Chromatin accessibility landscape of articular knee cartilage reveals aberrant enhancer regulation in osteoarthritis.
Chromatin accessibility landscape of articular knee cartilage reveals aberrant enhancer regulation in osteoarthritis.
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关节膝部软骨的染色质可及性景观显示骨关节炎中异常增强子调节。
DOI：
10.1038/s41598-018-33779-z
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发表时间：
2018-10-19
影响因子：
4.6
通讯作者：
Minoda A
中科院分区：
文献类型：
--
作者：
Liu Y;Chang JC;Hon CC;Fukui N;Tanaka N;Zhang Z;Lee MTM;Minoda A
骨关节炎（OA）是一种常见的关节疾病，在老龄化社会中的影响越来越大。虽然遗传学和转录组学分析揭示了一些基因和非编码基因座与OA相关，但发病机制仍不完全清楚。染色质谱，它提供了深入了解基因调控，尚未在OA中报告，主要是由于技术上的困难。在这里，我们采用高通量测序的转座酶可降解染色质测定法（ATAC-seq）来绘制OA患者关节膝关节软骨中可接近的染色质景观。我们确定了软骨的109，215个可访问的染色质区域，其中71%被注释为增强子。通过将它们与遗传和DNA甲基化数据叠加，我们确定了潜在的OA相关增强子及其推定的靶基因。此外，通过与RNA-seq数据的整合，我们表征了OA中在表观基因组和转录组水平上改变的基因。这些基因在调节骨化和间充质干细胞（MSC）分化的途径中富集。因此，骨关节炎中的差异可及区域富含MSC特异性增强子和成骨细胞分化相关转录因子家族的基序。总之，我们证明了如何直接染色质分析的临床组织可以提供全面的表观遗传信息的疾病，并建议候选基因和增强翻译潜力。
Osteoarthritis (OA) is a common joint disorder with increasing impact in an aging society. While genetic and transcriptomic analyses have revealed some genes and non-coding loci associated to OA, the pathogenesis remains incompletely understood. Chromatin profiling, which provides insight into gene regulation, has not been reported in OA mainly due to technical difficulties. Here, we employed Assay for Transposase-Accessible Chromatin with high throughput sequencing (ATAC-seq) to map the accessible chromatin landscape in articular knee cartilage of OA patients. We identified 109,215 accessible chromatin regions for cartilages, of which 71% were annotated as enhancers. By overlaying them with genetic and DNA methylation data, we have determined potential OA-relevant enhancers and their putative target genes. Furthermore, through integration with RNA-seq data, we characterized genes that are altered both at epigenomic and transcriptomic levels in OA. These genes are enriched in pathways regulating ossification and mesenchymal stem cell (MSC) differentiation. Consistently, the differentially accessible regions in OA are enriched for MSC-specific enhancers and motifs of transcription factor families involved in osteoblast differentiation. In conclusion, we demonstrate how direct chromatin profiling of clinical tissues can provide comprehensive epigenetic information for a disease and suggest candidate genes and enhancers of translational potential.
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影响因子：
2.6
作者：
den Hollander W;Meulenbelt I
通讯作者：
Meulenbelt I
影响因子：
30.8
作者：
Cao, Qin;Anyansi, Christine;Yip, Kevin Y.
通讯作者：
Yip, Kevin Y.
影响因子：
4
作者：
Ellman, M. B.;Yan, D.;Ahmadinia, K.;Chen, D.;An, H. S.;Im, H. J.
通讯作者：
Im, H. J.
DOI：
10.1126/science.1262110
发表时间：
2015-05-08
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
GTEx Consortium
通讯作者：
GTEx Consortium
影响因子：
4.9
作者：
Dreier R
通讯作者：
Dreier R