He Sha, Chen Juanzhi, Gao Huan, Yang Guixian, Zhang Feixiang, Ding Yanqing, Zhu Hao
Bioinformatics Section, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China.
Department of Pathology, Southern Hospital, Southern Medical University, China.
Comput Struct Biotechnol J. 2020 Nov 14;18:3507-3517. doi: 10.1016/j.csbj.2020.11.004. eCollection 2020.
It is estimated that the rate of epigenetic changes may be orders of magnitude higher than that of genetic changes and that purely epigenetic mechanisms may explain why cancers arise with few or no recurrent mutations. However, supporting evidence remains limited, partly due to the cost of experimentally studying genome-wide epigenetic dysregulation. Since genome modification enzymes are recruited by long noncoding RNAs (lncRNAs) to specific genomic sites, analyzing differentially expressed genes and differentially methylated regions (DMRs) at the DNA binding sites of differentially expressed lncRNAs is important for uncovering epigenetic dysregulation. We performed RNA-seq and MeDIP-seq on a set of colorectal cancer (CRC) and normal colon samples and developed an analysis pipeline for combined analyses of gene expression, DNA methylation, and lncRNA/DNA binding. The genes identified in our data and important for CRC agree with widely reported findings. We found that aberrantly transcribed noncoding transcripts may epigenetically dysregulate genes, that correlated gene expression is significantly determined by epigenetic dysregulation, that differentially expressed noncoding transcripts and their epigenetic targets form distinct modules in different cancer cells, and that many hub lncRNAs in these modules are primate-specific. These results suggest that lncRNA-mediated epigenetic dysregulation greatly determines aberrant gene expression and that epigenetic dysregulation is highly species-specific. The analysis pipeline can effectively unveil cancer- and cell-specific modules of epigenetic dysregulation, and such modules may provide novel clues for identifying diagnostic, therapeutic, and prognostic targets for epigenetic dysregulation.
据估计，表观遗传变化的速率可能比遗传变化的速率高几个数量级，而且纯粹的表观遗传机制可能解释了癌症为何在很少发生或不发生复发性突变的情况下出现。然而，支持性证据仍然有限，部分原因是在全基因组范围内对表观遗传失调进行实验研究的成本较高。由于长链非编码RNA（lncRNA）会将基因组修饰酶招募到特定的基因组位点，因此分析差异表达lncRNA的DNA结合位点处的差异表达基因和差异甲基化区域（DMR）对于揭示表观遗传失调很重要。我们对一组结直肠癌（CRC）和正常结肠样本进行了RNA测序和甲基化DNA免疫沉淀测序（MeDIP-seq），并开发了一种用于基因表达、DNA甲基化和lncRNA/DNA结合联合分析的分析流程。我们数据中鉴定出的对CRC重要的基因与广泛报道的研究结果一致。我们发现，异常转录的非编码转录本可能在表观遗传上使基因失调，相关基因表达由表观遗传失调显著决定，差异表达的非编码转录本及其表观遗传靶点在不同癌细胞中形成不同的模块，并且这些模块中的许多枢纽lncRNA是灵长类动物特有的。这些结果表明，lncRNA介导的表观遗传失调极大地决定了异常基因表达，并且表观遗传失调具有高度的物种特异性。该分析流程可以有效地揭示表观遗传失调的癌症特异性和细胞特异性模块，并且这样的模块可能为鉴定表观遗传失调的诊断、治疗和预后靶点提供新线索。
