Kumar Krishan, Banerjee Dixit Aparna, Tripathi Manjari, Dubey Vivek, Siraj Fouzia, Sharma Mehar Chand, Lalwani Sanjeev, Chandra P Sarat, Banerjee Jyotirmoy
Dr. B.R. Ambedkar Center for Biomedical Research, University of Delhi, Delhi, India.
Department of Neurology, AIIMS, New Delhi, India.
Funct Integr Genomics. 2022 Oct;22(5):905-917. doi: 10.1007/s10142-022-00869-1. Epub 2022 May 28.
Low-grade dysembryoplastic neuroepithelial tumors (DNTs) are a frequent cause of drug-refractory epilepsy. Molecular mechanisms underlying seizure generation in these tumors are poorly understood. This study was conducted to identify altered genes in nonneoplastic epileptogenic cortical tissues (ECTs) resected from DNT patients during electrocorticography (ECoG)-guided surgery. RNA sequencing (RNAseq) was used to determine the differentially expressed genes (DEGs) in these high-spiking ECTs compared to non-epileptic controls. A total of 477 DEGs (180 upregulated; 297 downregulated) were observed in the ECTs compared to non-epileptic controls. Gene ontology analysis revealed enrichment of genes belonging to the following Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways: (i) glutamatergic synapse; (ii) nitrogen metabolism; (iii) transcriptional misregulation in cancer; and (iv) protein digestion and absorption. The glutamatergic synapse pathway was enriched by DEGs such as GRM4, SLC1A6, GRIN2C, GRM2, GRM5, GRIN3A, and GRIN2B. Enhanced glutamatergic activity was observed in the pyramidal neurons of ECTs, which could be attributed to altered synaptic transmission in these tissues compared to non-epileptic controls. Besides glutamatergic synapse, altered expression of other genes such as GABRB1 (synapse formation), SLIT2 (axonal growth), and PROKR2 (neuron migration) could be linked to epileptogenesis in ECTs. Also, upregulation of GABRA6 gene in ECTs could underlie benzodiazepine resistance in these patients. Neural cell-type-specific gene set enrichment analysis (GSEA) revealed transcriptome of ECTs to be predominantly contributed by microglia and neurons. This study provides first comprehensive gene expression profiling of nonneoplastic ECTs of DNT patients and identifies genes/pathways potentially linked to epileptogenesis.
低级发育异常性神经上皮肿瘤（DNTs）是药物难治性癫痫的常见病因。这些肿瘤中癫痫发作的分子机制尚不清楚。本研究旨在识别在皮层脑电图（ECoG）引导手术期间从DNT患者切除的非肿瘤性致痫性皮质组织（ECTs）中发生改变的基因。RNA测序（RNAseq）用于确定这些高棘波ECTs与非癫痫对照相比的差异表达基因（DEGs）。与非癫痫对照相比，在ECTs中总共观察到477个DEGs（180个上调；297个下调）。基因本体分析显示属于以下京都基因与基因组百科全书（KEGG）途径的基因富集：（i）谷氨酸能突触；（ii）氮代谢；（iii）癌症中的转录失调；以及（iv）蛋白质消化和吸收。谷氨酸能突触途径被GRM4、SLC1A6、GRIN2C、GRM2、GRM5、GRIN3A和GRIN2B等DEGs富集。在ECTs的锥体神经元中观察到谷氨酸能活性增强，这可能归因于与非癫痫对照相比这些组织中突触传递的改变。除了谷氨酸能突触外，其他基因如GABRB1（突触形成）、SLIT2（轴突生长）和PROKR2（神经元迁移）的表达改变可能与ECTs中的癫痫发生有关。此外，ECTs中GABRA6基因的上调可能是这些患者对苯二氮䓬耐药的基础。神经细胞类型特异性基因集富集分析（GSEA）显示ECTs的转录组主要由小胶质细胞和神经元贡献。本研究首次提供了DNT患者非肿瘤性ECTs的全面基因表达谱，并确定了可能与癫痫发生相关的基因/途径。
