Inactivation of nuclear histone deacetylases disrupts the MiCEE complex in Idiopathic Pulmonary Fibrosis

Objective Idiopathic Pulmonary Fibrosis (IPF) is a chronic, irreversible and highly lethal disease. The majority of the eukaryotic genome is transcribed into noncoding RNAs (ncRNAs), which are important regulators of different nuclear processes by controlling chromatin structure. However, the full extent of ncRNA function has remained elusive. We showed that the MiCEE complex mediated silencing of bi-directional expressed genes in lung epithelial and mesenchymal cells. However, the clinical relevance of these findings was not known.

Results Here we deciphered the function of the microRNA Mirlet7 d as a key regulator of bidirectionally transcribed genes. We found that nuclear Mirlet7 d binds ncRNAs expressed from these genes. Mirlet7 d −ncRNA duplexes are further bound by C1D, which in turn targets the RNA exosome complex and the polycomb repressive complex 2 (PRC2) to the bidirectionally active loci. The exosome degrades the ncRNAs, whereas PRC2 induces heterochromatin and transcriptional silencing through EZH2. Moreover, this multicomponent RNA-protein complex, which we named MiCEE, tethers the regulated genes to the perinucleolar region and thus is required for proper nucleolar organization. Reduced nuclear MIRLET7D levels in idiopathic pulmonary fibrosis (IPF) compromised epigenetic silencing mediated by the MiCEE complex. In addition, we found that reduced nuclear HDAC activity in IPF interferes with MiCEE-dependent H3K27 tri-methylation. Furthermore, we demonstrated that MIRLET7D gain-of-function in vitro reduced fibrotic hallmarks of human primary fibroblast.

Conclusion Our study demonstrates that the MiCEE complex mediates epigenetic silencing of bidirectionally expressed genes and global genome organization. We elucidated the clinical relevance of the MiCEE complex within a highly lethal pulmonary disease. Our results together highlight the potential of MIRLET7D as basis for therapeutic approaches against IPF.

• References

• 1 MiCEE is a ncRNA-protein complex that mediates epigenetic silencing and nucleolar organization. Nat Genet 2018; 50 (07) 990-1001 doi:10.1038/s41588-018-0139-3
• 2 Rubio K et. al. (2018), Nat Comm. MIRLET7D delivery as therapeutic approach against Idiopathic Pulmonary Fibrosis. Manuscript in revision. .