Epigenetic Deregulation of Telomere-Related Genes in Newly Diagnosed Multiple Myeloma Patients.
Epigenetic Deregulation of Telomere-Related Genes in Newly Diagnosed Multiple Myeloma Patients.
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DOI：
10.3390/cancers13246348
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发表时间：
2021-12-17
期刊：
影响因子：
5.2
通讯作者：
van Rhee F
中科院分区：
文献类型：
--
作者：
Roy Choudhury S;Ashby C;Zhan F;van Rhee F
端粒相关基因(TRGS)的异常表达和端粒缩短促进了不同类型癌症的发生。鉴于高危多发性骨髓瘤(MM)患者存在严重的端粒缩短的事实，我们调查了新诊断的MM患者TRG表达的表观遗传学基础。我们证明，DNA甲基化单独或与重叠的染色质标记和潜在的基因组序列一起建立了TRGS中异常基因表达的表观遗传网络。此外，我们确定了五个TRG，它们是表观遗传控制的，在MM的主要分子亚群中持续解除调控，可在疾病的早期阶段识别。高危多发性骨髓瘤(MM)患者的端粒长度(TL)维持在短临界长度的边缘以下，与端粒酶的主动过度表达一致。此前，DNA甲基化已被证明是端粒相关基因(TRG)表达和TL的决定因素，用于评估不同类型癌症的风险。我们绘制了主要分子亚群的53名新诊断多发性骨髓瘤(NDMM；n=53)患者的全基因组DNA甲基化图谱，并与年龄匹配的健康捐赠者(n=4)进行了比较。结合重叠的染色质标记和潜在的DNA序列分析差异甲基化和TRG基因座的表达。我们观察到选择性TRG之间的DNA甲基化和表达之间有很强的相关性(R2 RAP10.5)，因此DDX1和≥启动子上的去甲基化与它们的致癌上调有关，而两个关键的肿瘤抑制基因ZNF208和RAP1A体上的去甲基化导致基因下调。我们证明，TRG的表达可以由DNA甲基化单独控制，也可以与染色质修饰或CCCTC结合因子一起控制在调节区。此外，我们还发现，NDMM中TRGS的低甲基化的DMRS是由G-四链形成序列稳定的，这表明这些表观遗传易感基因在MM发病中起着关键作用。我们已经确定了一个由五个TRG组成的小组，它们在NDMM患者中是表观遗传学上的去调控的，可以作为疾病的早期检测生物标记物或治疗靶点。
Aberrant expression of telomere-related genes (TRGs) and telomere-shortening facilitates development of different types of cancer. Given the fact that high-risk multiple myeloma (MM) patients harbor critically shortened telomeres, we investigated the epigenetic basis of TRG-expression in newly diagnosed MM patients. We demonstrated that DNA methylation alone or in cooperation with overlapping chromatin marks and underlying genomic sequence build up an epigenetic network of aberrant gene expression in TRGs. Furthermore, we identified five TRGs, which are epigenetically controlled and consistently deregulated across the major molecular subgroups of MM, identifiable at the early stage of the disease. High-risk Multiple Myeloma (MM) patients were found to maintain telomere length (TL), below the margin of short critical length, consistent with proactive overexpression of telomerase. Previously, DNA methylation has been shown as a determinant of telomere-related gene (TRG) expression and TL to assess risk in different types of cancer. We mapped genome-wide DNA methylation in a cohort of newly diagnosed MM (NDMM; n = 53) patients of major molecular subgroups, compared to age-matched healthy donors (n = 4). Differential methylation and expression at TRG-loci were analyzed in combination with overlapping chromatin marks and underlying DNA-sequences. We observed a strong correlation (R2 ≥ 0.5) between DNA methylation and expression amongst selective TRGs, such that demethylation at the promoters of DDX1 and TERF1 were associated to their oncogenic upregulation, while demethylation at the bodies of two key tumor suppressors ZNF208 and RAP1A led to downregulation of the genes. We demonstrated that TRG expression may be controlled by DNA methylation alone or in cooperation with chromatin modifications or CCCTC-binding factor at the regulatory regions. Additionally, we showed that hypomethylated DMRs of TRGs in NDMM are stabilized with G-quadruplex forming sequences, suggesting a crucial role of these epigenetically vulnerable loci in MM pathogenesis. We have identified a panel of five TRGs, which are epigenetically deregulated in NDMM patients and may serve as early detection biomarkers or therapeutic targets in the disease.
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影响因子：
5.4
作者：
Jara-Espejo, Manuel;Peres Line, Sergio Roberto
通讯作者：
Peres Line, Sergio Roberto
影响因子：
12.8
作者：
Giaccherini M;Macauda A;Orciuolo E;Rymko M;Gruenpeter K;Dumontet C;Raźny M;Moreno V;Buda G;Beider K;Varkonyi J;Avet-Loiseau H;Martinez-Lopez J;Marques H;Watek M;Sarasquete ME;Andersen V;Karlin L;Suska A;Kruszewski M;Abildgaard N;Dudziński M;Butrym A;Nagler A;Vangsted AJ;Kadar K;Waldemar T;Jamroziak K;Jacobsen SEH;Ebbesen LH;Taszner M;Mazur G;Lesueur F;Pelosini M;Garcia-Sanz R;Jurczyszyn A;Demangel D;Reis RM;Iskierka-Jażdżewska E;Markiewicz M;Gemignani F;Subocz E;Zawirska D;Druzd-Sitek A;Stępień A;Alonso MH;Sainz J;Canzian F;Campa D
通讯作者：
Campa D
表观遗传学在多发性骨髓瘤生物学中的作用。
影响因子：
12.8
作者：
Dimopoulos, K.;Gimsing, P.;Gronbaek, K.
通讯作者：
Gronbaek, K.
影响因子：
4.6
作者：
Buxton JL;Suderman M;Pappas JJ;Borghol N;McArdle W;Blakemore AI;Hertzman C;Power C;Szyf M;Pembrey M
通讯作者：
Pembrey M
影响因子：
3.1
作者：
Cottliar, A;Pedrazzini, E;Slavutsky, I
通讯作者：
Slavutsky, I