Regulatory architecture underlying the carotid body-specific expression of HIGD1C

Abstract HIGD1C is a mitochondrial protein that exhibits highly tissue-specific expression in the carotid body, a specialized peripheral chemoreceptor responsible for oxygen sensing. However, the cis-regulatory mechanisms governing its tissue-specific expression remain poorly understood. In this study, we investigated the regulatory architecture surrounding the human HIGD1C locus using comparative genomic analyses and publicly available epigenomic datasets integrated through the UCSC Genome Browser. ENCODE candidate cis-regulatory elements (cCREs), predicted transcription factor binding motifs from the JASPAR database, and public regulatory annotations were analyzed to identify candidate regulatory elements associated with HIGD1C expression. Six cCREs were identified upstream of HIGD1C, including chromatin accessibility elements, promoter/enhancer-like signatures, and CTCF-associated regions. Among these, the candidate enhancer EH38E3016616 overlapped with a CTCF-binding region and was located adjacent to predicted PHOX2B and ASCL1 binding motifs, two transcription factors implicated in carotid body development and neuroendocrine differentiation. Integration of these observations supports a model in which enhancer-associated chromatin organization and lineage-specific transcription factors may cooperatively contribute to the regulation of HIGD1C. Based on these findings, we propose a putative cis-regulatory landscape that summarizes the regulatory architecture surrounding the HIGD1C locus and provides a conceptual framework for understanding its tissue- specific expression in the carotid body. Although the proposed model is based on computational analyses and requires experimental validation, this study establishes a foundation for future investigations into the coordinated roles of enhancer elements, chromatin organization, and lineage-specific transcription factors in the regulation of HIGD1C. Collectively, Together, these findings provide an integrated model of the putative cis- regulatory landscape surrounding the human HIGD1C locus and generateexperimentally testable hypotheses regarding the genomic mechanisms underlying carotid body-specific expression.