Scripps Research, Department of Molecular Medicine, 10550 North Torrey Pines Road, La Jolla, CA, 92037, USA.
Cell Death Dis. 2023 Feb 27;14(2):168. doi: 10.1038/s41419-023-05683-6.
MYC controls most of the non-coding genome. Several long noncoding transcripts were originally identified in the human B cell line P496-3 and then shown to be required for MYC-driven proliferation of Burkitt lymphoma-derived RAMOS cells. In this study, we used RAMOS cells exclusively as a representative of the human B cell lineage. One of the MYC-controlled lncRNAs required for RAMOS cell proliferation is ENSG00000254887 which we will term LNROP (long non-coding regulator of POU2F2). In the genome, LNROP is located in close proximity of POU2F2, the gene encoding OCT2. OCT2 is a transcription factor with important roles in sustaining the proliferation of human B cells. Here we show that LNROP is a nuclear RNA and a direct target of MYC. Downregulation of LNROP attenuates the expression of OCT2. This effect of LNROP on the expression of OCT2 is unidirectional as downregulation of OCT2 does not alter the expression of LNROP. Our data suggest that LNROP is a cis-acting regulator of OCT2. To illustrate the downstream reach of LNROP, we chose a prominent target of OCT2, the tyrosine phosphatase SHP-1. Downregulation of OCT2 elevates the expression of SHP-1. Our data suggest the following path of interactions: LNROP enables the proliferation of B cells by positively and unidirectionally regulating the growth-stimulatory transcription factor OCT2. In actively proliferating B cells, OCT2 attenuates the expression and anti-proliferative activity of SHP-1.
MYC 控制着大部分非编码基因组。最初在人 B 细胞系 P496-3 中鉴定出几种长链非编码转录本，然后证明它们是 Burkitt 淋巴瘤衍生的 RAMOS 细胞中 MYC 驱动增殖所必需的。在这项研究中，我们专门使用 RAMOS 细胞作为人 B 细胞系的代表。需要 MYC 控制的长链非编码 RNA 之一是 ENSG00000254887，我们将其称为 LNROP（POU2F2 的长链非编码调节剂）。在基因组中，LNROP 位于编码 OCT2 的基因 POU2F2 附近。OCT2 是一种转录因子，在维持人 B 细胞增殖方面具有重要作用。在这里，我们表明 LNROP 是一种核 RNA，是 MYC 的直接靶标。下调 LNROP 会减弱 OCT2 的表达。LNROP 对 OCT2 表达的这种影响是单向的，因为下调 OCT2 不会改变 LNROP 的表达。我们的数据表明，LNROP 是 OCT2 的顺式作用调节剂。为了说明 LNROP 的下游作用，我们选择了 OCT2 的一个重要靶标，即酪氨酸磷酸酶 SHP-1。下调 OCT2 会增加 SHP-1 的表达。我们的数据表明了以下相互作用途径：LNROP 通过正向和单向调节生长刺激转录因子 OCT2，使 B 细胞增殖。在活跃增殖的 B 细胞中，OCT2 减弱了 SHP-1 的表达和抗增殖活性。
