A dual role for the RNA helicase DHX34 in NMD and pre-mRNA splicing and its function in hematopoietic differentiation. RNA 28:1224–1238
2. Haward F^±, Maslon MM^±, Yeyati PL^±, Bellora N, Hansen JN, Aitken S, Lawson J, von Kriegsheim A, Wachten D, Mill, P^*, Adams IR^*, Cáceres JF^* (2021) Nucleo-cytoplasmic shuttling of splicing factor SRSF1 is required for development and cilia function. eLife 10:e65104.  ^±Joint first authors |^*Co-corresponding authors  
3. Longman D, Jackson-Jones KA, Maslon MM, Murphy LC, Young RS, Stoddart JJ, Hug N, Taylor MS, Papadopoulos DK, Cáceres JF (2020) Identification of a localized nonsense-mediated decay pathway at the endoplasmic reticulum. Genes Dev 34: 1075-1088 
4. Maslon MM, Braunschweig U, Aitken S, Mann AR, Kilanowski F, Hunter CJ, Blencowe BJ, Kornblihtt AR, Adams IR^*, Cáceres JF^* (2019) A slow transcription rate causes embryonic lethality and perturbs kinetic coupling of neuronal genes. EMBO J 38: e101244. ^*Co-corresponding authors 
5.  Fernandez N^±, Cordiner RA^±, Young RS, Hug N, Macias S, Cáceres JF (2017) Genetic variation and RNA structure regulate microRNA biogenesis. Nat Commun 8: 15114. ^±Joint first authors

Full publication list can be found on Research Explorer: Javier Caceres — University of Edinburgh Research Explorer

Collaborations

• Professor Ian Adams, MRC Human Genetics Unit, University of Edinburgh 
• Professor Malcolm G Dunlop, CRUK and MRC Human Genetics Unit, University of Edinburgh 
• Professor David Rueda, MRC London Institute of Medical Sciences, Imperial College
• Professor Andrew Jackson, MRC Human Genetics Unit, University of Edinburgh 
• Dr Luke Boulter, MRC Human Genetics Unit, University of Edinburgh 
• Dr Andrew Wood, MRC Human Genetics Unit, University of Edinburgh 
• Dr Maria Doitsidou (University of Edinburgh)
• Professor Oscar Llorca (CNIO, Madrid, Spain)

Partners and Funders

• Medical Research Council