Biophysical Society Thematic Meeting| Santa Cruz 2018

Genome Biophysics: Integrating Genomics and Biophysics to Understand Structural and Functional Aspects of Genomes

Wednesday Speaker Abstracts

Capturing the 3D Folds of Whole Mammalian Genomes in Single Cells Tim J Stevens 1 ; David Lando 2 ; Xiaoyan Ma 2 ; Srinjan Basu 2 ; Ernest D Laue 2 ; 1 MRC Laboratory of Molecular Biology, Cell Biology, Cambridge, Cambridgeshire, United Kingdom 2 University of Cambridge, Biochemistry, Cambridge, Cambridgeshire, United Kingdom We have calculated 3D structures of entire mammalian genomes using single-cell Hi-C data. Using up to 200,000 DNA ligation events per haploid genome, a particle-on-a-string representation of chromosomes, with segment sizes down to 25 kb, is folded to generate a precise, packed, whole-genome structure. This allow us to know where, within certain limits, all the different DNA sequences of an entire genome reside in the 3D volume of the nucleus. By studying genome structures from several cells it is clear that different G1-phase genomes have completely different chromosomal arrangements and that smaller-scale features like TADs and loops are observable but somewhat dynamic. Nonetheless, all structures show consistent organisational principles: an overall 3D genome organisation is observed that segregates inactive and gene sparse regions from the transcriptionally active regions, thus helping to confirm the origin of the A/B compartment pattern observed in population Hi-C. ChIP-seq and RNA-seq data from cell populations suggest that factors and markers associated with gene activity have greater 3D co-localisation where there is increased transcription and at the interior inter-chromosomal interfaces. Also, detailed analysis of transcription factor (TF) binding sites reveals two co- localising groups of TFs with distinct cellular roles. These and similar observations suggest that whole genome structures can become an important resource for investigating genome function and testing molecular hypotheses.

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