Project description
Exploring the role of centromeres in cellular phenotypes
All somatic cells have the same genetic information, a complete copy of the genome enabling them to produce any of the millions of proteins encoded. Individual cells produce only a fraction of these according to their functions. Could the centromere play a role? The centromere, a region of DNA that links sister chromatids and attaches to the spindle during cell division, is also among the 5 % of human DNA whose sequences are not fully described. Centromeres’ sequences and sizes vary across tissues, between individuals and in disease states. The ERC-funded CentroFun project will investigate genetic variation in human centromeres and how differences in sequence, structure and function might drive cellular phenotypes.
Objective
The last decades have seen an extraordinary leap in our knowledge of the human genome and its role in health and disease. Yet, approximately 5% of our DNA still lacks sequence annotation and has been largely excluded from functional and disease-association studies. These genomic gaps include DNA repeats such as centromeres, which are large tandem arrays of alpha-satellite DNA. Centromeres chromatin is functionally essential for chromosome segregation serving as the basal template for the mitotic kinetochore. A recent breakthrough has been the complete genome assembly, including centromeres, of a haploid cell line derived from fetoplacental growth of a molar pregnancy. However, centromeres sequence and size vary across tissues, between individuals and in disease states. The main challenges are to understand how is centromere variation generated and especially, the consequences at a functional level. The specific objectives of my project are: (1) Identify the mutagenic processes and DNA repair responses operating at centromeres; (2) Determine the impact of centromeres sequence variation on chromatin structure, kinetochore function and chromosome behavior; and (3) Understand how these changes contribute to genome instability, cellular phenotypes and disease predisposition. The originality of this project is to follow a multidisciplinary approach that combines experimental studies spanning structural biochemistry to cell biology and bioinformatic analyses, that will benefit from the information on centromere reference already available and soon to be generated. The proposed research therefore represents a very appropriate and timely contribution to provide an integrated view of human centromere variation and its role in determining phenotypic traits. Furthermore, it will provide important insight on the functional role of the missing genome in human diseases and promises to yield key information and tools for expanding this novel field.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques.
- natural sciencesbiological sciencesbiochemistry
- natural sciencesbiological sciencesgeneticsDNA
- medical and health sciencesclinical medicineobstetrics
- natural sciencesbiological sciencesgeneticschromosomes
- natural sciencesbiological sciencesgeneticsgenomes
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Programme(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Topic(s)
Funding Scheme
HORIZON-ERC - HORIZON ERC GrantsHost institution
00185 Roma
Italy