How do cells ""remember"" their transcriptional programme after cell division?

The structure of chromosomes in eukaryotic cells is dramatically altered in mitosis, and it is known that the 3D structure of the genome is critical to define the transcriptional program of a cell. Little is known, however, about how the changes in structure of chromosomes in mitosis affect transcription programmes, and how cell identity can be maintained during cell division. Knowledge of this process is crucial to understand organism development and for regenerative medicine.

In interphase, a network of intra- and inter-chromosomal interactions connect active gene promoters with other promoters and regulatory elements, while repressed heterochromatic regions tend to locate in the nuclear periphery1,2. During mitosis, the nuclear envelope disappears and chromosomes undergo major topological changes where most interactions are lost and transcription is dramatically decreased.

Accumulating evidence suggests that the epigenome can store transcriptional memory during transcriptional silencing in mitosis. However, it is still unclear how cell type specific promoters and enhancers are "bookmarked" during mitosis3. Indeed, whether a mitotic-specific epigenome guides the reestablishment of cell type-specific 3D genomic contacts to re-orchestrate gene expression is unclear. Our preliminary ChIP-seq data in mitotic HeLa cells implicate certain histone marks and topological proteins in bookmarking active enhancers and promoters in cells.

In this project, you will use both laboratory-based and bioinformatic methods for the analysis of whole epigenomes to test the hypothesis that these bookmarked regions are required for appropriate transcriptional re-activation after cell division. You will generate mitotic-specific epigenomes using ChIP-seq to analyse how the cell type-specific 3D architecture observed during interphase is encoded in linear mitotic chromosomes.

We will take advantage of genomic long-range interaction maps in matching cell types generated by HiC, capture HiC and ChIA-PET techniques. We will develop new computational approaches to study the relationship between the mitotic linear epigenomes and the interphase 3D structure. For example, we will project the location of mitotic-specific histone marks, RNApol2 and chromatin related proteins into 3D genomic networks to identify the mitotic bookmarking of anchor regions that may subsequently serve to form again cell type-specific DNA loops. This work will reveal how specific factors are maintained on the linear sequence of the genome in mitosis to allow its three-dimensional structure to be recreated after cell division so that appropriate gene expression programmes can be reinstated.

The proposed project will provide a unique opportunity for the student to be trained in both bench science and bioinformatics/AI techniques relevant to the burgeoning field of epigenetics, including systems approaches to the biosciences and data driven biology. The supervisory team is composed of experts in the experimental analysis of mitosis at the genomic, molecular and cellular level (Jonathan Higgins) and the computational analysis of high-throughput chromatin datasets (Daniel Rico). By combining experimental work and bioinformatics training, the student will benefit of working in a multidisciplinary team interested in understanding a key biological process by the integrative analysis of multiple complex types of quantitative data.