Genome-Wide Occupancy Profiling Reveals Critical Roles of FoxO1 in Regulating Extracellular Matrix and Circadian Rhythm Genes in Human Chondrocytes.
Genome-Wide Occupancy Profiling Reveals Critical Roles of FoxO1 in Regulating Extracellular Matrix and Circadian Rhythm Genes in Human Chondrocytes.
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DOI：
10.1002/art.41284
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发表时间：
2020-09
期刊：
影响因子：
--
通讯作者：
Lotz MK
中科院分区：
文献类型：
--
作者：
Duffy T;Bekki H;Lotz MK
骨关节炎（OA）是最常见的年龄相关性关节疾病。随着年龄的增长和OA，FOXO转录因子的表达减少，削弱了它们的软骨保护作用。为了阐明FOXO 1保护软骨细胞的分子机制，我们鉴定了FOXO 1的全基因组占据谱。我们对人原代软骨细胞进行FOXO 1染色质免疫沉淀，然后进行高通量测序（ChIP-seq）。将ChIP-seq数据与RNA-seq数据集整合。在用FOXO 1抑制剂处理的原代软骨细胞中证实了生物信息学结果。对人原代软骨细胞FOXO 1 ChIP-seq的分析表明，与OA发病机制有关的途径主要由FOXO 1与具有次优结合位点的组织特异性增强子结合来调节（20%的峰），而更普遍存在的FOXO 1通路通过与其典型结合基序的相互作用在启动子水平上调节将FOXO 1占有率数据与RNA-seq整合，比较OA和健康人软骨，揭示了428个在OA中失调的推定FOXO 1靶基因。通路分析显示，属于衰老（logP −6.73）、细胞外基质（ECM）（logP −12.97）和昼夜节律钟（logP −6.30）通路的基因富集，表明FOXO 1失调在OA中的异常表达中起重要作用。使用FOXO 1的抑制剂，我们证实FOXO 1在培养的人软骨细胞中调节这些通路。FOXO 1通过不同的机制调节软骨细胞中普遍存在的和软骨特异性的基因。FOXO 1转录网络在调节稳态、ECM和生物钟基因中具有直接作用，并且在OA发病机制中观察到的这些通路的异常表达中起重要作用。
Osteoarthritis (OA) is the most common age-related joint disease. With aging and in OA, the expression of FOXO transcription factors is reduced, diminishing their chondroprotective actions. To elucidate the molecular mechanisms by which FOXO1 protects chondrocytes we identified the genome-wide occupancy profile of FOXO1. We performed FOXO1 chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) on human primary chondrocytes. ChIP-seq data were integrated with RNA-seq datasets. Bioinformatics results were confirmed in primary chondrocytes that were treated with a FOXO1 inhibitor. Analysis of FOXO1 ChIP-seq on human primary chondrocytes showed that pathways implicated in OA pathogenesis are mainly regulated by FOXO1 binding to tissue-specific enhancers with suboptimal binding sites (20% of the peaks), while more ubiquitous FOXO1 pathways are regulated at the promoter level through interaction with its canonical binding motif (7% of the peaks) Integrating FOXO1 occupancy data with RNA-seq comparing OA and healthy human cartilage revealed 428 putative FOXO1 target genes that are dysregulated in OA. Pathway analysis showed enrichment for genes belonging to senescence (logP −6.73), extracellular matrix (ECM) (logP −12.97) and circadian clock (logP −6.30) pathways suggesting that FOXO1 dysregulation plays an important role in their abnormal expression in OA. Using an inhibitor of FOXO1, we confirmed that FOXO1 regulates these pathways in cultured human chondrocytes. FOXO1 regulates ubiquitous and cartilage-specific genes in chondrocytes by using different mechanisms. The FOXO1 transcriptional network has a direct role in regulating homeostasis, ECM and circadian clock genes and plays an important role in the abnormal expression of these pathways observed in OA pathogenesis.
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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
影响因子：
64.5
作者：
Long, Hannah K.;Prescott, Sara L.;Wysocka, Joanna
通讯作者：
Wysocka, Joanna
影响因子：
64.8
作者：
Heintzman, Nathaniel D.;Hon, Gary C.;Hawkins, R. David;Kheradpour, Pouya;Stark, Alexander;Harp, Lindsey F.;Ye, Zhen;Lee, Leonard K.;Stuart, Rhona K.;Ching, Christina W.;Ching, Keith A.;Antosiewicz-Bourget, Jessica E.;Liu, Hui;Zhang, Xinmin;Green, Roland D.;Lobanenkov, Victor V.;Stewart, Ron;Thomson, James A.;Crawford, Gregory E.;Kellis, Manolis;Ren, Bing
通讯作者：
Ren, Bing
影响因子：
29
作者：
Ambrogini E;Almeida M;Martin-Millan M;Paik JH;Depinho RA;Han L;Goellner J;Weinstein RS;Jilka RL;O'Brien CA;Manolagas SC
通讯作者：
Manolagas SC
影响因子：
17.1
作者：
Matsuzaki T;Alvarez-Garcia O;Mokuda S;Nagira K;Olmer M;Gamini R;Miyata K;Akasaki Y;Su AI;Asahara H;Lotz MK
通讯作者：
Lotz MK