Ana Pombo, PhD
Professor, Humboldt University & Berlin Institute for Medical System Biology
Max Delbrück Center for Molecular Medicine
Genome architecture mapping: exploring mechanisms of 3D chromatin folding
The folding of chromosomes and the structural organization of the genome impacts human health and disease. Gene expression is controlled by long-range chromatin contacts between non-coding regulatory regions and their target genes. Disruption of chromatin contacts due to disease-associated structural changes in the linear genome can result in altered patterns of gene expression. We explore the relationship between 3D genome folding and gene expression using complementary approaches.
We developed Genome Architecture Mapping (GAM), a novel ligation-free technique to map chromatin contacts genome-wide, which is highly suitable for rare cell types and overcomes limitations of current 3C-based approaches. GAM extracts spatial information by sequencing DNA from a large collection of thin nuclear sections, before quantifying the frequency of locus co-segregation. We have identified specific chromatin contacts in mouse ES cells, which are enriched for interactions between active genes and enhancers spanning large genomic distances across tens of megabases. We currently apply GAM in specific neuronal types in the murine brain. We also employ high-resolution cryoFISH and polymer modeling to explore mechanisms of chromatin folding at specific genomic regions. Exploration of the gene-dense HoxB locus in mouse ES cells identifies homotypic contacts between active and Polycomb-repressed promoters within short (<120 nm) physical distances. Our work shows that genome architecture is highly dependent on cell-type specific gene expression patterns at both short and long genomic distances.
