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H3K36 trimethylation mediated by SETD2 regulates the fate of bone marrow mesenchymal stem cells
- Source :
- PLoS Biology, PLoS Biology, Vol 16, Iss 11, p e2006522 (2018)
- Publication Year :
- 2018
-
Abstract
- During the aging process, bone marrow mesenchymal stem cells (BMSCs) exhibit declined osteogenesis accompanied by excess adipogenesis, which will lead to osteoporosis. Here, we report that the H3 lysine 36 trimethylation (H3K36me3), catalyzed by histone methyltransferase SET-domain-containing 2 (SETD2), regulates lineage commitment of BMSCs. Deletion of Setd2 in mouse bone marrow mesenchymal stem cells (mBMSCs), through conditional Cre expression driven by Prx1 promoter, resulted in bone loss and marrow adiposity. Loss of Setd2 in BMSCs in vitro facilitated differentiation propensity to adipocytes rather than to osteoblasts. Through conjoint analysis of RNA sequencing (RNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq) data, we identified a SETD2 functional target gene, Lbp, on which H3K36me3 was enriched, and its expression was affected by Setd2 deficiency. Furthermore, overexpression of lipopolysaccharide-binding protein (LBP) could partially rescue the lack of osteogenesis and enhanced adipogenesis resulting from the absence of Setd2 in BMSCs. Further mechanistic studies demonstrated that the trimethylation level of H3K36 could regulate Lbp transcriptional initiation and elongation. These findings suggest that H3K36me3 mediated by SETD2 could regulate the cell fate of mesenchymal stem cells (MSCs) in vitro and in vivo, indicating that the regulation of H3K36me3 level by targeting SETD2 and/or the administration of downstream LBP may represent a potential therapeutic way for new treatment in metabolic bone diseases, such as osteoporosis.<br />Author summary During the aging process, the ability of the mesenchymal stem cells (MSCs) in the bone marrow to generate bone cells declines, and they become more likely to produce fat cells, resulting in brittle, or osteoporotic, bones. Here, we demonstrate that a histone modification—H3 lysine 36 trimethylation (H3K36me3), which is mediated by the enzyme SET-domain-containing 2 (SETD2) and regulates gene expression—plays an essential role in MSC lineage commitment in the bone marrow. We deleted the Setd2 gene in bone marrow mesenchymal stem cells (BMSCs) in mice and found that these mice exhibited reduced bone formation and increased marrow fat accumulation. Notably, we identified Lbp as one of SETD2 functional downstream genes. Overexpression of lipopolysaccharide-binding protein (LBP) could partially rescue the phenotype of SETD2 deficiency in bone marrow stem cells. Further mechanistic studies revealed that H3K36me3 could regulate Lbp transcription by modulating its transcriptional initiation and elongation. Thus, our study provides a new mechanism for MSC fate determination and a therapeutic target for the treatment of osteoporosis.
- Subjects :
- 0301 basic medicine
Male
RNA viruses
Physiology
Gene Expression
Ossification
Pathology and Laboratory Medicine
Biochemistry
Histones
Mice
0302 clinical medicine
Animal Cells
Gene expression
Adipocytes
Medicine and Health Sciences
Biology (General)
Promoter Regions, Genetic
Connective Tissue Cells
Membrane Glycoproteins
General Neuroscience
Stem Cells
Cell Differentiation
Lipids
Cell biology
Adipogenesis
Connective Tissue
Medical Microbiology
030220 oncology & carcinogenesis
Histone methyltransferase
Viral Pathogens
Viruses
Bone Remodeling
Cellular Types
Anatomy
Pathogens
General Agricultural and Biological Sciences
Research Article
QH301-705.5
Bone Marrow Cells
Biology
Cell fate determination
Microbiology
General Biochemistry, Genetics and Molecular Biology
03 medical and health sciences
SETD2
In vivo
Retroviruses
Adipocyte Differentiation
Genetics
Animals
Microbial Pathogens
General Immunology and Microbiology
Lysine
Mesenchymal stem cell
Lentivirus
Organisms
Biology and Life Sciences
Mesenchymal Stem Cells
Histone-Lysine N-Methyltransferase
Cell Biology
DNA Methylation
In vitro
Mice, Inbred C57BL
030104 developmental biology
Biological Tissue
Carrier Proteins
Physiological Processes
Oils
Acute-Phase Proteins
Developmental Biology
Subjects
Details
- ISSN :
- 15457885
- Volume :
- 16
- Issue :
- 11
- Database :
- OpenAIRE
- Journal :
- PLoS biology
- Accession number :
- edsair.doi.dedup.....23a0cdab724411b1df4378536ea5e3da