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

He Fang,Zhijun Duan,Steven Henikoff,Jay Shendure,Christine M Disteche,William S Noble,Jitendra Thakur,Xinxian Deng,John L Rinn,Giancarlo Bonora,Jordan P Lewandowski,Galina N Filippova

doi:10.1038/s41467-020-19879-3

Abstract

Firre encodes a lncRNA involved in nuclear organization. Here, we show that Firre RNA expressed from the active X chromosome maintains histone H3K27me3 enrichment on the inactive X chromosome (Xi) in somatic cells. This trans-acting effect involves SUZ12, reflecting interactions between Firre RNA and components of the Polycomb repressive complexes. Without Firre RNA, H3K27me3 decreases on the Xi and the Xi-perinucleolar location is disrupted, possibly due to decreased CTCF binding on the Xi. We also observe widespread gene dysregulation, but not on the Xi. These effects are measurably rescued by ectopic expression of mouse or human Firre/FIRRE transgenes, supporting conserved trans-acting roles. We also find that the compact 3D structure of the Xi partly depends on the Firre locus and its RNA. In common lymphoid progenitors and T-cells Firre exerts a cis-acting effect on maintenance of H3K27me3 in a 26 Mb region around the locus, demonstrating cell type-specific trans- and cis-acting roles of this lncRNA.

Highlights

Firre encodes a long noncoding RNA (lncRNA) involved in nuclear organization
We report that the lncRNA Firre transcribed from the Xa acts in trans and in cis on the Xi to maintain its epigenetic features, nuclear location, and 3D structure
We find that maintenance of H3K27me[3] on the Xi mediated by Firre RNA involve the PRC complexes, which is supported by our reanalyses of RNA/protein interaction datasets[39,40,41,42,43,44,45]

Summary

Introduction

We show that Firre RNA expressed from the active X chromosome maintains histone H3K27me[3] enrichment on the inactive X chromosome (Xi) in somatic cells This trans-acting effect involves SUZ12, reflecting interactions between Firre RNA and components of the Polycomb repressive complexes. A Firre knockout (KO) mouse model is viable, but results in cell-type-specific defects in hematopoiesis that impact common lymphoid progenitors (CLPs)[32,33] These defects are rescued by ectopic expression of Firre from an autosomal location, defining a trans-acting role for Firre[32,33]. Our results are supported by rescue experiments using cDNA transgenes We demonstrate both trans- and cis-acting roles of Firre RNA and its locus, with evidence of cell-type-specific effects in cell lines and in vivo

Methods

Results

Conclusion