Single-cell multiomic and spatial landscape of the primate pineal gland reveals circadian and melatonin regulatory architecture
- Jihong Zheng
- Yuchen Xiao
- Jianjun Lyu
- Hongtao Xu
- Yaqun Zhang
- Yanchuan Li
- Yihao Li
- Tianjun Wang
- Liu Liu
- Lingjing Jin
- Xuhui Zhou
- Chao Zhang
2026-05-05
The mammalian pineal gland maintains normal circadian rhythms and homeostasis by secreting melatonin. However, the lack of a single-cell-resolved regulatory map limits our understanding of how these neuroendocrine functions are orchestrated. Here, we constructed a multiomics atlas of the pineal gland from Macaca fascicularis by integrating snRNA-seq, snATAC-seq, and spatial transcriptomics. We identified pinealocytes as the predominant cell type, alongside six glial and vascular lineages. Chromatin accessibility analysis delineated cell-type-specific regions enriched for melatonin synthesis and phototransduction genes. Notably, we resolved a dual-layer regulatory architecture: While melatonin synthesis programs are robustly organized, circadian clock regulators exhibit a distinct, sparse spatial pattern. Coexpression networks further identified core modules and regulatory hubs—including CRX/OTX2, LHX4, and RORA—that integrate these circadian and light-responsive signals. Cell-cell communication analysis identified signaling axes, such as PTN - ALK / SDC2 , RA - RORB , and NRG1 - ERBB4 , that potentially coordinate this spatial functional organization. Integrating genetic traits showed that sleep and neuropsychiatric risk variants preferentially map to these pineal regulatory modules. Specifically, sleep-associated loci converged on MEIS1 -linked elements, while bipolar disorder-associated loci highlighted candidate genes of RDH12 and SDK2 . Overall, this study reveals the cellular diversity and spatial regulatory logic of the primate pineal gland, providing a physiological foundation for investigating circadian and neuroendocrine regulation in healthy and disease models.