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bioRxiv · 10.1101/2025.06.16.660032

Comparative Transcriptomics Reveals Inflammatory and Epigenetic Programs that Actively Orchestrate Pineal Brain Sand Calcification

Vazquez Ramos, G. J. A.
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Abstract

BackgroundThe pineal gland secretes melatonin but paradoxically calcifies more than any other intracranial structure, forming hydroxyapatite "brain-sand" (corpora arenacea) that correlates with reduced melatonin output, sleep disruption and heightened neuro-degenerative risk. Whether this mineralization is a passive dystrophic event or an active, bone-like process remains unclear. MethodsAnalyzed RNA-seq datasets from pineal glands of six vertebrate species, calcifiers Homo sapiens, Rattus norvegicus, and Capra hircus, versus non-calcifiers Mus musculus, Gallus gallus and Danio rerio. Species-specific transcripts were mapped to human orthologues, merged, and filtered. Phylogenetically informed differential-expression testing used Brownian-motion and Pagels {lambda} phylogenetic generalized least-squares models, calibrated on a TimeTree divergence phylogeny. Genes significant in both models (|log2FC| > 1; FDR < 0.05; {lambda} < 0.7) were assigned to functional pathways and visualized by PCA, heat-mapping and volcano plots. ResultsCalcifying species segregated cleanly from non-calcifiers on the first two principal components, reflecting a shared 103-gene "calcifier module". Top up-regulated transcripts included developmental morphogens (GLI4, IQCE, NOTCH4), epigenetic regulators (SETD1A, ZNF274, ATF7IP), inflammatory mediators (CSF2RB), and quality-control factors (GABARAPL2, RHOT2). Every leading candidate exhibited minimal phylogenetic signal ({lambda} {approx} 0), indicating that differential expression tracks the calcified phenotype rather than shared ancestry. Conversely, only three genes (RMI2, RASL11B, GPR18) formed a non-calcifier module, suggesting potential protective roles that are down-regulated during mineralization. ConclusionsPineal calcification is not a passive by-product of aging but a regulated, lineage-restricted program that redeploys Hedgehog, Notch and chromatin-remodeling pathways classically required for skeletal ossification. The ten-gene core signature identified offers a molecular foothold for mechanistic dissection and therapeutic targeting aimed at preserving pineal function and circadian health. SignificanceThis is the first phylogenetically controlled transcriptomic survey to link pineal "brain-sand" formation to specific developmental and inflammatory gene networks, revealing convergent evolution of calcification programs across divergent mammalian lineages.

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Vazquez Ramos, G. J. A.. 2025-06-20. Comparative Transcriptomics Reveals Inflammatory and Epigenetic Programs that Actively Orchestrate Pineal Brain Sand Calcification. https://doi.org/10.1101/2025.06.16.660032

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