DOT1L decelerates the development of osteoporosis by inhibiting SRSF1 transcriptional activity via microRNA-181-mediated KAT2B inhibition

Changsheng Wang; Rongsheng Chen; Xitian Zhu; Xiaobo Zhang; Nancheng Lian

doi:10.1016/j.ygeno.2023.110759

DOT1L decelerates the development of osteoporosis by inhibiting SRSF1 transcriptional activity via microRNA-181-mediated KAT2B inhibition

Genomics. 2024 Jan;116(1):110759. doi: 10.1016/j.ygeno.2023.110759. Epub 2023 Dec 10.

Authors

Changsheng Wang¹, Rongsheng Chen², Xitian Zhu², Xiaobo Zhang², Nancheng Lian²

Affiliations

¹ Department of Spinal Surgery, First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian 350005, PR China. Electronic address: wangchangsheng085@163.com.
² Department of Spinal Surgery, First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian 350005, PR China.

PMID: 38072145
DOI: 10.1016/j.ygeno.2023.110759

Abstract

Objective: Our study explored the function of DOT1L in osteoporosis (OP) via the microRNA (miR)-181/KAT2B/SRSF1 axis.

Methods: Osteoclast (OC) number was evaluated via TRAP staining, and serum CTXI, PINP, and ALP contents were tested by ELISA. Following identification of bone marrow mesenchymal stem cells (BMSCs), OC differentiation was induced by M-CSF and RANKL, followed by the detection of OC differentiation and the expression of bone resorption-related genes, DOT1L, miR-181, KAT2B, and SRSF1.

Results: Overexpressed DOT1L or miR-181 stimulated calcified nodule formation and increased alkaline phosphatase activity and osteogenic marker gene expression. KAT2B knockdown enhanced the osteogenic differentiation of BMSCs by reducing SRSF1 acetylation. The enhancement of OC differentiation induced by overexpressed SRSF1 was inhibited by simultaneous DOT1L or miR-181 overexpression. DOT1L suppressed OP development in vivo via the miR-181/KAT2B/SRSF1 axis.

Conclusion: DOT1L overexpression slowed down bone loss and promoted bone formation via the miR-181/KAT2B/SRSF1 axis, thereby alleviating OP development.

Keywords: Bone marrow mesenchymal stem cells; DOT1L; Lysine acetyltransferase 2B; MicroRNA-181; Osteoclasts; Osteogenic differentiation; Osteoporosis; Serine and arginine rich splicing factor 1.

MeSH terms

Cell Differentiation / genetics
Cells, Cultured
Histone-Lysine N-Methyltransferase
Humans
MicroRNAs* / metabolism
Osteogenesis / genetics
Osteoporosis* / genetics
Serine-Arginine Splicing Factors / genetics
p300-CBP Transcription Factors / metabolism

Substances

MicroRNAs
DOT1L protein, human
Histone-Lysine N-Methyltransferase
SRSF1 protein, human
Serine-Arginine Splicing Factors
KAT2B protein, human
p300-CBP Transcription Factors
MIrn181 microRNA, human