Identification of transcription factors responsible for dysregulated networks in human osteoarthritis cartilage by global gene expression analysis.
Identification of transcription factors responsible for dysregulated networks in human osteoarthritis cartilage by global gene expression analysis.
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DOI：
10.1016/j.joca.2018.07.012
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发表时间：
2018-11
影响因子：
7
通讯作者：
Lotz MK
中科院分区：
文献类型：
--
作者：
Fisch KM;Gamini R;Alvarez-Garcia O;Akagi R;Saito M;Muramatsu Y;Sasho T;Koziol JA;Su AI;Lotz MK
骨关节炎（OA）是最常见的关节疾病。由于疾病修饰疗法不可用，需要发现新的治疗靶点，并优先考虑它们在介导OA影响关节中细胞异常表型中的重要性。在这里，我们产生了一个全基因组的OA分子概况，阐明OA发病机制的调控机制，并确定可能的治疗目标，使用从人膝关节软骨获得的mRNA测序数据的综合分析。对18个正常和20个OA人膝关节软骨组织进行RNA测序（RNA-seq）。分析RNA-seq数据集以鉴定OA中失调的基因、途径和调控网络。RNA-seq数据分析揭示了OA和非OA样本之间的1332个差异表达（DE）基因，包括已知和新的转录因子（TF）。通路分析确定了OA中15个显著干扰的通路，其中ECM相关、PI 3 K-Akt、HIF-1、FoxO和昼夜节律通路是最显著失调的通路。我们选择了差异表达的TF，这些TF富集用于调节OA中的DE基因，并通过创建软骨特异性相互作用子网络来优先考虑这些转录因子。该分析揭示了8种TF，包括JUN、EGR 1、JUND、FOSL 2、MYC、KLF 4、RELA和FOS，它们都靶向OA中大量失调的基因，并且它们本身在OA中被抑制。我们发现了一个新的转录因子失调的子网络，代表了OA中异常基因表达的新介质和有前途的治疗靶点。
Osteoarthritis (OA) is the most prevalent joint disease. As disease-modifying therapies are not available, novel therapeutic targets need to be discovered and prioritized for their importance in mediating the abnormal phenotype of cells in OA-affected joints. Here, we generated a genome-wide molecular profile of OA to elucidate regulatory mechanisms of OA pathogenesis and to identify possible therapeutic targets using integrative analysis of mRNA-sequencing data obtained from human knee cartilage. RNA-sequencing (RNA-seq) was performed on 18 normal and 20 OA human knee cartilage tissues. RNA-seq datasets were analysed to identify genes, pathways and regulatory networks that were dysregulated in OA. RNA-seq data analysis revealed 1332 differentially expressed (DE) genes between OA and non-OA samples, including known and novel transcription factors (TFs). Pathway analysis identified 15 significantly perturbed pathways in OA with ECM-related, PI3K-Akt, HIF-1, FoxO and circadian rhythm pathways being the most significantly dysregulated. We selected differentially expressed TFs that are enriched for regulating DE genes in OA and prioritized these transcription factors by creating a cartilage-specific interaction subnetwork. This analysis revealed 8 TFs, including JUN, EGR1, JUND, FOSL2, MYC, KLF4, RELA, and FOS that both target large numbers of dysregulated genes in OA and are themselves suppressed in OA. We identified a novel subnetwork of dysregulated TFs that represent new mediators of abnormal gene expression and promising therapeutic targets in OA.
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影响因子：
4
作者：
Hess, J;Angel, P;Schorpp-Kistner, M
通讯作者：
Schorpp-Kistner, M
影响因子：
7
作者：
Akagi R;Akatsu Y;Fisch KM;Alvarez-Garcia O;Teramura T;Muramatsu Y;Saito M;Sasho T;Su AI;Lotz MK
通讯作者：
Lotz MK
DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
通过诱导抗凋亡和分解代谢靶基因对软骨细胞的双相调节。
影响因子：
16.6
作者：
Kobayashi, Hiroshi;Chang, Song Ho;Mori, Daisuke;Itoh, Shozo;Hirata, Makoto;Hosaka, Yoko;Taniguchi, Yuki;Okada, Keita;Mori, Yoshifumi;Yano, Fumiko;Chung, Ung-il;Akiyama, Haruhiko;Kawaguchi, Hiroshi;Tanaka, Sakae;Saito, Taku
通讯作者：
Saito, Taku
影响因子：
25
作者：
Krishnan A;Zhang R;Yao V;Theesfeld CL;Wong AK;Tadych A;Volfovsky N;Packer A;Lash A;Troyanskaya OG
通讯作者：
Troyanskaya OG