Conserved transcriptional co-regulation of pyrophosphatehomeostasis genes governs systemic mineralization factorsin mice and humans

Tamatey, V., Varhegyi, M., Blaha, B., Winberger, J., Juhasz, D., Bata, E., Toth, D. M., Muazu, M., Demjen Nagy, Z., Kovacs, D., Nagy, A., Nagy, A. I., Vanakker, O., Aranyi, T., Szeri, F.

HUN-REN Research Centre for Natural Sciences, Institute of Molecular Life Sciences, Budapest, Hungary · biorxiv

Paper

Abstract

Inorganic pyrophosphate (PPi) is a critical inhibitor of ectopic calcification, yet transcriptional regulation of genes controlling its systemic production and degradation (ABCC6, ALPL, ANKH, ENPP1) remains elusive. We hypothesized that PPi homeostasis is governed by evolutionarily conserved transcription factor (TF) network. Promoter-motif analysis of PPi genes revealed conserved enrichment of nuclear receptor TFs (ESR1, NR4A1, RXRA, NR1H3/LXR) and metabolic regulators (SREBF1, CEBPB, HNF4A) across mouse and human orthologues. Supporting this, analysis of public RNA-seq datasets and RT-qPCR in wild-type and Abcc6-/- mice demonstrated tight co-expression of these genes in the liver and the kidney, as central transcriptional hub of systemic PPi regulation. Functionally, analyses in mice revealed age-dependent inverse coupling between plasma PPi concentration and serum alkaline phosphatase (AP) activity, with strongest impact during early life. Abcc6-/- mice exhibited persistently reduced although gradually increasing PPi and altered Pi/PPi ratios during aging. Translating these findings to humans, plasma PPi correlated inversely with AP activity and positively with Pi, though associations were weaker in ABCC6-deficient pseudoxanthoma elasticum patients. These results establish a conserved TF-driven program coordinating hepatic and renal expression of PPi homeostatic genes, highlight early-life sensitivity of PPi balance, and link gene-regulation to circulating mineralization factors, highlighting species-specific and pathology-driven differences.

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Research summary

The paper claims that conserved transcriptional co-regulation of pyrophosphate homeostasis genes influences systemic mineralization factors in both mice and humans. This research is relevant as it explores the mechanisms of mineralization and pyrophosphate regulation, which are linked to aging processes and age-related diseases such as ectopic calcification.

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