The long non-coding RNA Morrbid regulates Bim and short-lived myeloid cell lifespan.
The long non-coding RNA Morrbid regulates Bim and short-lived myeloid cell lifespan.
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DOI：
10.1038/nature19346
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发表时间：
2016-09-08
期刊：
影响因子：
64.8
通讯作者：
Henao-Mejia, Jorge
中科院分区：
文献类型：
--
作者：
Kotzin, Jonathan J.;Spencer, Sean P.;McCright, Sam J.;Kumar, Dinesh B. Uthaya;Collet, Magalie A.;Mowel, Walter K.;Elliott, Ellen N.;Uyar, Asli;Makiya, Michelle A.;Dunagin, Margaret C.;Harman, Christian C. D.;Virtue, Anthony T.;Zhu, Stella;Bailis, Will;Stein, Judith;Hughes, Cynthia;Raj, Arjun;Wherry, E. John;Goff, Loyal A.;Klion, Amy D.;Rinn, John L.;Williams, Adam;Flavell, Richard A.;Henao-Mejia, Jorge
中性粒细胞、嗜酸性粒细胞和“经典”单核细胞共占人类血液白细胞的70%，是人体内寿命最短的细胞之一。精确调节这些髓系细胞的寿命对于维持保护性免疫反应，同时将长期炎症的有害后果降至最低至关重要。然而，这些细胞的寿命如何受到严格控制仍在很大程度上不得而知。在这里，我们识别了一种新的长非编码RNA(LncRNA)，我们将其命名为Morrbit，它严格控制中性粒细胞、嗜酸性粒细胞和“经典”单核细胞对支持生存的细胞因子的反应。为了控制这些细胞的寿命，Morrid通过促进Bcl2l11启动子上的PRC2复合体的浓缩来调节其邻近的促凋亡基因Bcl2l11(Bim)的转录，以保持该基因处于稳定状态。值得注意的是，Morrid在顺式基因中调节这一过程，使得能够对Bcl2L11转录进行等位基因特异性控制。因此，在这些高度炎症的细胞中，Morrid水平的变化提供了一种特定于位点的调节机制，允许对细胞外促生存信号做出反应，快速控制细胞凋亡。由于MORRBID存在于人类中，并且在高嗜酸性粒细胞综合征患者中调节失调，这种lncRNA可能是以异常短暂的髓细胞寿命为特征的炎症性疾病的潜在治疗靶点。
Neutrophils, eosinophils and “classical” monocytes collectively account for ~70% of human blood leukocytes and are among the shortest-lived cells in the body. Precise regulation of the lifespan of these myeloid cells is critical to maintain protective immune responses while minimizing the deleterious consequences of prolonged inflammation. However, how the lifespan of these cells is strictly controlled remains largely unknown. Here, we identify a novel long non-coding RNA (lncRNA) that we termed Morrbid, which tightly controls the survival of neutrophils, eosinophils and “classical” monocytes in response to pro-survival cytokines. To control the lifespan of these cells, Morrbid regulates the transcription of its neighboring pro-apoptotic gene, Bcl2l11 (Bim), by promoting the enrichment of the PRC2 complex at the Bcl2l11 promoter to maintain this gene in a poised state. Notably, Morrbid regulates this process in cis, enabling allele-specific control of Bcl2l11 transcription. Thus, in these highly inflammatory cells, changes in Morrbid levels provide a locus-specific regulatory mechanism that allows for rapid control of apoptosis in response to extracellular pro-survival signals. As MORRBID is present in humans and dysregulated in patients with hypereosinophilic syndrome, this lncRNA may represent a potential therapeutic target for inflammatory disorders characterized by aberrant short-lived myeloid cell lifespan.
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DOI：
10.1073/pnas.1419030111
发表时间：
2014-11-11
影响因子：
11.1
作者：
Csorba, Tibor;Questa, Julia I.;Dean, Caroline
通讯作者：
Dean, Caroline
影响因子：
4.4
作者：
Bouffi, Carine;Kartashov, Andrey V.;Fulkerson, Patricia C.
通讯作者：
Fulkerson, Patricia C.
影响因子：
15.9
作者：
Maass, Philipp G.;Rump, Andreas;Baehring, Sylvia
通讯作者：
Baehring, Sylvia
影响因子：
64.5
作者：
Rinn, John L.;Kertesz, Michael;Chang, Howard Y.
通讯作者：
Chang, Howard Y.
影响因子：
56.9
作者：
Heo, Jae Bok;Sung, Sibum
通讯作者：
Sung, Sibum