The noncoding RNA linc-ADAMTS5 cooperates with RREB1 to protect from intervertebral disc degeneration through inhibiting ADAMTS5 expression.
Previous studies have indicated the important roles of ADAMTS5 in intervertebral disc degeneration (IDD). However, the mechanisms that regulate ADAMTS5 expression in nuclear pulposus (NP) cells remain largely unknown. Evidence suggests that intergenic transcription may be associated with genes that encode transcriptional regulators. Here, we identified a long intergenic noncoding RNA, linc-ADAMTS5, which was transcribed in the opposite direction to ADAMTS5. In the present study, through mining computational algorithm programs, and publicly available data sets, we identified Ras-responsive element-binding protein 1 (RREB1) as a crucial transcription factor regulating the expression of ADAMTS5 in NP cells. RNA pull-down, RNA immunoprecipitation (RIP),in vitrobinding assays, and gain- and loss-of-function studies indicated that a physical interaction between linc-ADAMTS5 and splicing factor proline/glutamine-rich (SFPQ) facilitated the recruitment of RREB1 to binding sites within the ADAMTS5 promoter to induce chromatin remodeling. This resulted in subdued ADAMTS5 levels in cultured NP cells involving histone deacetylases (HDACs). In clinical NP tissues, linc-ADAMTS5 and RREB1 were correlated negatively with ADAMTS5 expression. Taken together, these results demonstrate that RREB1 cooperates with noncoding RNA linc-ADAMTS5 to inhibit ADAMTS5 expression, thereby affecting degeneration of the extracellular matrix (ECM) of the intervertebral disc (IVD).
Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Kun
K
Wang
Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Yu
Y
Song
Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.|Department of Orthopedics, First Hospital of Wuhan, Wuhan, China.
Wei
W
Liu
Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Xinghuo
X
Wu
Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Yukun
Y
Zhang
Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Shuai
S
Li
Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Liang
L
Kang
Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Ji
J
Tu
Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Kangcheng
K
Zhao
Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Wenbin
W
Hua
Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China yangcao1971@sina.com.
Cao
C
Yang
D000071116:ADAMTS5 Protein / Q000235:genetics* / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D005260:Female; D006801:Humans; D055959:Intervertebral Disc Degeneration / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D062085:RNA, Long Noncoding / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult
D004268:DNA-Binding Proteins; C000613136:LOC101926975 long non-coding RNA, human; C000621498:LOC105372760 lncRNA, human; D062085:RNA, Long Noncoding; C101743:RREB1 protein, human; D014157:Transcription Factors; D000071116:ADAMTS5 Protein
ADAMTS5; intervertebral disc degeneration; noncoding RNA