Dynamic changes of enhancer and super enhancer landscape in degenerated nucleus pulposus cells

Inflammatory cascade and extracellular matrix remodeling have been identified as pivotal pathological factors in the progression of intervertebral disc degeneration (IDD), but the mechanisms underlying the aberrant activation of transcription during nucleus pulposus (NP) cell degeneration remain elusive. Superenhancers (SEs) are large clusters of adjacent lone enhancers, which control expression modes of cellular fate and pathogenic genes. Here, we showed that SEs underwent tremendous remodeling during NP cell degeneration and that SE-related transcripts were most abundant in inflammatory cascade and extracellular matrix remodeling processes. Inhibition of cyclindependent kinase 7, a transcriptional kinase-mediated transcriptional initiation in trans-acting SE complex, constricted the transcription of inflammatory cascades, and extracellular matrix remodeling-related genes such as IL1 beta and MMP3 in NP cells, meanwhile, also restrained the transcription of Mmp16, Tnfrsf21, and Il11ra1 to retard IDD in rats. In summary, our findings clarify SEs control the transcription of genes associated with inflammatory cascade and extracellular matrix remodeling during NP cell degeneration and identify inhibition of the cyclin-dependent kinase 7, required for SE-mediated transcriptional activation, as a therapeutic option for IDD.