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Anti-fibrotische Effekte des Mirlet7/NuRD-Ribonukleoproteinkomplexes in idiopathischer pulmonaler fibrose

Fachliche Zuordnung Pneumologie,Thoraxchirurgie
Biochemie
Förderung Förderung von 2018 bis 2022
Projektkennung Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 408916879
 
Erstellungsjahr 2023

Zusammenfassung der Projektergebnisse

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and highly lethal lung disease affecting over 3 million persons worldwide, a number that is increasing due to pollution caused by industrialization. IPF is a disease with poor prognosis and unknown etiology. Unfortunately, curative therapies against IPF have not yet been developed. Current approaches against IPF aim to ameliorate patient symptoms and to delay disease progression. As a result, IPF patients die within 4 years following diagnosis mostly due to respiratory failure. The majority of the eukaryotic genome is transcribed into noncoding RNAs (ncRNAs), which through controlling chromatin structure are important regulators of various nuclear processes. The full extent of ncRNA function has, however, remained elusive. We deciphered the function of the microRNA Mirlet7d as a key regulator of bidirectionally transcribed genes. We found that nuclear Mirlet7d binds ncRNAs expressed from these genes. Mirlet7d–ncRNA duplexes are subsequently 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 proceeds to degrade the ncRNAs, whereas PRC2 induces heterochromatin formation and transcriptional silencing through EZH2. Moreover, this multicomponent RNA–protein complex, which we named MiCEE, tethers the regulated genes to the perinucleolar region and is thus required for proper nucleolar organization. Our study demonstrates that the MiCEE complex mediates epigenetic silencing of bidirectionally expressed genes and global genome organization. The mechanism of transcriptional repression of bi-directional transcribed genes mediated by the MICEEE complex was also confirmed in human cells [ref]. We found that reduced MIRLET7D levels in IPF compromise epigenetic gene silencing mediated by the ribonucleoprotein complex MiCEE. In addition, we showed that hyperactive EP300 reduces nuclear HDAC activity and interferes with MiCEE function in IPF. Remarkably, EP300 inhibition reduced fibrotic hallmarks of in vitro (patient-derived primary fibroblast), in vivo (bleomycin mouse model) and ex vivo (precision-cut lung slices, PCLS) IPF models. Our work provides the molecular basis for therapies against IPF using EP300 inhibition. During the present Research Project we also found that the high-mobility group AT-hook 2 protein (HMGA2) induces DNA nicks at the transcription start site, which are required by the histone chaperone FACT complex to incorporate nucleosomes containing the histone variant H2A.X. Further, phosphorylation of H2A.X at S139 (γ-H2AX) is required for repair-mediated DNA demethylation and transcription activation. The relevance of these findings is demonstrated within the context of TGFB1 signaling and idiopathic pulmonary fibrosis, suggesting therapies against this lethal disease. Our data support the concept that chromatin opening during transcriptional initiation involves intermediates with DNA breaks that subsequently require DNA repair mechanisms to ensure genome integrity.

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