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Trans- and cis-acting effects of the lncRNA Firre on epigenetic and structural features of the inactive X chromosome

He Fang, Giancarlo Bonora, Jordan P. Lewandowski, Jitendra Thakur, Galina N. Filippova, Steven Henikoff, Jay Shendure, Zhijun Duan, View ORCID ProfileJohn L. Rinn, Xinxian Deng, William S. Noble, Christine M. Disteche
doi: https://doi.org/10.1101/687236
He Fang
1Department of Pathology, University of Washington, Seattle WA, USA
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Giancarlo Bonora
2Department of Genome Sciences, University of Washington, Seattle WA, USA
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Jordan P. Lewandowski
3Department of Stem Cell and Regenerative Biology, Harvard University, Boston, MA, USA
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Jitendra Thakur
4Fred Hutchinson Cancer Research Center, Seattle WA, USA
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Galina N. Filippova
1Department of Pathology, University of Washington, Seattle WA, USA
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Steven Henikoff
4Fred Hutchinson Cancer Research Center, Seattle WA, USA
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Jay Shendure
2Department of Genome Sciences, University of Washington, Seattle WA, USA
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Zhijun Duan
5Institute for Stem Cell and Regenerative Medicine, University of Washington, USA
6Division of Hematology, Department of Medicine, University of Washington, USA
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John L. Rinn
7Department of Biochemistry, University of Colorado at Boulder, Boulder, CO, USA
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  • ORCID record for John L. Rinn
Xinxian Deng
1Department of Pathology, University of Washington, Seattle WA, USA
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  • For correspondence: cdistech@uw.edu dengx2@uw.edu wnoble@uw.edu
William S. Noble
2Department of Genome Sciences, University of Washington, Seattle WA, USA
8Paul G. Allen School of Computer Science and Engineering, University of Washington, Seattle WA, USA
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  • For correspondence: cdistech@uw.edu dengx2@uw.edu wnoble@uw.edu
Christine M. Disteche
1Department of Pathology, University of Washington, Seattle WA, USA
9Department of Medicine University of Washington, Seattle WA, USA
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  • For correspondence: cdistech@uw.edu dengx2@uw.edu wnoble@uw.edu
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Abstract

Firre encodes a lncRNA involved in nuclear organization in mammals. Here we find that Firre RNA is transcribed from the active X chromosome (Xa) and exerts trans-acting effects on the inactive X chromosome (Xi). Allelic deletion of Firre on the Xa in a mouse hybrid fibroblast cell line results in a dramatic loss of the histone modification H3K27me3 and of components of the PRC2 complex on the Xi as well as the disruption of the perinucleolar location of the Xi. These features are measurably rescued by ectopic expression of a mouse or human Firre/FIRRE cDNA transgene, strongly supporting a conserved trans-acting role of the Firre transcript in maintaining the Xi heterochromatin environment. Surprisingly, CTCF occupancy is decreased on the Xi upon loss of Firre RNA, but is partially recovered by ectopic transgene expression, suggesting a functional link between Firre RNA and CTCF in maintenance of epigenetic features and/or location of the Xi. Loss of Firre RNA results in dysregulation of genes implicated in cell division and development, but not in reactivation of genes on the Xi, which retains its bipartite structure despite some changes in chromatin contact distribution. Allelic deletion or inversion of Firre on the Xi causes localized redistribution of chromatin contacts, apparently dependent on the orientation of CTCF binding sites clustered at the locus. Thus, the Firre locus and its RNA have roles in the maintenance of epigenetic features and structure of the Xi.

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Posted June 30, 2019.
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Trans- and cis-acting effects of the lncRNA Firre on epigenetic and structural features of the inactive X chromosome
He Fang, Giancarlo Bonora, Jordan P. Lewandowski, Jitendra Thakur, Galina N. Filippova, Steven Henikoff, Jay Shendure, Zhijun Duan, John L. Rinn, Xinxian Deng, William S. Noble, Christine M. Disteche
bioRxiv 687236; doi: https://doi.org/10.1101/687236
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Trans- and cis-acting effects of the lncRNA Firre on epigenetic and structural features of the inactive X chromosome
He Fang, Giancarlo Bonora, Jordan P. Lewandowski, Jitendra Thakur, Galina N. Filippova, Steven Henikoff, Jay Shendure, Zhijun Duan, John L. Rinn, Xinxian Deng, William S. Noble, Christine M. Disteche
bioRxiv 687236; doi: https://doi.org/10.1101/687236

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