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We aim to uncover a novel transcriptional regulatory mechanism in kidney development mediated by adipocytes located between the kidney and its capsule. This previously unrecognized population of capsular adipocytes appears to influence gene expression in proximal tubule cells, suggesting a unique cellular and molecular interaction between adipose tissue and the developing kidney. If confirmed, this discovery would represent a paradigm shift in our understanding of renal organogenesis by introducing adipose tissue as a critical extrarenal signaling source. Our preliminary data show that ablating capsular adipocytes in a mouse model leads to selective downregulation of proximal tubule-specific genes and postnatal lethality. These transcriptional changes are not fully explained by known lipid-responsive transcription factors such as Hnf4a, indicating the likely involvement of an unidentified regulator that responds to adipocyte-derived signals—possibly fatty acids or other metabolites—and orchestrates a specific gene expression program during postnatal kidney development. To identify this transcription factor, we will perform multiome analysis—integrating single-cell RNA sequencing (scRNA-seq) and ATAC-seq—on kidneys from mutant and control mice. This approach will allow us to simultaneously profile gene expression and chromatin accessibility at single-cell resolution. scRNA-seq will be used to assess the developmental status and transcriptional changes in proximal tubule cells affected by adipocyte loss. Motif enrichment analysis of differentially accessible chromatin regions will be used to pinpoint candidate transcription factors and link them to altered gene expression patterns. If successful, this work will redefine the role of adipose tissue in organ development, positioning capsular adipocytes as key signaling hubs in kidney maturation. It will also establish a new framework for understanding metabolic regulation of transcription in non-adipose tissues and may have implications for developmental kidney disorders and metabolic kidney diseases. Ultimately, this discovery could open new therapeutic avenues targeting adipocyte-kidney signaling pathways to modulate renal function and repair.
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