Biological and genomic signals and images
Multiscale and multivariate methodologies for genomic data analysis
(ANR REFOPOL, O. Hyrien, ENS Paris, C. Thermes, CGM, Gif/Yvette, A. Goldar, CEA/Saclay) Multiscale and multivariate concepts and methodologies are necessary to account for the complexity of genome organization accommodating the tradeoff between DNA compaction and gene accessibility. We developed multiscale wavelet-based algorithms providing us with original clues about the mammalian DNA replication program. These signal-processing tools have now been accepted as bona fide molecular biology protocols.
Using a wavelet-based multiscale pattern recognition framework, we described megabase sized replication domain covering about 1/3 of the human genome as N-shaped regions in DNA strand compositional asymmetry (skew) profiles. Determination of genome-wide replication timing profiles provided us with the experimental confirmation of that skew N-domain border are active replication origins.
Further multiscale analysis of replication timing profiles lead us (i) to describe replication U-domains that display a characteristic U- shaped replication timing profile as the counter part to skew N-domains and (ii) to compute space-scale maps of effective DNA replication speed. These latter measurements are central to our modeling of DNA replication kinetic in mammalian genome. Using PCA, the apparent complexity of a dataset of 13 epigenetic marks was reduced to 4 epigenetic states. Each states correspond to a well defined replication timing window so that the progression of the replication along U-domains corresponds to a directional path across the four chromatin states. These results sheds a new light on the epigenetic regulation of the spatio-temporal replication program in human and provides a framework for further studies in different cell types, in both health and disease.
Finally, in a preliminary work using a graph representation of high throughput chromatin conformation capture data, we showed that replication domain borders are hubs of the chromatin conformation interaction network.
Microscopy image analysis
(PEPS PROMIS, L. Condat, GIPSA-lab, J. Boulanger, Institut Curie) Structured illumination microscopy increases fluorescence microscopy resolution without constraint on protein marking. This modality is based on the acqui- sition on several low resolution modulated images fol- lowed by a post-processing that aims at reconstruct- ing the high resolution image. The first contribution concerns the estimation of the modulation parameters from the low resolution modulated images while the second contribution aims at providing an efficient reconstruction procedure based on non-smooth convex optimization. Such a framework allows us to deal with a variational approach where the data fidelity term and the regularization term are fitted to the degradation model (Poisson noise) and to the data (filaments that models actin and microtubules, spots such as single molecules or vesicles).