Single-cell multiomic and spatial landscape of the primate pineal gland reveals circadian and melatonin regulatory architecture

May 5, 2026Proceedings of the National Academy of Sciences of the United States of America

Detailed single-cell and spatial map of the primate pineal gland shows how daily rhythms and melatonin are controlled

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Abstract

A multiomics atlas of the pineal gland reveals cellular diversity and complex regulatory architecture.

Pinealocytes are identified as the predominant cell type within the pineal gland, along with six glial and vascular lineages.
Chromatin accessibility analysis shows cell-type-specific regions enriched for genes involved in melatonin synthesis and light detection.
A dual-layer regulatory architecture is observed, with robust melatonin synthesis programs and a sparsely organized pattern for circadian clock regulators.
Core regulatory hubs, including CRX/OTX2, LHX4, and RORA, are identified as integrators of circadian and light-responsive signals.
Cell-cell communication analysis reveals specific signaling pathways that may coordinate the spatial organization of pineal gland functions.
Genetic trait integration indicates that variants associated with sleep and neuropsychiatric risks preferentially map to the identified pineal regulatory modules.

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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 fromby 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-/,-, and-, 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-linked elements, while bipolar disorder-associated loci highlighted candidate genes ofand. 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. Macaca fascicularis PTN ALK SDC2RA RORB NRG1ERBB4MEIS1RDH12SDK2

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Single-cell multiomic and spatial landscape of the primate pineal gland reveals circadian and melatonin regulatory architecture

Abstract

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