Mechanical-Stress-Related Epigenetic Regulation of ZIC1 Transcription Factor in the Etiology of Postmenopausal Osteoporosis

Abstract

Mechanical loading exerts a profound influence on bone density and architecture, but the exact mechanism is unknown. Our study shows that expression of the neurological transcriptional factor zinc finger of the cerebellum 1 (ZIC1) is markedly increased in trabecular bone biopsies in the lumbar spine compared with the iliac crest, skeletal sites of high and low mechanical stress, respectively. Human trabecular bone transcriptome analyses revealed a strong association between ZIC1 mRNA levels and gene transcripts characteristically associated with osteoblasts, osteocytes and osteoclasts. This supposition is supported by higher ZIC1 expression in iliac bone biopsies from postmenopausal women with osteoporosis compared with age-matched control subjects, as well as strongly significant inverse correlation between ZIC1 mRNA levels and BMI-adjusted bone mineral density (BMD) (Z-score). ZIC1 promoter methylation was decreased in mechanically loaded vertebral bone compared to unloaded normal iliac bone, and its mRNA levels correlated inversely with ZIC1 promoter methylation, thus linking mechanical stress to epigenetic control of gene expression. The findings were corroborated in cultures of rat osteoblast progenitors and osteoblast-like cells. This study demonstrates for the first time how skeletal epigenetic changes that are affected by mechanical forces give rise to marked alteration in bone cell transcriptional activity and translate to human bone pathophysiology.

Identification of novel meQTLs strongly associated with rheumatoid arthritis by large‐scale epigenome‐wide analysis

“…Located on chromosome 3, ZIC1 is a known meningeal identity gene. Studies have shown that ZIC1 promoter methylation was related to the etiology of postmenopausal osteoporosis [16], and patients with RA are at high risk of osteoporosis [17–20]. Our findings suggest that ZIC1 may be associated with RA susceptibility, and deserve further in‐depth research.…”

The genetic overlap between osteoporosis and craniosynostosis

“…Our skull-BMD study underscored genes with mechanosensing properties, including the novel BMD-associated gene ZIC1 , which encodes a zinc-finger transcription factor. A few studies have demonstrated mechano-function properties of ZIC1 , including its differential expression in skeletal regions of higher and lower mechanical load, also ZIC1 immunolocalization in the cytoplasm, and translocation to the nucleus of murine osteocytes upon fluid shear and stress experiments ( 111 , 112 ). While more studies are needed to evaluate ZIC1 function in osteocytes and its function as a mechanosensing gene, its current understanding corroborates the high potential of GWAS for SK-BMD to identify genes with mechanosensing properties.…”