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TET蛋白调节iNKT细胞中Drosha的表达并影响微小RNA。

TET proteins regulate Drosha expression and impact microRNAs in iNKT cells.

作者信息

Gioulbasani Marianthi, Äijö Tarmo, Valenzuela Jair E, Bettes Julia Buquera, Tsagaratou Ageliki

机构信息

Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

School of Biology, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece.

出版信息

bioRxiv. 2024 Jul 31:2024.07.31.605991. doi: 10.1101/2024.07.31.605991.

DOI:10.1101/2024.07.31.605991
PMID:39131272
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11312547/
Abstract

DNA demethylases TET2 and TET3 play a fundamental role in thymic invariant natural killer T (iNKT) cell differentiation by mediating DNA demethylation of genes encoding for lineage specifying factors. Paradoxically, differential gene expression analysis revealed that significant number of genes were upregulated upon TET2 and TET3 loss in iNKT cells. This unexpected finding could be potentially explained if loss of TET proteins was reducing the expression of proteins that suppress gene expression. In this study, we discover that TET2 and TET3 synergistically regulate expression, by generating 5hmC across the gene body and by impacting chromatin accessibility. As DROSHA is involved in microRNA biogenesis, we proceed to investigate the impact of TET2/3 loss on microRNAs in iNKT cells. We report that among the downregulated microRNAs are members of the Let-7 family that downregulate the expression of the iNKT cell lineage specifying factor PLZF. Our data link TET proteins with microRNA expression and reveal an additional layer of TET mediated regulation of gene expression.

摘要

DNA去甲基化酶TET2和TET3通过介导编码谱系特异性因子的基因的DNA去甲基化，在胸腺不变自然杀伤T（iNKT）细胞分化中发挥重要作用。矛盾的是，差异基因表达分析显示，iNKT细胞中TET2和TET3缺失后，大量基因上调。如果TET蛋白的缺失降低了抑制基因表达的蛋白质的表达，那么这一意外发现可能得到潜在解释。在本研究中，我们发现TET2和TET3通过在基因体上产生5-羟甲基胞嘧啶（5hmC）并影响染色质可及性，协同调节基因表达。由于DROSHA参与微小RNA的生物合成，我们进而研究TET2/3缺失对iNKT细胞中微小RNA的影响。我们报告称，下调的微小RNA中有Let-7家族成员，它们下调iNKT细胞谱系特异性因子PLZF的表达。我们的数据将TET蛋白与微小RNA表达联系起来，并揭示了TET介导的基因表达调控的另一层面。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/98a3/11312547/ae9fe4e441d1/nihpp-2024.07.31.605991v1-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/98a3/11312547/f01d604407f8/nihpp-2024.07.31.605991v1-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/98a3/11312547/91d047943855/nihpp-2024.07.31.605991v1-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/98a3/11312547/ae9fe4e441d1/nihpp-2024.07.31.605991v1-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/98a3/11312547/f01d604407f8/nihpp-2024.07.31.605991v1-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/98a3/11312547/91d047943855/nihpp-2024.07.31.605991v1-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/98a3/11312547/ae9fe4e441d1/nihpp-2024.07.31.605991v1-f0003.jpg

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本文引用的文献

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Deciphering the TET3 interactome in primary thymic developing T cells.解析原发性胸腺发育中T细胞的TET3相互作用组。
iScience. 2024 Apr 18;27(5):109782. doi: 10.1016/j.isci.2024.109782. eCollection 2024 May 17.
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Defining iNKT Cell Subsets and Their Function by Flow Cytometry.通过流式细胞术定义 iNKT 细胞亚群及其功能。
Curr Protoc. 2023 Jul;3(7):e838. doi: 10.1002/cpz1.838.
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TET Proteins in the Spotlight: Emerging Concepts of Epigenetic Regulation in T Cell Biology.TET 蛋白成为焦点：T 细胞生物学中表观遗传调控的新观点。
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Protocol to isolate mature thymic T cell subsets using fluorescence-activated cell sorting for assessing gene expression by RNA-seq and transcription factor binding across the genome by CUT&RUN.使用荧光激活细胞分选分离成熟胸腺 T 细胞亚群的方案，用于通过 RNA-seq 评估基因表达，并通过 CUT&RUN 评估转录因子在全基因组上的结合。
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TET proteins regulate T cell and iNKT cell lineage specification in a TET2 catalytic dependent manner.TET 蛋白以 TET2 催化依赖性方式调节 T 细胞和 iNKT 细胞谱系的特异性。
Front Immunol. 2022 Aug 5;13:940995. doi: 10.3389/fimmu.2022.940995. eCollection 2022.
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TCR-engineered iNKT cells induce robust antitumor response by dual targeting cancer and suppressive myeloid cells.T 细胞受体工程化 iNKT 细胞通过双重靶向肿瘤和抑制性髓系细胞诱导强烈的抗肿瘤反应。
Sci Immunol. 2022 Aug 12;7(74):eabn6563. doi: 10.1126/sciimmunol.abn6563. Epub 2022 Aug 19.
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Genomic and Transcriptional Mechanisms Governing Innate-like T Lymphocyte Development.调控固有样T淋巴细胞发育的基因组和转录机制
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EMBO Rep. 2021 Aug 4;22(8):e52716. doi: 10.15252/embr.202152716. Epub 2021 Jul 21.
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