GATA4 and estrogen receptor alpha bind at SNPs rs9921222 and rs10794639 to regulate AXIN1 expression in osteoblasts

Suthon, Sarocha; Perkins, Rachel S.; Lin, Jianjian; Crockarell, John R.; Miranda-Carboni, Gustavo A.; Krum, Susan A.

doi:10.1007/s00439-022-02463-8

Cited by 6 publications

(5 citation statements)

References 51 publications

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“…Furthermore, knockout of Gata4 decreases Wnt10b expression, corresponding with a decrease in trabecular bone properties. GATA4 also transcriptionally regulates other components of the WNT signaling pathway, including Wnt3a , Fzd6 , and Dkk1 ( Khalid et al, 2021 ; Suthon et al, 2022b ).…”

Section: Wnt10b and Bonementioning

confidence: 99%

The role of WNT10B in physiology and disease: A 10-year update

Perkins

Singh

Abell

et al. 2023

Front. Cell Dev. Biol.

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WNT10B, a member of the WNT family of secreted glycoproteins, activates the WNT/β-catenin signaling cascade to control proliferation, stemness, pluripotency, and cell fate decisions. WNT10B plays roles in many tissues, including bone, adipocytes, skin, hair, muscle, placenta, and the immune system. Aberrant WNT10B signaling leads to several diseases, such as osteoporosis, obesity, split-hand/foot malformation (SHFM), fibrosis, dental anomalies, and cancer. We reviewed WNT10B a decade ago, and here we provide a comprehensive update to the field. Novel research on WNT10B has expanded to many more tissues and diseases. WNT10B polymorphisms and mutations correlate with many phenotypes, including bone mineral density, obesity, pig litter size, dog elbow dysplasia, and cow body size. In addition, the field has focused on the regulation of WNT10B using upstream mediators, such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). We also discussed the therapeutic implications of WNT10B regulation. In summary, research conducted during 2012–2022 revealed several new, diverse functions in the role of WNT10B in physiology and disease.

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Section: Wnt10b and Bonementioning

confidence: 99%

The role of WNT10B in physiology and disease: A 10-year update

Perkins

Singh

Abell

et al. 2023

Front. Cell Dev. Biol.

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“…U2OS-ERα cells are an osteosarcoma cell line that has an inducible expression of ERα. Overexpression of ERα in U2OS cells leads to an osteoblast phenotype that serves as a model for normal osteoblasts [ 12 , 23 , 24 , 32 ]. The ERα binding site with the highest enrichment was near FOXC1 and FOXC1 has been shown to be important for osteoblast biology [ 18 , 19 , 33 ].…”

Section: Resultsmentioning

confidence: 99%

“…GATA4 and ERα show synchronized actions on osteoblast differentiation by activating the expression of RUNX2 , ALPL , and BGLAP [ 3 , 6 ]. GATA4 and ERα interact and bind at either estrogen response elements or GATA binding sites for the cis-regulation of many genes [ 32 ]. We elucidate that GATA4 and ERα control the expression of Foxc1 by binding to enhancers in mouse osteoblasts.…”

Section: Discussionmentioning

confidence: 99%

Regulation and Function of FOXC1 in Osteoblasts

Suthon,

Lin,

Perkins

et al. 2023

JDB

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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 FOXC1 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 Foxc1. Knockdown of Gata4 in mouse osteoblasts in vitro decreases Foxc1 expression as does knockout of Gata4 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 FOXC1, 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.

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“…Investigations into the transcriptional regulation of the AXIN1 gene have unveiled a myriad of transcription factors that actively engaged in promoting its transcriptional activation. These factors include GATA4 [ 13 ], RUNX1 [ 14 ], VDR [ 15 ], C/EPB-β [ 16 ], PHB1 [ 17 ], and EGR1 [ 18 ]. Intriguingly, the transcriptional activation of AXIN1 can be modulated through competitive inhibition exerted by ERα/ESR1, which counters the activities of GATA4 and RUNX1 [ 13 , 14 ] (Fig.…”

Section: Introductionmentioning

confidence: 99%

“…These factors include GATA4 [ 13 ], RUNX1 [ 14 ], VDR [ 15 ], C/EPB-β [ 16 ], PHB1 [ 17 ], and EGR1 [ 18 ]. Intriguingly, the transcriptional activation of AXIN1 can be modulated through competitive inhibition exerted by ERα/ESR1, which counters the activities of GATA4 and RUNX1 [ 13 , 14 ] (Fig. 3 A).…”

Section: Introductionmentioning

confidence: 99%

The scaffold protein AXIN1: gene ontology, signal network, and physiological function

Qiu,

Sun,

Ning

et al. 2024

Cell Commun Signal

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AXIN1, has been initially identified as a prominent antagonist within the WNT/β-catenin signaling pathway, and subsequently unveiled its integral involvement across a diverse spectrum of signaling cascades. These encompass the WNT/β-catenin, Hippo, TGFβ, AMPK, mTOR, MAPK, and antioxidant signaling pathways. The versatile engagement of AXIN1 underscores its pivotal role in the modulation of developmental biological signaling, maintenance of metabolic homeostasis, and coordination of cellular stress responses. The multifaceted functionalities of AXIN1 render it as a compelling candidate for targeted intervention in the realms of degenerative pathologies, systemic metabolic disorders, cancer therapeutics, and anti-aging strategies. This review provides an intricate exploration of the mechanisms governing mammalian AXIN1 gene expression and protein turnover since its initial discovery, while also elucidating its significance in the regulation of signaling pathways, tissue development, and carcinogenesis. Furthermore, we have introduced the innovative concept of the AXIN1-Associated Phosphokinase Complex (AAPC), where the scaffold protein AXIN1 assumes a pivotal role in orchestrating site-specific phosphorylation modifications through interactions with various phosphokinases and their respective substrates.

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GATA4 and estrogen receptor alpha bind at SNPs rs9921222 and rs10794639 to regulate AXIN1 expression in osteoblasts

Cited by 6 publications

References 51 publications

The role of WNT10B in physiology and disease: A 10-year update

The role of WNT10B in physiology and disease: A 10-year update

Regulation and Function of FOXC1 in Osteoblasts

The scaffold protein AXIN1: gene ontology, signal network, and physiological function

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