The long non-coding RNA Morrbid regulates Bim and short-lived myeloid cell lifespan (ChIP-Seq). Mus musculus

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 also 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. Overall design: Examination of 4 different histone modifications in mouse neutrophils.

中性粒细胞（Neutrophils）、嗜酸性粒细胞（eosinophils）与“经典型”单核细胞（monocytes）合计约占人类血液白细胞（leukocytes）的70%，且是体内寿命最短的细胞类群之一。精准调控这类髓系细胞（myeloid cells）的寿命，对于维持保护性免疫应答同时最小化长期炎症带来的有害后果至关重要。然而，目前学界对这类细胞寿命的严格调控机制仍知之甚少。本研究鉴定出一种全新的长链非编码RNA（long non-coding RNA, lncRNA），将其命名为Morrbid，该RNA可在促存活细胞因子刺激下，紧密调控中性粒细胞、嗜酸性粒细胞与“经典型”单核细胞的存活。为调控这类细胞的寿命，Morrbid通过促进多梳抑制复合体2（PRC2 complex）在其邻近的促凋亡基因（pro-apoptotic gene）Bcl2l11（Bim）的启动子区域富集，使该基因维持在预激活（poised）状态。值得注意的是，Morrbid以顺式（cis）方式调控该过程，从而实现对Bcl2l11转录的等位基因特异性调控。因此，在这类高炎症性细胞中，Morrbid表达水平的变化提供了一种位点特异性调控机制，可快速响应细胞外促存活信号以调控细胞凋亡。由于MORRBID在人类中同样存在，且在嗜酸性粒细胞增多综合征（hypereosinophilic syndrome）患者体内存在表达失调，该长链非编码RNA或可作为以异常短寿命髓系细胞为特征的炎症性疾病的潜在治疗靶点。实验整体设计：在小鼠中性粒细胞中检测4种不同的组蛋白修饰。