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首页> 外文期刊>Nature >The long non-coding RNA Morrbid regulates Bim and short-lived myeloid cell lifespan
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The long non-coding RNA Morrbid regulates Bim and short-lived myeloid cell lifespan

机译：较长的非编码RNA Morrbid调节Bim和短暂的髓样细胞寿命

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摘要

Neutrophils, eosinophils and 'classical' monocytes collectively account for about 70% of human blood leukocytes and are among the shortest-lived cells in the body(1,2). Precise regulation of the lifespan of these myeloid cells is critical to maintain protective immune responses and minimize the deleterious consequences of prolonged inflammation(1,2). However, how the lifespan of these cells is strictly controlled remains largely unknown. Here we identify a long non-coding RNA that we termed Morrbid, which tightly controls the survival of neutrophils, eosinophils and classical monocytes in response to pro-survival cytokines in mice. To control the lifespan of these cells, Morrbid regulates the transcription of the neighbouring pro-apoptotic gene, Bcl2l11 (also known as 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 rapid control of apoptosis in response to extracellular pro-survival signals. As MORRBID is present in humans and dysregulated in individuals with hypereosinophilic syndrome, this long non-coding RNA may represent a potential therapeutic target for inflammatory disorders characterized by aberrant short-lived myeloid cell lifespan.
机译：中性粒细胞，嗜酸性粒细胞和“经典”单核细胞合计约占人类血液白细胞的70％，属于人体中寿命最短的细胞（1,2）。精确调节这些髓样细胞的寿命对于维持保护性免疫反应并最大程度地减少长期炎症的有害后果至关重要（1,2）。然而，如何严格控制这些细胞的寿命仍然未知。在这里，我们确定了一个长的非编码RNA，我们将其称为Morrbid，它可以严格控制嗜中性粒细胞，嗜酸性粒细胞和经典单核细胞的存活，以响应小鼠中的存活细胞因子。为了控制这些细胞的寿命，Morrbid通过促进Bcl2l11启动子上PRC2复合物的富集来维持该基因处于平衡状态，从而调节邻近的促凋亡基因Bcl2l11（也称为Bim）的转录。值得注意的是，Morrbid顺式调节了这一过程，从而实现了Bcl211转录的等位基因特异性控制。因此，在这些高度发炎的细胞中，Morrbid水平的变化提供了基因座特异性调节机制，该机制允许响应于细胞外促存活信号而快速控制细胞凋亡。由于MORRBID存在于人类中，并且在嗜酸性粒细胞增高综合症患者体内表达失调，因此这种长的非编码RNA可能代表了以异常短暂的骨髓细胞寿命为特征的炎症性疾病的潜在治疗靶标。

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  • 来源
    《Nature》 |2016年第7619期|239-243|共5页
  • 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;

  • 作者单位

    Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA|Univ Penn, Perelman Sch Med, Inst Immunol, Philadelphia, PA 19104 USA;

    Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA|Univ Penn, Perelman Sch Med, Inst Immunol, Philadelphia, PA 19104 USA|Massachusetts Gen Hosp, Dept Med, 55 Fruit St, Boston, MA 02114 USA;

    Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA|Univ Penn, Perelman Sch Med, Inst Immunol, Philadelphia, PA 19104 USA;

    Jackson Lab Genom Med, Farmington, CT 06032 USA|Univ Connecticut, Ctr Hlth, Dept Genet & Genom Sci, Farmington, CT 06032 USA;

    Jackson Lab Genom Med, Farmington, CT 06032 USA;

    Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA|Univ Penn, Perelman Sch Med, Inst Immunol, Philadelphia, PA 19104 USA;

    Jackson Lab Genom Med, Farmington, CT 06032 USA;

    Jackson Lab Genom Med, Farmington, CT 06032 USA;

    NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA;

    Univ Penn, Dept Bioengn, Philadelphia, PA 19104 USA;

    Yale Univ, Sch Med, Dept Immunobiol, 333 Cedar St, New Haven, CT 06520 USA|Yale Univ, Howard Hughes Med Inst, New Haven, CT 06510 USA;

    Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA|Univ Penn, Perelman Sch Med, Inst Immunol, Philadelphia, PA 19104 USA;

    Jackson Lab Genom Med, Farmington, CT 06032 USA;

    Yale Univ, Sch Med, Dept Immunobiol, 333 Cedar St, New Haven, CT 06520 USA;

    Yale Univ, Sch Med, Dept Immunobiol, 333 Cedar St, New Haven, CT 06520 USA|Yale Univ, Howard Hughes Med Inst, New Haven, CT 06510 USA;

    Yale Univ, Sch Med, Dept Immunobiol, 333 Cedar St, New Haven, CT 06520 USA|Yale Univ, Howard Hughes Med Inst, New Haven, CT 06510 USA;

    Univ Penn, Dept Bioengn, Philadelphia, PA 19104 USA;

    Univ Penn, Perelman Sch Med, Inst Immunol, Philadelphia, PA 19104 USA|Univ Penn, Perelman Sch Med, Dept Microbiol, Philadelphia, PA 19104 USA;

    Johns Hopkins Univ, McKusick Nathans Inst Genet Med, Baltimore, MD 21205 USA|Johns Hopkins Univ, Dept Neurosci, Baltimore, MD 21205 USA;

    NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA;

    Harvard Med Sch, Biol & Biomed Sci, Boston, MA 02115 USA|Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA;

    Jackson Lab Genom Med, Farmington, CT 06032 USA|Univ Connecticut, Ctr Hlth, Dept Genet & Genom Sci, Farmington, CT 06032 USA;

    Yale Univ, Sch Med, Dept Immunobiol, 333 Cedar St, New Haven, CT 06520 USA|Yale Univ, Howard Hughes Med Inst, New Haven, CT 06510 USA;

    Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA|Univ Penn, Perelman Sch Med, Inst Immunol, Philadelphia, PA 19104 USA|Childrens Hosp Philadelphia, Div Transplant Immunol, Philadelphia, PA 19104 USA;

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