Epigenetic reactivation of LINE-1 retrotransposon disrupts NuRD corepressor functions and induces oncogenic transformation in human bronchial epithelial cells.

Pasano Bojang,Kenneth S Ramos

doi:10.1002/1878-0261.12329

Abstract

Long interspersed nuclear element‐1 (LINE‐1 or L1) reactivation is linked to poor prognosis in non‐small‐cell lung carcinoma (NSCLC), but the molecular bases of this response remain largely unknown. In this report, we show that challenge of human bronchial epithelial cells (HBECs) with the lung carcinogen, benzo(a)pyrene (BaP), shifted the L1 promoter from a heterochromatic to euchromatic state through disassembly of the nucleosomal and remodeling deacetylase (NuRD) complex. Carcinogen challenge was also associated with partial displacement of constituent proteins from the nuclear to the cytoplasmic compartment. Disruption of NuRD corepression by genetic ablation or carcinogen treatment correlated with accumulation of L1 mRNA and proteins. Mi2β bound directly to the L1 promoter to effect retroelement silencing, and this response required the DNA‐ and ATPase‐binding domains of Mi2β. Sustained expression of L1 in HBECs was tumorigenic in a human–SCID mouse xenograft model, giving rise to tumors that regressed over time. Together, these results show that functional modulation of the NuRD constituent proteins is a critical molecular event in the activation of L1 retrotransposon. L1 expression creates a microenvironment in HBECs that is conducive to neoplasia and malignant transformation.

Highlights

Human L1 is ~6 kb and consists of an internal promoter located within the 50untranslated region (50UTR), two open reading frames (ORFs) encoding ORF1p and ORF2p, and a 30UTR with a poly(A) tail and signal (Dombroski et al, 1991; Scott et al, 1987)
Evidence is presented here establishing a functional linkage between nucleosomal and remodeling deacetylase (NuRD) macromolecular complex disassembly, L1-Ta reactivation, and malignant transformation in human bronchial epithelial cells (HBECs) challenged with the lung carcinogen BaP
The association of NuRD complexes with the L1 promoter may serve as a key regulatory signal for the formation of regional domains of heterochromatin that can be disrupted by the lung carcinogen BaP during the course of malignant progression

Summary

Introduction

Human L1 is ~6 kb and consists of an internal promoter located within the 50untranslated region (50UTR), two open reading frames (ORFs) encoding ORF1p and ORF2p, and a 30UTR with a poly(A) tail and signal (Dombroski et al, 1991; Scott et al, 1987). L1 elements constitute a large family of mammalian retrotransposons that have continuously replicated for over 100 Myr (Boissinot et al, 2000). 100 retrotransposition-competent L1s remain in the human genome that function as autonomous elements through a copy-and-paste mechanism (Brouha et al, 2003). The human L1 promoter is highly conserved among active L1s, except for a single nucleotide deletion at position 74, and a single nucleotide polymorphism (SNP) at 711 (t/c), both of which differentiate Ta-1d from the Ta-Ind, Ta-0, and Pre-Ta families (Boissinot et al, 2000; Swergold, 1990). The active human Ta family arose ~4MYA and subsequently differentiated into two major subfamilies, Ta-0 and Ta-1, each of which contains additional members. Ta-1 is younger than Ta-0 and accounts for at least 50% of the Ta family (Boissinot et al, 2000)

Methods

Results

Conclusion