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1.
Mob DNA ; 14(1): 20, 2023 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-38037122

RESUMO

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.

2.
Immunol Rev ; 305(1): 165-178, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34816452

RESUMO

In recent years, there has been significant progress toward understanding the transcriptional networks underlying mammalian immune responses, fueled by advances in regulatory genomic technologies. Epigenomic studies profiling immune cells have generated detailed genome-wide maps of regulatory elements that will be key to deciphering the regulatory networks underlying cellular immune responses and autoimmune disorders. Unbiased analyses of these genomic maps have uncovered endogenous retroviruses as an unexpected ally in the regulation of human immune systems. Despite their parasitic origins, studies are finding an increasing number of examples of retroviral sequences having been co-opted for beneficial immune function and regulation by the host cell. Here, we review how endogenous retroviruses have given rise to numerous regulatory elements that shape the epigenetic landscape of host immune responses. We will discuss the implications of these elements on the function, dysfunction, and evolution of innate immunity.


Assuntos
Retrovirus Endógenos , Animais , Retrovirus Endógenos/genética , Epigênese Genética , Humanos , Imunidade Inata/genética , Mamíferos/genética
3.
Nat Commun ; 9(1): 1861, 2018 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-29748537

RESUMO

Human immunodeficiency virus type 1 (HIV-1) assembly occurs on the inner leaflet of the host cell plasma membrane, incorporating the essential viral envelope glycoprotein (Env) within a budding lattice of HIV-1 Gag structural proteins. The mechanism by which Env incorporates into viral particles remains poorly understood. To determine the mechanism of recruitment of Env to assembly sites, we interrogate the subviral angular distribution of Env on cell-associated virus using multicolor, three-dimensional (3D) superresolution microscopy. We demonstrate that, in a manner dependent on cell type and on the long cytoplasmic tail of Env, the distribution of Env is biased toward the necks of cell-associated particles. We postulate that this neck-biased distribution is regulated by vesicular retention and steric complementarity of Env during independent Gag lattice formation.


Assuntos
HIV-1/fisiologia , Montagem de Vírus/fisiologia , Produtos do Gene env do Vírus da Imunodeficiência Humana/metabolismo , Produtos do Gene gag do Vírus da Imunodeficiência Humana/metabolismo , Animais , Células COS , Linhagem Celular Tumoral , Membrana Celular/virologia , Chlorocebus aethiops , Citoesqueleto/metabolismo , Células HEK293 , Humanos , Microscopia/métodos , Vírion/metabolismo , Produtos do Gene env do Vírus da Imunodeficiência Humana/ultraestrutura , Produtos do Gene gag do Vírus da Imunodeficiência Humana/ultraestrutura
4.
Mol Biol Cell ; 2016 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-26960797

RESUMO

Cell movement and cytokinesis are facilitated by contractile forces generated by the molecular motor, non-muscle myosin II (NMII). NMII molecules form a filament (NMII-F) through interactions of their C-terminal rod domains, positioning groups of N-terminal motor domains on opposite sides. The NMII motors then bind and pull actin filaments toward the NMII-F, thus driving contraction. Inside of crawling cells, NMIIA-Fs form large macromolecular ensembles (i.e., NMIIA-F stacks) but how this occurs is unknown. Here we show NMIIA-F stacks are formed through two non-mutually exclusive mechanisms: expansion and concatenation. During expansion, NMIIA molecules within the NMIIA-F spread out concurrent with addition of new NMIIA molecules. Concatenation occurs when multiple NMIIA-F/NMIIA-F stacks move together and align. We found NMIIA-F stack formation was regulated by both motor-activity and the availability of surrounding actin filaments. Furthermore, our data showed expansion and concatenation also formed the contractile ring in dividing cells. Thus, interphase and mitotic cells share similar mechanisms for creating large contractile units, and these are likely to underlie how other myosin II-based contractile systems are assembled.

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