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Chromatin Conformation in Development and Disease

Chromatin Conformation in Development and Disease

Speaker: Juan Manuel Vaquerizas

Max Planck Institute for Molecular Biomedicine [Münster, Germany]
Host: Mercedes Dosil

Fecha: 17/01/2019

Hora: 12:30

Salón de actos del Centro de Investigación del Cáncer

The three-dimensional organisation of the genome plays a fundamental role in the regulation of gene expression. Recent examinations of chromatin conformation have revealed the presence of hundreds of self-associating domains and thousands of regulatory loops between enhancers and target genes that ensure a correct deployment of developmental programmes. Mutations affecting these highly conserved and relatively tissue-unspecific regulatory features often result in striking developmental defects and disease. Despite the characterisation of such regulatory features, it is currently unknown when chromatin conformation is established and the cellular mechanisms that drive this process.

In the first part of my talk, I will focus on recent work in which, using Drosophila as a model system, we investigated chromatin conformation in tightly staged, hand-sorted embryos at different time points during early development. In situ Hi-C maps for these embryos revealed that chromatin structure is significantly and rapidly remodelled at hundreds of loci during embryo development. We further demonstrate that specific expressed loci serve as nucleation sites for early topologically associating domain (TAD) boundaries. Strikingly, inhibition of RNA polymerase II does not preclude the formation of TADs, suggesting that transcription is not necessary for the establishment of such domains. We furthermore characterize the role of the pioneer transcription factor Zelda in establishing this organisation.

In the second part of my talk, I will present unpublished work demonstrating the use of Hi-C technologies as a tool for disease characterisation in primary tissue from patients. First, I will introduce an improved Hi-C method for very low amounts of input material, down to one thousand cells. By systematically comparing Hi-C libraries made with decreasing amounts of starting material I will show that the method is highly reproducible and robust to experimental noise. Then, I will show the applicability of this approach in primary B-cells from a Large Diffuse B-cell lymphoma patient, highlighting patient-specific translocation and abundant local structural variation when compared with control B-cells.

Overall, our results have important implications for our understanding of how the three-dimensional structure of the genome is established and how the mechanisms that trigger this organisation are affected in disease.