INSERM UMR_S 1256, Nutrition, Genetics, and Environmental Risk Exposure (NGERE), Faculty of Medicine of Nancy, University of Lorraine, 9 Avenue de la Forêt de Haye, 54000, Nancy, France.
Reference Center for Inborn Errors of Metabolism (ORPHA67872), University Hospital of Nancy, 54000, Nancy, France.
Clin Epigenetics. 2022 Apr 19;14(1):52. doi: 10.1186/s13148-022-01271-1.
epi-cblC is a recently discovered inherited disorder of intracellular vitamin B metabolism associating hematological, neurological, and cardiometabolic outcomes. It is produced by an epimutation at the promoter common to CCDC163P and MMACHC, which results from an aberrant antisense transcription due to splicing mutations in the antisense PRDX1 gene neighboring MMACHC. We studied whether the aberrant transcription produced a second epimutation by encompassing the CpG island of the TESK2 gene neighboring CCDC163P.
We unraveled the methylome architecture of the CCDC163P-MMACHC CpG island (CpG:33) and the TESK2 CpG island (CpG:51) of 17 epi-cblC cases. We performed an integrative analysis of the DNA methylome profiling, transcriptome reconstruction of RNA-sequencing (RNA-seq), chromatin immunoprecipitation sequencing (ChIP-Seq) of histone H3, and transcription expression of MMACHC and TESK2.
The PRDX1 splice mutations and activation of numerous cryptic splice sites produced antisense readthrough transcripts encompassing the bidirectional MMACHC/CCDC163P promoter and the TESK2 promoter, resulting in the silencing of both the MMACHC and TESK2 genes through the deposition of SETD2-dependent H3K36me3 marks and the generation of epimutations in the CpG islands of the two promoters.
The antisense readthrough transcription of the mutated PRDX1 produces an epigenetic silencing of MMACHC and TESK2. We propose using the term 'epi-digenism' to define this epigenetic disorder that affects two genes. Epi-cblC is an entity that differs from cblC. Indeed, the PRDX1 and TESK2 altered expressions are observed in epi-cblC but not in cblC, suggesting further evaluating the potential consequences on cancer risk and spermatogenesis.
epi-cblC 是一种最近发现的与血液学、神经学和心脏代谢结果相关的细胞内维生素 B 代谢的遗传性疾病。它是由 CCDC163P 和 MMACHC 启动子上的表观突变引起的，该突变是由于 PRDX1 基因的反义剪接突变导致反义转录异常，该基因紧邻 MMACHC。我们研究了异常转录是否通过包含紧邻 CCDC163P 的 TESK2 基因的 CpG 岛产生第二个表观突变。
我们揭示了 17 例 epi-cblC 病例中 CCDC163P-MMACH CpG 岛（CpG：33）和 TESK2CpG 岛（CpG：51）的甲基组结构。我们对 DNA 甲基组谱、RNA 测序（RNA-seq）的转录本重建、组蛋白 H3 的染色质免疫沉淀测序（ChIP-Seq）以及 MMACHC 和 TESK2 的转录表达进行了综合分析。
PRDX1 剪接突变和许多隐匿剪接位点的激活产生了反义通读转录本，包含双向 MMACHC/CCDC163P 启动子和 TESK2 启动子，导致 MMACHC 和 TESK2 基因沉默，通过 SETD2 依赖性 H3K36me3 标记的沉积和两个启动子 CpG 岛的表观突变。
突变的 PRDX1 反义通读转录导致 MMACHC 和 TESK2 的表观遗传沉默。我们建议使用“表观遗传学”一词来定义这种影响两个基因的表观遗传疾病。Epi-cblC 与 cblC 不同。事实上，在 epi-cblC 中观察到 PRDX1 和 TESK2 表达改变，但在 cblC 中没有，这表明需要进一步评估其对癌症风险和精子发生的潜在影响。
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