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

IF 4.7 2区 生物学 Q1 GENETICS & HEREDITY Mobile DNA Pub Date : 2023-11-30 DOI:10.1186/s13100-023-00308-3
Carmen A Buttler, Daniel Ramirez, Robin D Dowell, Edward B Chuong
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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.

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内含子LINE-1调控人免疫细胞中IFNAR1的表达。
背景:尽管它们起源于自私的寄生序列,但人类基因组中的一些转座子已被用作调控元件,促进了转录网络的进化。转座子衍生的调控元件的最典型的例子来自内源性逆转录病毒(erv),由于原病毒长末端重复区域的内在调控活性。然而,转座子的一个亚类,长分散核元件(LINEs),在寻找功能调节转座子的过程中很大程度上被忽视了,并且被认为是广泛的表观遗传抑制。结果:通过分析人类免疫细胞的表观基因组数据,我们检测了LINEs的染色质状态。许多细胞系被抑制的H3K9me3修饰标记,但是一个亚群在人类免疫细胞中表现出增强子活性的证据,尽管也显示出表观遗传抑制的证据。我们假设这些抑制和激活表观遗传标记的竞争力量可能导致诱导增强子活性。我们研究了位于干扰素α / β受体1 (IFNAR1)第一个内含子内的特定L1M2a元件。该元件显示了B细胞特异性增强子活性的表观遗传特征,尽管被Human Silencing Hub (HUSH)复合物抑制。CRISPR在B淋巴母细胞样细胞中删除该元件表明,该元件作为增强子调节IFNAR1的稳态和干扰素诱导表达。结论:我们的实验研究表明,L1M2a元件被增选为IFNAR1的干扰素诱导增强子,创建一个反馈回路,其中IFNAR1通过干扰素信号转录上调。这一发现表明,其他LINEs可能表现出隐细胞类型特异性或上下文依赖性增强子活性。在理解转座子对细胞基因组调控格局的贡献方面,LINEs受到的关注不如erv,但它们可能是免疫系统调控网络快速进化中重要的、谱系特异性的参与者,值得进一步研究。
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来源期刊
Mobile DNA
Mobile DNA GENETICS & HEREDITY-
CiteScore
8.20
自引率
6.10%
发文量
26
审稿时长
11 weeks
期刊介绍: Mobile DNA is an online, peer-reviewed, open access journal that publishes articles providing novel insights into DNA rearrangements in all organisms, ranging from transposition and other types of recombination mechanisms to patterns and processes of mobile element and host genome evolution. In addition, the journal will consider articles on the utility of mobile genetic elements in biotechnological methods and protocols.
期刊最新文献
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