Degener Max J F, van Cruchten Remco T P, Otero Brittney A, Wang Eric T, Wansink Derick G, 't Hoen Peter A C
Centre for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands.
Department of Molecular Genetics and Microbiology, Center for NeuroGenetics, Genetics Institute, University of Florida, FL 32610-0266 Gainesville, FL, USA.
NAR Genom Bioinform. 2022 Mar 8;4(1):lqac016. doi: 10.1093/nargab/lqac016. eCollection 2022 Mar.
In patients with myotonic dystrophy type 1 (DM1), dysregulation of RNA-binding proteins like MBNL and CELF1 leads to alternative splicing of exons and is thought to induce a return to fetal splicing patterns in adult tissues, including the central nervous system (CNS). To comprehensively evaluate this, we created an atlas of developmentally regulated splicing patterns in the frontal cortex of healthy individuals and DM1 patients, by combining RNA-seq data from BrainSpan, GTEx and DM1 patients. Thirty-four splice events displayed an inclusion pattern in DM1 patients that is typical for the fetal situation in healthy individuals. The regulation of DM1-relevant splicing patterns could partly be explained by changes in mRNA expression of the splice regulators , and . On the contrary, interindividual differences in splicing patterns between healthy adults could not be explained by differential expression of these splice regulators. Our findings lend transcriptome-wide evidence to the previously noted shift to fetal splicing patterns in the adult DM1 brain as a consequence of an imbalance in antagonistic and activities. Our atlas serves as a solid foundation for further study and understanding of the cognitive phenotype in patients.
在1型强直性肌营养不良（DM1）患者中，像MBNL和CELF1这样的RNA结合蛋白失调会导致外显子的可变剪接，并被认为会促使成年组织（包括中枢神经系统，CNS）恢复到胎儿期的剪接模式。为了全面评估这一点，我们通过整合来自BrainSpan、GTEx和DM1患者的RNA测序数据，创建了一份健康个体和DM1患者额叶皮质中发育调控剪接模式图谱。34个剪接事件在DM1患者中呈现出一种在健康个体胎儿期才典型出现的包含模式。与DM1相关的剪接模式的调控部分可由剪接调节因子 、 和 的mRNA表达变化来解释。相反，健康成年人之间剪接模式的个体差异无法用这些剪接调节因子的差异表达来解释。我们的研究结果为先前指出的成年DM1大脑因拮抗的 和 活性失衡而向胎儿期剪接模式转变提供了全转录组范围的证据。我们的图谱为进一步研究和理解患者的认知表型奠定了坚实基础。
