Journal
MOLECULAR SYSTEMS BIOLOGY
Volume 11, Issue 12, Pages -Publisher
WILEY
DOI: 10.15252/msb.20156492
Keywords
chromatin contacts; chromosome architecture; epigenetics; gene expression; polymer modelling
Categories
Funding
- Canadian Institutes of Health Research (CIHR) [MOP-86716, CAP-120350]
- CIHR
- FRSQ
- Helmholtz Foundation (Germany)
- RIKEN Omics Science Center from MEXT
- Innovative Technology (Cell Innovation Program) from the MEXT, Japan
- RIKEN Preventive Medicine and Diagnosis Innovation Program (RIKEN PMI)
- RIKEN Centre for Life Science Technologies
- Division of Genomic Technologies (RIKEN CLST (DGT)
- MEXT, Japan
- Biotechnology and Biological Sciences Research Council [BB/H008098/1] Funding Source: researchfish
- Medical Research Council [MC_U120061476] Funding Source: researchfish
- BBSRC [BB/H008098/1] Funding Source: UKRI
- MRC [MC_U120061476] Funding Source: UKRI
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Mammalian chromosomes fold into arrays of megabase-sized topologically associating domains (TADs), which are arranged into compartments spanning multiple megabases of genomic DNA. TADs have internal substructures that are often cell type specific, but their higher-order organization remains elusive. Here, we investigate TAD higher-order interactions with Hi-C through neuronal differentiation and show that they form a hierarchy of domains-within-domains (metaTADs) extending across genomic scales up to the range of entire chromosomes. We find that TAD interactions are well captured by tree-like, hierarchical structures irrespective of cell type. metaTAD tree structures correlate with genetic, epigenomic and expression features, and structural tree rearrangements during differentiation are linked to transcriptional state changes. Using polymer modelling, we demonstrate that hierarchical folding promotes efficient chromatin packaging without the loss of contact specificity, highlighting a role far beyond the simple need for packing efficiency.
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