Asxl1 exerts an antiproliferative effect on mouse lung maturation via epigenetic repression of the E2f1-Nmyc axis

Seungtae Moon,So-Jung An,Nackhyoung Kim,Ui-Hyun Park,Sun-Kyoung Im,A.-Reum Kim,Jin-Taek Hwang,Woong Sun,Hyesook Youn,Joo-Yeon Kim,Ji-Hoon Kim,Soo-Jong Um,Eun-Joo Kim

doi:10.1038/s41419-018-1171-z

Seungtae Moon, So-Jung An + Show 11 more

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https://doi.org/10.1038/s41419-018-1171-z

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Abstract

Although additional sex combs-like 1 (ASXL1) has been extensively described in hematologic malignancies, little is known about the molecular role of ASXL1 in organ development. Here, we show that Asxl1 ablation in mice results in postnatal lethality due to cyanosis, a respiratory failure. This lung defect is likely caused by higher proliferative potential and reduced expression of surfactant proteins, leading to reduced air space and defective lung maturation. By microarray analysis, we identified E2F1-responsive genes, including Nmyc, as targets repressed by Asxl1. Nmyc and Asxl1 are reciprocally expressed during the fetal development of normal mouse lungs, whereas Nmyc downregulation is impaired in Asxl1-deficient lungs. Together with E2F1 and ASXL1, host cell factor 1 (HCF-1), purified as an Asxl1-bound protein, is recruited to the E2F1-binding site of the Nmyc promoter. The interaction occurs between the C-terminal region of Asxl1 and the N-terminal Kelch domain of HCF-1. Trimethylation (me3) of histone H3 lysine 27 (H3K27) is enriched in the Nmyc promoter upon Asxl1 overexpression, whereas it is downregulated in Asxl1-deleted lung and -depleted A549 cells, similar to H3K9me3, another repressive histone marker. Overall, these findings suggest that Asxl1 modulates proliferation of lung epithelial cells via the epigenetic repression of Nmyc expression, deficiency of which may cause hyperplasia, leading to dyspnea.

Highlights

1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; Introduction The additional sex combs-like (ASXL) family is the mammalian homolog of the additional sex combs (Asx) gene, which is an enhancer of trithorax group (TrxG) and polycomb group (PcG) proteins in Drosophila[1]
As shown by hematoxylin and eosin (H&E) staining, the homozygous Asxl1−/− lung failed to inflate with air because of its thicker alveolar wall (Fig. 1b), smaller air space, and more numerous small alveoli (Fig. 1c) compared to the WT or the heterozygote
Given that additional sex combs-like 1 (ASXL1) is functionally associated with either EZH2, an H3K27 methyltransferase of the polycomb repressive complex 2 (PRC2) complex[7,8], or with HP1α, a binder of methylated H3K9, for transcriptional silencing[4], we addressed whether ASXL1, in cooperation with host cell factor 1 (HCF-1), affects the enrichment of these epigenetic histone markers at the E2F1-binding locus of the Nmyc promoter

Summary

Introduction

The additional sex combs-like (ASXL) family is the mammalian homolog of the additional sex combs (Asx) gene, which is an enhancer of trithorax group (TrxG) and polycomb group (PcG) proteins in Drosophila[1]. There are three members of the ASXL family—ASXL1, ASXL2, and ASXL32. ASXL family proteins are chromatin factors that exert diverse effects, including on tumor suppression and development, by modulating gene expression. We previously demonstrated that ASXL1 is primarily located in the nucleus and regulates nuclear hormone receptors forms a polycomb repressive deubiquitinase (PR-DUB). The enzymatic activity of the PR-DUB complex was examined in mammals using the ASXL family[6]. ASXL1 interacts with EZH2, a member of polycomb repressive complex 2 (PRC2) and responds to PRC2-mediated gene silencing[7,8]

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