Abstract
The fat mass and obesity-associated gene (FTO) encodes an m6A RNA demethylase that controls mRNA processing and has been linked to both obesity and bone mineral density in humans by genome-wide association studies. To examine the role of FTO in bone, we characterized the phenotype of mice lacking Fto globally (FtoKO) or selectively in osteoblasts (FtoOc KO). Both mouse models developed age-related reductions in bone volume in both the trabecular and cortical compartments. RNA profiling in osteoblasts following acute disruption of Fto revealed changes in transcripts of Hspa1a and other genes in the DNA repair pathway containing consensus m6A motifs required for demethylation by Fto. Fto KO osteoblasts were more susceptible to genotoxic agents (UV and H2O2) and exhibited increased rates of apoptosis. Importantly, forced expression of Hspa1a or inhibition of NF-êB signaling normalized the DNA damage and apoptotic rates in Fto KO osteoblasts. Furthermore, increased metabolic stress induced in mice by feeding a high-fat diet induced greater DNA damage in osteoblast of FtoOc KO mice compared to controls. These data suggest that FTO functions intrinsically in osteoblasts through Hspa1a-NF-κB signaling to enhance the stability of mRNA of proteins that function to protect cells from genotoxic damage.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 17980-17989 |
| Number of pages | 10 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 116 |
| Issue number | 36 |
| DOIs | |
| State | Published - Sep 3 2019 |
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Keywords
- Bone
- DNA damage
- Epigenetics
- Osteoblasts
- Osteoporosis
ASJC Scopus subject areas
- General
Cite this
The RNA demethylase FTO is required for maintenance of bone mass and functions to protect osteoblasts from genotoxic damage. / Zhang, Qian; Riddle, Ryan C.; Yang, Qian; Rosen, Clifford R.; Guttridge, Denis C.; Dirckx, Naomi; Faugere, Marie Claude; Farber, Charles R.; Clemens, Thomas L.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 116, No. 36, 03.09.2019, p. 17980-17989.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - The RNA demethylase FTO is required for maintenance of bone mass and functions to protect osteoblasts from genotoxic damage
AU - Zhang, Qian
AU - Riddle, Ryan C.
AU - Yang, Qian
AU - Rosen, Clifford R.
AU - Guttridge, Denis C.
AU - Dirckx, Naomi
AU - Faugere, Marie Claude
AU - Farber, Charles R.
AU - Clemens, Thomas L.
PY - 2019/9/3
Y1 - 2019/9/3
N2 - The fat mass and obesity-associated gene (FTO) encodes an m6A RNA demethylase that controls mRNA processing and has been linked to both obesity and bone mineral density in humans by genome-wide association studies. To examine the role of FTO in bone, we characterized the phenotype of mice lacking Fto globally (FtoKO) or selectively in osteoblasts (FtoOc KO). Both mouse models developed age-related reductions in bone volume in both the trabecular and cortical compartments. RNA profiling in osteoblasts following acute disruption of Fto revealed changes in transcripts of Hspa1a and other genes in the DNA repair pathway containing consensus m6A motifs required for demethylation by Fto. Fto KO osteoblasts were more susceptible to genotoxic agents (UV and H2O2) and exhibited increased rates of apoptosis. Importantly, forced expression of Hspa1a or inhibition of NF-êB signaling normalized the DNA damage and apoptotic rates in Fto KO osteoblasts. Furthermore, increased metabolic stress induced in mice by feeding a high-fat diet induced greater DNA damage in osteoblast of FtoOc KO mice compared to controls. These data suggest that FTO functions intrinsically in osteoblasts through Hspa1a-NF-κB signaling to enhance the stability of mRNA of proteins that function to protect cells from genotoxic damage.
AB - The fat mass and obesity-associated gene (FTO) encodes an m6A RNA demethylase that controls mRNA processing and has been linked to both obesity and bone mineral density in humans by genome-wide association studies. To examine the role of FTO in bone, we characterized the phenotype of mice lacking Fto globally (FtoKO) or selectively in osteoblasts (FtoOc KO). Both mouse models developed age-related reductions in bone volume in both the trabecular and cortical compartments. RNA profiling in osteoblasts following acute disruption of Fto revealed changes in transcripts of Hspa1a and other genes in the DNA repair pathway containing consensus m6A motifs required for demethylation by Fto. Fto KO osteoblasts were more susceptible to genotoxic agents (UV and H2O2) and exhibited increased rates of apoptosis. Importantly, forced expression of Hspa1a or inhibition of NF-êB signaling normalized the DNA damage and apoptotic rates in Fto KO osteoblasts. Furthermore, increased metabolic stress induced in mice by feeding a high-fat diet induced greater DNA damage in osteoblast of FtoOc KO mice compared to controls. These data suggest that FTO functions intrinsically in osteoblasts through Hspa1a-NF-κB signaling to enhance the stability of mRNA of proteins that function to protect cells from genotoxic damage.
KW - Bone
KW - DNA damage
KW - Epigenetics
KW - Osteoblasts
KW - Osteoporosis
UR - http://www.scopus.com/inward/record.url?scp=85071788831&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85071788831&partnerID=8YFLogxK
U2 - 10.1073/pnas.1905489116
DO - 10.1073/pnas.1905489116
M3 - Article
C2 - 31434789
AN - SCOPUS:85071788831
VL - 116
SP - 17980
EP - 17989
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 36
ER -