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H2020Individual fellowship2015–2017

3Dconvert · The dynamics of the mammalian epigenome during transcription factor-induced cell fate conversion

Horizon 2020 — Marie Skłodowska-Curie Actions

Duration
2015-05-01 → 2017-04-30
EU contribution
€158,122
Participants
1
Scheme
MSCA-IF-EF-ST

Lines connect the coordinator with its partners.

Results in brief

The dynamics of the mammalian epigenome during transcription factor-induced cell fate conversion

The genetic code stored in our DNA is continuously read by the cells in our body in order for them - and our body as a whole - to function properly. The basic unit of genetic information is the gene, and the human genome contains ten of thousands of such genes. The combination of genes used ('read') by a cell determines its identity and function, granting the cell a unique 'gene expression' signature. Gene expression needs to be tightly controlled for cells to continue doing their job and to adapt to sudden changes in circumstances, for example when cells have to respond to an infection. Perhaps not surprisingly, the improper regulation of gene expression can have disastrous consequences: cells can no longer function or will start to behave differently. In the latter this can lead to developmental defects or give rise to cancer. It is therefore of utmost importance to understand the mechanisms that control our genes and what goes wrong in diseases to improve predicting and treating human illnesses. In this research project, we have studied in great detail how the three-dimensional organisation of our DNA and genes influences the control of gene expression.Our objectives are to map the map the dynamics of 3D DNA folding at high resolution as cells change their identity and to relate this the regulation of gene expression.

Data: CORDIS, © European Union

Project objective

Cell fate conversion processes bear considerable therapeutic potential yet are poorly understood, and have thus remained slow, inefficient and difficult to translate into medical applications. The low conversion frequency in current systems, such as classic reprogramming to ‘induced’ pluripotent stem (iPS) cells, has precluded a molecular study of the critical early conversion events. We propose an interdisciplinary, exhaustive and unbiased approach to unravel the molecular events that accompany cell fate conversion processes, in particular during the early phase, using two uniquely efficient and controllable experimental systems. Special emphasis will be put on documenting the dynamics of three-dimensional genome topology, as this potential epigenetic conversion barrier has not yet been systemically characterized during cell fate conversions. We will apply genome-wide chromosome conformation capture and other genomic technologies on B cells undergoing nearly 100% efficient transdifferentiation into macrophages or reprogramming into iPS cells. In-depth computational analyses and dataset integration will reveal the dynamic relationships between transcription factor binding, key epigenetic regulatory mechanisms including genome topology, and the gene expression changes that ultimately lead to the implementation of a new cellular phenotype. Acquiring such insights will signify a breakthrough in our understanding of the epigenetic features that underpin cell identity and plasticity. Besides significantly advancing the state-of-the-art, the proposed action will maximize the applicant’s capacity of reaching professional maturity and scientific independence.

Original text from CORDIS.

Participants

  • FUNDACIO CENTRE DE REGULACIO GENOMICA · BarcelonaCoordinatorSpain

Links

Data: CORDIS, © European Union