Deciphering the gene regulation of oxygen homeostasis and human fitness

Objetivo

Oxygen (O2) homeostasis is essential for human survival, yet how it is sensed, regulated, and encoded at the genomic level across cell types is unclear. Central to this system are the Norn cells—a rare, fibroblast-like kidney cells that I recently discovered and molecularly defined as the exclusive source of erythropoietin (EPO), the hormone that controls red blood cells production and thereby systemic O2 supply. Norn cells serve as a key O2 sensor, coupling tissue hypoxia to systemic responses. However, the gene regulatory mechanisms governing Norn cell function and consequently O2 homeostasis remain unexplored because the cells are scarce, hard to access, and human model systems are lacking.

In the ERC project ErythrO2Reg, I will build upon my discovery of Norn cells to decipher the genomic regulation of O2 sensing, hypoxia response, and in human hypoxia fitness. We will combine single-cell and spatial multi-omics, genome editing, and human kidney organoids to map and manipulate the O2-sensing circuitry.
Aim 1: Chart the dynamic transcriptional and epigenetic landscape of Norn cells in vivo to uncover the enhancers and transcription factors orchestrating the hypoxia response.
Aim 2: Engineer human Norn-like cells and vascularized kidney organoids from Tibetan and Han-Chinese induced pluripotent stem cells to reveal how evolutionary selection at hypoxia-responsive loci confers O2 adaptation.
Aim 3: Perturb candidate enhancers and regulators in situ to decipher the critical cis-regulatory elements and switches that control O2 homeostasis and fitness.

By unravelling the molecular logic of O2 sensing through the lens of Norn cells and Tibetan adaptation, we will establish a new framework to understand how genomes maintain systems O2 levels and adapt to fluctuating environments. ErythrO2Reg will uncover fundamental principles of homeostasis and open translational avenues for treating hypoxia-related diseases such as chronic kidney disease and anaemia.

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