Developing a Multi-Organ Multi-Omics Computational Framework for StudyingMammalian Iron Systems Biology

PROJECT SUMMARY/ABSTRACT Iron disorders are caused by changes in iron levels in blood, tissues, or both. Iron deficiency, which can lead to anemia, represents a major component of the global disease burden worldwide, especially in women. Iron deficiency-related anemia affects >1.2 billion individuals worldwide, and iron deficiency without anemia is even more frequent. Understanding the basic molecular mechanisms underlying specific iron disorders is critical to designing future therapeutic strategies. Approaches using iron supplementation or iron chelators are employed globally to improve iron metabolism. However, their effectiveness can vary among patients due to the diverse mechanisms underlying iron disorders. Some etiologies are linked to impaired iron absorption in the intestine, while others involve issues with iron delivery to the bone marrow, which is crucial for sustaining erythropoiesis. The goal of my program at The Jackson Laboratory is to identify the root causes of iron disorders, including iron deficiency, iron deficiency anemia, anemia, and/or iron overload, by holistically investigating the fundamental biological mechanisms of iron metabolism. By focusing on the etiology of these disorders rather than merely addressing the symptoms, we aim to facilitate personalized medicine tailored to each patient’s specific needs. During the next five years, the AgoroLab will develop a novel computational framework, the Multi-Omics-Multi- Organ sequencing (MOMO-seq), for studying mammalian iron systems biology in different tissues associated with iron metabolism phenotypes and identify key organs, cells, and molecular features that drive iron disorders. MOMO-seq couples the power of single-cell multi-omics technology to profile DNA accessibility with transcriptomics/histopathology approaches to study iron biology across multiorgan systems, enabling the identification of cell-specific mechanisms and inter-organ communication circuits associated with iron metabolism. Within our framework, we will be able to shed light on some of the key yet unanswered questions in iron biology. This includes deconvoluting the complex multiorgan signaling network that maintains iron homeostasis. For instance, how does the bone marrow communicate with the spleen to meet the high iron demand of erythropoiesis? How do kidneys regulate iron reabsorption? Developing MOMO-seq will be pivotal in establishing and strengthening my independent research program, as well as laying the groundwork for an innovative, comprehensive approach to studying iron metabolism and its implications in health and disease.