The microRNA-212/132 cluster regulates B cell development and apoptosis by targeting SOX4. Mus musculus

MicroRNAs have emerged as key regulators of B cell fate decisions and immune function. Deregulation of several microRNAs in B cells leads to the development of autoimmune disease and cancer in mice. We demonstrate that the microRNA-212/132 cluster (miR-212/132) is induced in B cells in response to B cell receptor signaling. Enforced expression of miR-132 results in a block in early B cell development at the pre-pro-B cell to pro-B cell transition and induces apoptosis in primary bone marrow B cells. Importantly, loss of miR-212/132 results in increased B cell output under non-homeostatic conditions. We find that miR-212/132 regulates B lymphopoiesis by targeting the transcription factor SOX4. Co-expression of SOX4 with miR-132 rescues the defect in B cell development from over-expression of miR-132 alone. In addition, we show that the expression of miR-132 in cells that are prone to spontaneous B cell cancers can have a protective effect on cancer development. We have thus uncovered a novel regulator of B cell lineage specification that may potential applications in B cell cancer therapy Overall design: RNA-seq of wild-type and microRNA-212/132 knock-out B-cells after IgM stimulation

微小RNA（microRNAs，miRNAs）已被证实是B细胞命运决定与免疫功能的关键调控因子。B细胞内多种微小RNA的表达失调，可导致小鼠自身免疫性疾病与肿瘤的发生。本研究证实，微小RNA-212/132基因簇（miR-212/132）可在B细胞受到B细胞受体信号刺激时被诱导表达。强制过表达miR-132会阻断早期B细胞发育中从前前B细胞（pre-pro-B cell）到前B细胞（pro-B cell）的转变过程，并诱导原代骨髓B细胞发生凋亡。值得注意的是，在非稳态条件下，miR-212/132的缺失会导致B细胞生成量增加。本研究发现，miR-212/132通过靶向转录因子SOX4调控B淋巴细胞生成。将SOX4与miR-132共表达，可挽救仅过表达miR-132所导致的B细胞发育缺陷。此外，本研究表明，在易发生自发性B细胞肿瘤的细胞中表达miR-132，可对肿瘤发生起到保护作用。因此本研究发现了一个全新的B细胞谱系特化调控因子，其在B细胞肿瘤治疗中具备潜在应用价值。实验整体设计：对经IgM刺激后的野生型与微小RNA-212/132敲除型B细胞进行RNA测序（RNA-seq）。