A microRNA expression and regulatory element activity atlas of the mouse immune system

Rose, Samuel A.; Wroblewska, Aleksandra; Dhainaut, Maxime; Yoshida, Hideyuki; Shaffer, James; Bektesevic, Anela; Ben-Zvi, Benjamin; Rhoads, Andrew; Kim, Edy Y.; Yu, Bingfei; Lavin, Yonit; Mérad, Miriam; Buenrostro, Jason D.; Brown, Brian D.

doi:10.1038/s41590-021-00944-y

Cited by 29 publications

(20 citation statements)

References 80 publications

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“…miR-124a was initially described as a neuron-specific miRNA and is not detected at appreciable levels in cells outside the nervous system ( 29 , 30 ). It has an important role in neuronal differentiation ( 31 ) and was subsequently shown to function as a tumor suppressor gene in the brain and found to be lost in glioblastoma ( 32 ).…”

Section: Resultsmentioning

confidence: 99%

In Vivo miRNA Decoy Screen Reveals miR-124a as a Suppressor of Melanoma Metastasis

et al. 2022

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Melanoma is a highly prevalent cancer with an increasing incidence worldwide and high metastatic potential. Brain metastasis is a major complication of the disease, as more than 50% of metastatic melanoma patients eventually develop intracranial disease. MicroRNAs (miRNAs) have been found to play an important role in the tumorigenicity of different cancers and have potential as markers of disease outcome. Identification of relevant miRNAs has generally stemmed from miRNA profiling studies of cells or tissues, but these approaches may have missed miRNAs with relevant functions that are expressed in subfractions of cancer cells. We performed an unbiased in vivo screen to identify miRNAs with potential functions as metastasis suppressors using a lentiviral library of miRNA decoys. Notably, we found that a significant fraction of melanomas that metastasized to the brain carried a decoy for miR-124a, a miRNA that is highly expressed in the brain/neurons. Additional loss- and gain-of-function in vivo validation studies confirmed miR-124a as a suppressor of melanoma metastasis and particularly of brain metastasis. miR-124a overexpression did not inhibit tumor growth in vivo, underscoring that miR-124a specifically controls processes required for melanoma metastatic growth, such as seeding and growth post-extravasation. Finally, we provide proof of principle of this miRNA as a promising therapeutic agent by showing its ability to impair metastatic growth of melanoma cells seeded in distal organs. Our efforts shed light on miR-124a as an antimetastatic agent, which could be leveraged therapeutically to impair metastatic growth and improve patient survival.

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Section: Resultsmentioning

confidence: 99%

In Vivo miRNA Decoy Screen Reveals miR-124a as a Suppressor of Melanoma Metastasis

et al. 2022

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“…Here, we used specific primers to assess both miR‐181a‐5p and ‐2‐3p expression in different γδ T cell samples and observed a consistent higher expression of the ‐5p compared to the ‐2‐3p strand. Of note, a recent elegant study in mouse shows that miRNA activity is dependent on its concentration and thus suggests that miRNA signatures should incorporate abundance thresholds to establish their regulatory relevance (Rose et al , 2021 ).…”

Section: Resultsmentioning

confidence: 99%

MicroRNA‐181a restricts human γδ T cell differentiation by targeting Map3k2 and Notch2

et al. 2021

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cd T cells are a conserved population of lymphocytes that contributes to anti-tumor responses through its overt type 1 inflammatory and cytotoxic properties. We have previously shown that human cd T cells acquire this profile upon stimulation with IL-2 or IL-15, in a differentiation process dependent on MAPK/ERK signaling. Here, we identify microRNA-181a as a key modulator of human cd T cell differentiation. We observe that miR-181a is highly expressed in patients with prostate cancer and that this pattern associates with lower expression of NKG2D, a critical mediator of cancer surveillance. Interestingly, miR-181a expression negatively correlates with an activated type 1 effector profile obtained from in vitro differentiated cd T cells and miR-181a overexpression restricts their levels of NKG2D and TNF-a. Upon in silico analysis, we identify two miR-181a candidate targets, Map3k2 and Notch2, which we validate via overexpression coupled with luciferase assays. These results reveal a novel role for miR-181a as critical regulator of human cd T cell differentiation and highlight its potential for manipulation of cd T cells in next-generation immunotherapies.

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“…Recently, the miRNA profiles of 63 primary mouse immune populations, also including spleen and liver NK cells from healthy or cytomegalovirus infected mice, have been established within the context of the ImmGen program, unveiling the expression of both shared and unique miRNAs by each cell type. By integrating data from miRNA profiles with global DNAaccessibility, histone mark distribution, and nascent RNA profiles, it has emerged that miRNAs can use multiple promoters as a mechanism capable of maintaining specificity and abundance in each immune population, thus adding further information on the regulatory landscape of immune cells [49].…”

Section: Mirnas and Ilcsmentioning

confidence: 99%

The Regulatory Activity of Noncoding RNAs in ILCs

Grimaldi

Pietropaolo

Stabile

et al. 2021

Cells

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Innate lymphoid cells (ILCs) are innate lymphocytes playing essential functions in protection against microbial infections and participate in both homeostatic and pathological contexts, including tissue remodeling, cancer, and inflammatory disorders. A number of lineage-defining transcription factors concur to establish transcriptional networks which determine the identity and the activity of the distinct ILC subsets. However, the contribution of other regulatory molecules in controlling ILC development and function is also recently emerging. In this regard, noncoding RNA (ncRNAs) represent key elements of the complex regulatory network of ILC biology and host protection. ncRNAs mostly lack protein-coding potential, but they are endowed with a relevant regulatory activity in immune and nonimmune cells because of their ability to control chromatin structure, RNA stability, and/or protein synthesis. Herein, we summarize recent studies describing how distinct types of ncRNAs, mainly microRNAs, long ncRNAs, and circular RNAs, act in the context of ILC biology. In particular, we comment on how ncRNAs can exert key effects in ILCs by controlling gene expression in a cell- or state-specific manner and how this tunes distinct functional outputs in ILCs.

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A microRNA expression and regulatory element activity atlas of the mouse immune system

Cited by 29 publications

References 80 publications

In Vivo miRNA Decoy Screen Reveals miR-124a as a Suppressor of Melanoma Metastasis

In Vivo miRNA Decoy Screen Reveals miR-124a as a Suppressor of Melanoma Metastasis

MicroRNA‐181a restricts human γδ T cell differentiation by targeting Map3k2 and Notch2

The Regulatory Activity of Noncoding RNAs in ILCs

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