MicroRNA-101a enhances trabecular bone accrual in male mice
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ABSTRACT:
PROVIDER: PRJNA649561 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12345926.fastq.gz | Fastqsanger.gz | |||
| SRR12345927.fastq.gz | Fastqsanger.gz | |||
| SRR12345928.fastq.gz | Fastqsanger.gz | |||
| SRR12345929.fastq.gz | Fastqsanger.gz | |||
| SRR12345930.fastq.gz | Fastqsanger.gz |
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Project description:High-throughput microRNA sequencing was used to identify microRNAs (miRs) that regulate osteoblast differentiation. We establish that miR-101a, which targets the epigenetic enzyme Ezh2, is up-regulated in differentiated MC3T3 cells and robustly expressed in mouse calvaria. Our previous studies showed that loss of Ezh2 function enhances osteogenesis and bone formation. Thus, we tested the attractive mechanistic model that increased miR-101s expression may suppress Ezh2 to stimulate the osteogenic process. Transient miR-101a over-expression suppresses Ezh2 levels and reduces tri-methylation on lysine 27 of histone 3 (H3K27me3), a heterochromatic mark catalyzed by Ezh2. Importantly, over-expression of miR-101a stimulates osteogenic differentiation of MC3T3 cells as quantified by alizarin red staining. Therefore, we examined skeletal phenotypes of mice transgenic for miR-101a under the control of Col1a1promoer and doxycycline administration. Experimental controls and mir-101 over-expressing mice were exposed to doxycycline during pregnancy and postnatal stages (phenotyping at 8 weeks) to maximize penetrance of skeletal phenotypes. Our analyses revealed that miR-101a over-expressing male mice are bigger as measured by total body weight and exhibit an increase in long bone length. These mice exhibit significant increases in trabecular bone volume fraction, trabecular number, trabecular thickness, as well as a reduction in trabecular spacing based on microCT analysis. Histomorphometric examination established a significant reduction in osteoid volume to bone volume and osteoid surface to bone surface. These findings suggest that the enhancement in trabecular bone may be due to accelerated bone mineralization in miR-101a over-expressing male mice. Remarkably, while female mice exhibit a significant increase in bone length, no significant changes were noted by microCT (trabecular bone parameters) and histomorphometry (osteoid parameters). We conclude that miR-101a upregulation during osteoblast maturation enhances trabecular bone parameters in male mice. Thus, miR-101 and Ezh2 may form part of an intricate epigenetic feed-forward mechanisms to regulate bone formation.
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Project description:High-throughput microRNA sequencing was performed during differentiation of MC3T3-E1 osteoblasts to develop working hypotheses for specific microRNAs that control osteogenesis. The expression data show that miR-101a, which targets the mRNAs for the epigenetic enzyme Ezh2 and many other proteins, is highly upregulated during osteoblast differentiation and robustly expressed in mouse calvaria. Transient elevation of miR-101a suppresses Ezh2 levels, reduces tri-methylation of lysine 27 in histone 3 (H3K27me3; a heterochromatic mark catalyzed by Ezh2), and accelerates mineralization of MC3T3-E1 osteoblasts. We also examined skeletal phenotypes of an inducible miR-101a transgene under direct control of doxycycline administration. Experimental controls and mir-101a over-expressing mice were exposed to doxycycline in utero and postnatally (up to 8 weeks of age) to maximize penetrance of skeletal phenotypes. Male mice that over-express miR-101a have increased total body weight and longer femora. MicroCT analysis indicate that these mice have increased trabecular bone volume fraction, trabecular number and trabecular thickness with reduced trabecular spacing as compared to controls. Histomorphometric analysis demonstrates a significant reduction in osteoid volume to bone volume and osteoid surface to bone surface. Remarkably, while female mice also exhibit a significant increase in bone length, no significant changes were noted by microCT (trabecular bone parameters) and histomorphometry (osteoid parameters). Hence, miR-101a upregulation during osteoblast maturation and the concomitant reduction in Ezh2 mediated H3K27me3 levels may contribute to the enhanced trabecular bone parameters in male mice. However, the sex-specific effect of miR-101a indicates that more intricate epigenetic mechanisms mediate physiological control of bone formation and homeostasis.
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