长非编码 RNA (lncRNA) 是细胞过程中的关键参与者，其独特的细胞类型特异性表达模式使它们成为有吸引力的生物标志物和治疗靶点。然而，大多数 lncRNA 的功能作用仍然是个谜。为了满足识别新的可成药 lncRNA 的需求，我们开发了一种综合方法，将转录因子结合数据与其他遗传特征相结合，生成机器学习模型，我们将其称为 INFLAMeR（利用高级机器学习资源识别新型功能性 LncRNA）。INFLAMeR 是接受了针对 7 种细胞系的高通量 CRISPR 干扰 (CRISPRi) 筛选的培训，该算法基于 71 种遗传特征。为了验证预测，我们在人类 K562 白血病细胞系中选择了候选 lncRNA，并确定了它们的敲低 (KD) 对细胞增殖和化疗药物反应的影响。我们进一步对候选基因进行了转录组分析。基于这些发现，我们评估了 lncRNA 小核仁 RNA 宿主基因 6 (SNHG6) 在骨髓分化中的作用。最后，我们建立了小鼠 K562 白血病异种移植模型，以确定 SNHG6 KD 是否能减弱体内肿瘤生长。 INFLAMeR 模型成功重建了 CRISPRi 筛选数据并预测了之前被忽视的功能性 lncRNA。对 K562 中近 50 个基因进行的强化细胞和转录组验证揭示了 85% 的预测 lncRNA 的细胞类型特异性功能。在这方面，我们基于细胞和转录组的分析预测了 SNHG6 在造血和白血病中的作用。与预测的造血分化作用一致，SNHG6 转录受到造血相关转录因子的调节。 SNHG6 KD 减少了白血病细胞的增殖并使它们对分化敏感。分别用氯高铁血红素和 PMA 处理 K562 白血病细胞表明，SNHG6 抑制红细胞分化，但强烈促进巨核细胞分化。使用异种移植小鼠模型，我们证明 SNHG6 KD 可以减弱体内肿瘤生长。我们的方法不仅通过基因组方法以细胞类型特异性的方式改进了功能性 lncRNA 的识别和表征，而且还鉴定了在造血和功能中发挥作用的新 lncRNA。白血病。这种方法可以很容易地应用于识别精准医学的新靶标。© 2024。作者。

Long non-coding RNAs (lncRNAs) are pivotal players in cellular processes, and their unique cell-type specific expression patterns render them attractive biomarkers and therapeutic targets. Yet, the functional roles of most lncRNAs remain enigmatic. To address the need to identify new druggable lncRNAs, we developed a comprehensive approach integrating transcription factor binding data with other genetic features to generate a machine learning model, which we have called INFLAMeR (Identifying Novel Functional LncRNAs with Advanced Machine Learning Resources).INFLAMeR was trained on high-throughput CRISPR interference (CRISPRi) screens across seven cell lines, and the algorithm was based on 71 genetic features. To validate the predictions, we selected candidate lncRNAs in the human K562 leukemia cell line and determined the impact of their knockdown (KD) on cell proliferation and chemotherapeutic drug response. We further performed transcriptomic analysis for candidate genes. Based on these findings, we assessed the lncRNA small nucleolar RNA host gene 6 (SNHG6) for its role in myeloid differentiation. Finally, we established a mouse K562 leukemia xenograft model to determine whether SNHG6 KD attenuates tumor growth in vivo.The INFLAMeR model successfully reconstituted CRISPRi screening data and predicted functional lncRNAs that were previously overlooked. Intensive cell-based and transcriptomic validation of nearly fifty genes in K562 revealed cell type-specific functionality for 85% of the predicted lncRNAs. In this respect, our cell-based and transcriptomic analyses predicted a role for SNHG6 in hematopoiesis and leukemia. Consistent with its predicted role in hematopoietic differentiation, SNHG6 transcription is regulated by hematopoiesis-associated transcription factors. SNHG6 KD reduced the proliferation of leukemia cells and sensitized them to differentiation. Treatment of K562 leukemic cells with hemin and PMA, respectively, demonstrated that SNHG6 inhibits red blood cell differentiation but strongly promotes megakaryocyte differentiation. Using a xenograft mouse model, we demonstrate that SNHG6 KD attenuated tumor growth in vivo.Our approach not only improved the identification and characterization of functional lncRNAs through genomic approaches in a cell type-specific manner, but also identified new lncRNAs with roles in hematopoiesis and leukemia. Such approaches can be readily applied to identify novel targets for precision medicine.© 2024. The Author(s).