Aranyi, T. | bioRxiv Science

bioRxiv2025

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

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.

physiology↗

bioRxiv2020

Single cell resolution regulatory landscape of the mouse kidney highlights cellular differentiation programs and renal disease targets

Determining the epigenetic program that generates unique cell types in the kidney is critical for understanding cell-type heterogeneity during tissue homeostasis and injury response. Here, we profiled open chromatin and gene expression in developing and adult mouse kidneys at single cell resolution. We show critical reliance of gene expression on distal regulatory elements (enhancers). We define key cell type-specific transcription factors and major gene-regulatory circuits for kidney cells. Dynamic chromatin and expression changes during nephron progenitor differentiation demonstrated that podocyte commitment occurs early and is associated with sustained Foxl1 expression. Renal tubule cells followed a more complex differentiation, where Hfn4a was associated with proximal and Tfap2b with distal fate. Mapping single nucleotide variants associated with human kidney disease identified critical cell types, developmental stages, genes, and regulatory mechanisms. We provide a global single cell resolution view of chromatin accessibility of kidney development. The dataset is available via interactive public websites.

developmental biology↗