Functions and Clinical Significance of Super-Enhancers in Bone-Related Diseases

Abstract

Super-enhancers (SEs) are a large cluster of cis-regulatory DNA elements that contain many binding motifs, which master transcription factors and cofactors bind to with high density. SEs usually regulate the expression of genes that can control the cell identity and fate, and SEs can be used to explain the patterns of the expression of cell-specific genes. Hence, it shows great potential for application in the treatment of diseases like cancer. At present, the clinical treatments for osteosarcoma, Ewing sarcoma, and other bone-related diseases remain challenging. The poor prognosis and difficult treatment of these diseases imposes heavy economic burden on patients and society. In recent years, research on SEs with respect to bone-related diseases has attracted increasing attention. In this paper, we first review the identification and functional mechanisms of SEs. Then, we integrate the findings of the emerging studies on SEs in bone-related diseases. Finally, we summarize recent strategies for targeting SEs for the treatment of bone-related diseases. This review aims to provide comprehensive insights into the roles of SEs in bone-related diseases.

Typical Enhancers, Super-Enhancers, and Cancers

“…Currently, SE biology is a fast-developed new era of cancer research and advanced studies have highlighted the function of SEs in distinct types and stages, including tumorigenesis, growth, metastasis, etc. In Osteosarcoma (OS), a type of bone cancer, advanced studies have addressed the critical role of SEs in the disease progression [ 90 ]. For instance, overexpression of MYC and its widespread binding across SEs landscapes characterize OS, while pharmacological treatment of OS cells with SEs inhibitors suppresses proliferation and enhances apoptosis [ 91 ].…”

“…In addition, the migration capacity of OS cells is decreased upon SEs “drugging” [ 91 ]. Moreover, Ewing Sarcoma, another type of bone cancer, is initiated and progressed by the chimeric oncoprotein EWS-FLI1 [ 90 , 92 ], and has been molecularly and mechanistically approached by a SEs angle. In Multiple Myeloma (MM), a malignancy originated from antibody-secreting plasma cells [ 90 , 93 ], fundamental studies have shown the commitment of SEs to the development of the disease.…”

Super-Enhancer-Associated Long Non-Coding RNA LINC01485 Promotes Osteogenic Differentiation of Human Bone Marrow Mesenchymal Stem Cells by Regulating MiR-619-5p/RUNX2 Axis

“…In recent years, accruing data has demonstrated a role of SEs in bone tissue regulation. Studies have reported that SEs are associated with various bone-related diseases, including osteosarcoma, Ewing sarcoma, chordoma, multiple myeloma, cartilage dysplasia, osteoporosis, rheumatoid arthritis, and osteoarthritis ( 23 ). These studies have typically identified disease-specific SEs and their target genes using bioinformatics, and then analyzed the functions of the target genes through experimental approaches ( 23 ).…”

“…Studies have reported that SEs are associated with various bone-related diseases, including osteosarcoma, Ewing sarcoma, chordoma, multiple myeloma, cartilage dysplasia, osteoporosis, rheumatoid arthritis, and osteoarthritis ( 23 ). These studies have typically identified disease-specific SEs and their target genes using bioinformatics, and then analyzed the functions of the target genes through experimental approaches ( 23 ). In conjunction, BRD4 and CDK7 based drugs targeting critical components of SEs have been developed to treat osteosarcoma, Ewing sarcoma, multiple myeloma, osteoarthritis, and other bone-related diseases ( 24 – 27 ).…”

Super-Enhancer Associated Five-Gene Risk Score Model Predicts Overall Survival in Multiple Myeloma Patients

“…SEs are generally occupied with abundant signals of H3K4me1, H3K27ac, p300, Mediator, RNA polymerase II, BRD4, CDK7, and other master transcription factors, which are responsible for the tissue-specific gene expression ( Wang et al, 2019 ). The recurrent loss or gain of SEs has been reported in various tumors ( He et al, 2019 ) including MM, indicating the important role of SEs in MM ( Qu et al, 2020 ). Lovén et al (2013) identified 681 SE-associated genes, including some key MM genes such as MYC , IRF4 , PRDM1 , and XBP1 .…”