Oxygen is essential for sustaining biochemical reactions in most organisms, and thus several mechanisms have evolved to cope with insufficient supply that results in hypoxia to ensure survival. While a hypoxic microenvironment is a critical part of normal embryonic development and angiogenesis, dysregulated and unwanted hypoxia underlies numerous pathologies such as ischaemia, anaemia, and cancer. At the cellular level, transcriptional, posttranscriptional, and chromatin changes shift cellular metabolism to cope with the low oxygen environment. This includes hypoxia inducible TFs (HIF-1a/2a) and its oxygen dependent negative enzymatic regulators (PHD). At the epigenetic level, oxygen sensitive histone demethylases rapidly detect hypoxia resulting in genome wide rewiring to activate hypoxia specific cellular programs. While these studies have pioneered our understanding of how cells sense and adapt to hypoxia, experimental findings are based on mouse models and 2D human culture systems using bulk methods. Investigating hypoxia regulatory dynamics using spatial and single-cell transcriptomics and epigenomics provides a transformative opportunity for novel discoveries. Larger organisms such as vertebrates and mammals have developed mechanisms that ensure a systemic oxygen supply: 1) The cardio-pulmonary response ensures higher oxygenation and circulation of oxygen carrying erythrocytes. This process is controlled by the neurovascular carotid body sitting on top of the carotid artery. Carotid body glomus cells function as a chemoreceptor to sense changes in blood gases and rapidly release neurotransmitters to increase respiratory and vascular outputs via the brainstem. 2) The erythropoietic response results in increased rate of erythropoiesis (i.e. production of erythrocytes that transport oxygen) to increase oxygen supply. This step-wise differentiation process relies on its master regulator hormone Erythropoietin (EPO) that binds to EPO receptor (EPO-R) on erythroid progenitors. EPO is produced and secreted by Norn cells that are embedded in kidney cortex and rapidly detect tissue hypoxia. Deregulation of EPO can lead to either renal anemia (too little EPO) or erythrocytosis (too much EPO) that may be life-threatening. In previous research, I discovered the molecular identity of EPO producing Norn cells and revealed its unique fibroblast-like cell type and identified novel transcription factors (TFs) TCF21, CEBPD, and GATA6. It is interesting to speculate that Norn-like cells or cell states are present in other critical tissues such as carotid body, lungs, heart, and brainstem. However, challenges to cell isolation and oxygen labile hypoxia cell states have challenged further investigation of these specialised oxygen sensing cells, regulatory mechanisms, and feedback loops. In this project, we aim to decipher the cellular identities and regulation of hypoxia transcriptional cell states in mice. We aim to identify and characterise the molecular identity of specialised hypoxia sensing cell types that are central to maintaining systemic oxygen homeostasis. We will decipher the regulatory principles of hypoxia transcriptional cell states in intact kidney, lung, and carotid body tissues from normoxic and hypoxic mice that are known to be critical sites of hypoxia response using spatial transcriptomics and single cell RNA/ATAC sequencing.