The non-canonical SMC protein SmcHD1 antagonises TAD formation and compartmentalisation on the inactive X chromosome

Michal R. Gdula, Tatyana B. Nesterova, Greta Pintacuda, Jonathan Godwin, Ye Zhan, Hakan Ozadam, Michael McClellan, Daniella Moralli, Felix Krueger, Catherine M. Green, Wolf Reik, Skirmantas Kriaucionis, Edith Heard, Job Dekker and Neil Brockdorff ()
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Michal R. Gdula: University of Oxford
Tatyana B. Nesterova: University of Oxford
Greta Pintacuda: University of Oxford
Jonathan Godwin: University of Oxford
Ye Zhan: University of Massachusetts Medical School, Howard Hughes Medical Institute
Hakan Ozadam: University of Massachusetts Medical School, Howard Hughes Medical Institute
Michael McClellan: University of Oxford
Daniella Moralli: University of Oxford
Felix Krueger: Bioinformatics Group, The Babraham Institute
Catherine M. Green: University of Oxford
Wolf Reik: Epigenetics Program, The Babraham Institute
Skirmantas Kriaucionis: University of Oxford
Edith Heard: Institut Curie, PSL Research University, CNRS UMR3215, INSERM U934, UPMC Paris-Sorbonne
Job Dekker: University of Massachusetts Medical School, Howard Hughes Medical Institute
Neil Brockdorff: University of Oxford

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: Abstract The inactive X chromosome (Xi) in female mammals adopts an atypical higher-order chromatin structure, manifested as a global loss of local topologically associated domains (TADs), A/B compartments and formation of two mega-domains. Here we demonstrate that the non-canonical SMC family protein, SmcHD1, which is important for gene silencing on Xi, contributes to this unique chromosome architecture. Specifically, allelic mapping of the transcriptome and epigenome in SmcHD1 mutant cells reveals the appearance of sub-megabase domains defined by gene activation, CpG hypermethylation and depletion of Polycomb-mediated H3K27me3. These domains, which correlate with sites of SmcHD1 enrichment on Xi in wild-type cells, additionally adopt features of active X chromosome higher-order chromosome architecture, including A/B compartments and partial restoration of TAD boundaries. Xi chromosome architecture changes also occurred following SmcHD1 knockout in a somatic cell model, but in this case, independent of Xi gene derepression. We conclude that SmcHD1 is a key factor in defining the unique chromosome architecture of Xi.

Date: 2019
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DOI: 10.1038/s41467-018-07907-2

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