Regulation and Function of FOXC1 in Osteoblasts
Estrogens, which bind to estrogen receptor alpha (ERα), are important for proper bone mineral density. When women go through menopause, estrogen levels decrease, and there is a decrease in bone quality, along with an increased risk for fractures. We previously identified an enhancer near <i>FO...
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| Format: | Article |
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MDPI AG
2023-09-01
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| Series: | Journal of Developmental Biology |
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| Online Access: | https://www.mdpi.com/2221-3759/11/3/38 |
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| author | Sarocha Suthon Jianjian Lin Rachel S. Perkins Gustavo A. Miranda-Carboni Susan A. Krum |
| author_facet | Sarocha Suthon Jianjian Lin Rachel S. Perkins Gustavo A. Miranda-Carboni Susan A. Krum |
| author_sort | Sarocha Suthon |
| collection | DOAJ |
| description | Estrogens, which bind to estrogen receptor alpha (ERα), are important for proper bone mineral density. When women go through menopause, estrogen levels decrease, and there is a decrease in bone quality, along with an increased risk for fractures. We previously identified an enhancer near <i>FOXC1</i> as the most significantly enriched binding site for estrogen receptor alpha (ERα) in osteoblasts. FOXC1 is a transcription factor belonging to a large group of proteins known as forkhead box genes and is an important regulator of bone formation. Here, we demonstrate that 17β-estradiol (E2) increases the mRNA and protein levels of FOXC1 in primary mouse and human osteoblasts. GATA4 is a pioneer factor for ERα and it is also recruited to enhancers near <i>Foxc1</i>. Knockdown of <i>Gata4</i> in mouse osteoblasts in vitro decreases <i>Foxc1</i> expression as does knockout of <i>Gata4</i> in vivo. Functionally, GATA4 and FOXC1 interact and regulate osteoblast proteins such as RUNX2, as demonstrated by ChIP-reChIP and luciferase assays. The most enriched motif in GATA4 binding sites from ChIP-seq is for <i>FOXC1</i>, supporting the notion that GATA4 and FOXC1 cooperate in regulating osteoblast differentiation. Together, these data demonstrate the interactions of the transcription factors ERα, GATA4, and FOXC1 to regulate each other’s expression and other osteoblast differentiation genes. |
| first_indexed | 2024-03-10T22:36:31Z |
| format | Article |
| id | doaj.art-bb8c4b1831f149dfaeb89eae33f13b36 |
| institution | Directory Open Access Journal |
| issn | 2221-3759 |
| language | English |
| last_indexed | 2024-03-10T22:36:31Z |
| publishDate | 2023-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Journal of Developmental Biology |
| spelling | doaj.art-bb8c4b1831f149dfaeb89eae33f13b362023-11-19T11:23:03ZengMDPI AGJournal of Developmental Biology2221-37592023-09-011133810.3390/jdb11030038Regulation and Function of FOXC1 in OsteoblastsSarocha Suthon0Jianjian Lin1Rachel S. Perkins2Gustavo A. Miranda-Carboni3Susan A. Krum4Department of Orthopaedic Surgery and Biomedical Engineering, University of Tennessee Health Science Center, Memphis, TN 38163, USADepartment of Orthopaedic Surgery and Biomedical Engineering, University of Tennessee Health Science Center, Memphis, TN 38163, USADepartment of Orthopaedic Surgery and Biomedical Engineering, University of Tennessee Health Science Center, Memphis, TN 38163, USADepartment of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USADepartment of Orthopaedic Surgery and Biomedical Engineering, University of Tennessee Health Science Center, Memphis, TN 38163, USAEstrogens, which bind to estrogen receptor alpha (ERα), are important for proper bone mineral density. When women go through menopause, estrogen levels decrease, and there is a decrease in bone quality, along with an increased risk for fractures. We previously identified an enhancer near <i>FOXC1</i> as the most significantly enriched binding site for estrogen receptor alpha (ERα) in osteoblasts. FOXC1 is a transcription factor belonging to a large group of proteins known as forkhead box genes and is an important regulator of bone formation. Here, we demonstrate that 17β-estradiol (E2) increases the mRNA and protein levels of FOXC1 in primary mouse and human osteoblasts. GATA4 is a pioneer factor for ERα and it is also recruited to enhancers near <i>Foxc1</i>. Knockdown of <i>Gata4</i> in mouse osteoblasts in vitro decreases <i>Foxc1</i> expression as does knockout of <i>Gata4</i> in vivo. Functionally, GATA4 and FOXC1 interact and regulate osteoblast proteins such as RUNX2, as demonstrated by ChIP-reChIP and luciferase assays. The most enriched motif in GATA4 binding sites from ChIP-seq is for <i>FOXC1</i>, supporting the notion that GATA4 and FOXC1 cooperate in regulating osteoblast differentiation. Together, these data demonstrate the interactions of the transcription factors ERα, GATA4, and FOXC1 to regulate each other’s expression and other osteoblast differentiation genes.https://www.mdpi.com/2221-3759/11/3/38FOXC1GATA4osteoblastestrogen |
| spellingShingle | Sarocha Suthon Jianjian Lin Rachel S. Perkins Gustavo A. Miranda-Carboni Susan A. Krum Regulation and Function of FOXC1 in Osteoblasts Journal of Developmental Biology FOXC1 GATA4 osteoblast estrogen |
| title | Regulation and Function of FOXC1 in Osteoblasts |
| title_full | Regulation and Function of FOXC1 in Osteoblasts |
| title_fullStr | Regulation and Function of FOXC1 in Osteoblasts |
| title_full_unstemmed | Regulation and Function of FOXC1 in Osteoblasts |
| title_short | Regulation and Function of FOXC1 in Osteoblasts |
| title_sort | regulation and function of foxc1 in osteoblasts |
| topic | FOXC1 GATA4 osteoblast estrogen |
| url | https://www.mdpi.com/2221-3759/11/3/38 |
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