Hierarchical folding and reorganization of chromosomes are linked to transcriptional changes in cellular differentiation

Hierarchical folding and reorganization of chromosomes are linked to transcriptional changes in cellular differentiation

Abstract 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...

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Main Authors: James Fraser, Carmelo Ferrai, Andrea M Chiariello, Markus Schueler, Tiago Rito, Giovanni Laudanno, Mariano Barbieri, Benjamin L Moore, Dorothee CA Kraemer, Stuart Aitken, Sheila Q Xie, Kelly J Morris, Masayoshi Itoh, Hideya Kawaji, Ines Jaeger, Yoshihide Hayashizaki, Piero Carninci, Alistair RR Forrest, The FANTOM Consortium, Colin A Semple, Josée Dostie, Ana Pombo, Mario Nicodemi
Format: Article
Language:English
Published: Springer Nature 2015-12-01
Series:Molecular Systems Biology
Subjects:
chromatin contacts
chromosome architecture
epigenetics
gene expression
polymer modelling
Online Access:https://doi.org/10.15252/msb.20156492
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Summary:Abstract 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.
ISSN:1744-4292

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