Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555, USA.
Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA.
Cell Rep. 2021 Nov 2;37(5):109910. doi: 10.1016/j.celrep.2021.109910.
RBFOX2, which has a well-established role in alternative splicing, is linked to heart diseases. However, it is unclear whether RBFOX2 has other roles in RNA processing that can influence gene expression in muscle cells, contributing to heart disease. Here, we employ both 3'-end and nanopore cDNA sequencing to reveal a previously unrecognized role for RBFOX2 in maintaining alternative polyadenylation (APA) signatures in myoblasts. RBFOX2-mediated APA modulates mRNA levels and/or isoform expression of a collection of genes, including contractile and mitochondrial genes. Depletion of RBFOX2 adversely affects mitochondrial health in myoblasts, correlating with disrupted APA of mitochondrial gene Slc25a4. Mechanistically, RBFOX2 regulation of Slc25a4 APA is mediated through consensus RBFOX2 binding motifs near the distal polyadenylation site, enforcing the use of the proximal polyadenylation site. In sum, our results unveil a role for RBFOX2 in fine-tuning expression of mitochondrial and contractile genes via APA in myoblasts relevant to heart diseases.
RBFOX2 在可变剪接中具有既定的作用，与心脏疾病有关。然而，目前尚不清楚 RBFOX2 在 RNA 处理中是否具有其他作用，这些作用可能会影响肌肉细胞中的基因表达，从而导致心脏病。在这里，我们同时采用 3'-末端和纳米孔 cDNA 测序来揭示 RBFOX2 在维持成肌细胞中可变多聚腺苷酸化（APA）特征方面的先前未被识别的作用。RBFOX2 介导的 APA 调节一系列基因的 mRNA 水平和/或异构体表达，包括收缩和线粒体基因。RBFOX2 的耗竭会对成肌细胞中的线粒体健康产生不利影响，这与线粒体基因 Slc25a4 的 APA 中断有关。从机制上讲，RBFOX2 对 Slc25a4 APA 的调节是通过靠近远端多聚腺苷酸化位点的共识 RBFOX2 结合基序介导的，从而强制使用近端多聚腺苷酸化位点。总之，我们的研究结果揭示了 RBFOX2 在通过 APA 精细调节与心脏疾病相关的成肌细胞中线粒体和收缩基因表达中的作用。
