Understanding chromosome conformation, 3D nuclear DNA architecture and gene expression in human embryogenesis at single-cell resolution

Our understanding of the organisation of DNA present in a cell’s nucleus into higher order structures is rudimentary, but crucial to comprehend varying gene expression and phenotypes of cells in normal and diseased conditions. In particular in the first cell cycles of life following fertilisation drastic changes occur in the DNA architecture of nuclei as well as in gene expression, whereby cells become committed and restricted in contributing to important embryonic tissues. When such processes go awry, this may lead to loss of pregnancy or severe developmental disorders in later foetal or postnatal life.
This project aims to develop and apply a novel, state-of-the-art single-cell sequencing method for studying the 3D nuclear DNA architecture as well as the expression of genes, both genome wide and of the same single cell. Application of this technology to whole human embryos in the various stages of development will provide the fundamental basis for understanding how the cells’ nuclear DNA architecture evolves during development within and across embryos, how this process is linked with gene expression and thus cellular differentiation and phenotypes, and how this process is perturbed by the numerical and structural chromosomal anomalies that often accumulate in human embryos. The technology will furthermore be portable to other tissues to understand normal organismal development, disease aetiology and ageing.