An intronic LINE-1 regulates IFNAR1 expression in human immune cells

Abstract

Background Despite their origins as selfish parasitic sequences, some transposons in the human genome have been co-opted to serve as regulatory elements, contributing to the evolution of transcriptional networks. Most well-characterized examples of transposon-derived regulatory elements derive from endogenous retroviruses (ERVs), due to the intrinsic regulatory activity of proviral long terminal repeat regions. However, one subclass of transposable elements, the Long Interspersed Nuclear Elements (LINEs), have been largely overlooked in the search for functional regulatory transposons, and considered to be broadly epigenetically repressed. Results We examined the chromatin state of LINEs by analyzing epigenomic data from human immune cells. Many LINEs are marked by the repressive H3K9me3 modification, but a subset exhibits evidence of enhancer activity in human immune cells despite also showing evidence of epigenetic repression. We hypothesized that these competing forces of repressive and activating epigenetic marks might lead to inducible enhancer activity. We investigated a specific L1M2a element located within the first intron of Interferon Alpha/Beta Receptor 1 (IFNAR1). This element shows epigenetic signatures of B cell-specific enhancer activity, despite being repressed by the Human Silencing Hub (HUSH) complex. CRISPR deletion of the element in B lymphoblastoid cells revealed that the element acts as an enhancer that regulates both steady state and interferon-inducible expression of IFNAR1. Conclusions Our study experimentally demonstrates that an L1M2a element was co-opted to function as an interferon-inducible enhancer of IFNAR1, creating a feedback loop wherein IFNAR1 is transcriptionally upregulated by interferon signaling. This finding suggests that other LINEs may exhibit cryptic cell type-specific or context-dependent enhancer activity. LINEs have received less attention than ERVs in the effort to understand the contribution of transposons to the regulatory landscape of cellular genomes, but these are likely important, lineage-specific players in the rapid evolution of immune system regulatory networks and deserve further study.

An eQTL-based approach reveals candidate regulators of LINE-1 RNA levels in lymphoblastoid cells

“…For example, one study suggested that intronic L1s are part of an important regulatory network maintaining T-cell quiescence [ 32 ]. This is consistent with the increasing appreciation for the importance of alternative splicing in immune regulation and cell death pathways [ 33 ] and with another pair of studies highlighting the importance of TE exonization and intronic TE co-option in interferon signaling [ 34 , 35 ]. Additionally, L1 RNA may be sufficient to induce an interferon response and alter cellular viability, even in the absence of transposition [ 36 , 37 ].…”

Navigating the brain and aging: exploring the impact of transposable elements from health to disease

“…In humans, most of these co-opted regulatory elements are found within ERVs ( Chuong et al, 2016 ). However, non-LTR elements, such as L1M2a, were also shown to act as IFN-inducible enhancers ( Buttler et al, 2023 ). In contrast, in mice, B2 elements are the predominant source of these regulatory sequences ( Horton et al, 2023 ).…”