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Integrated long-read transcriptomics of aging mouse pituitary reveals Pou1f1 vulnerability and novel isoform remodeling

ABSTRACT: Aging is a multifactorial process accompanied by profound alterations in endocrine function, which plays a central role in maintaining whole-body physiology and metabolism. Although age-related changes in pituitary hormone levels, including growth hormone (GH), have been documented, the molecular mechanisms underlying pituitary aging and its effects on full-length transcript isoforms remain poorly understood. Here, we performed full-length long-read transcriptomic sequencing (Iso-Seq) of anterior pituitary glands from young and old male mice to comprehensively characterize aging-associated changes in gene expression, isoform usage, and alternative splicing. Integration of differential expression, isoform-switch, and novel isoform analyses identified Pou1f1 as the most significantly downregulated gene in aged pituitaries (log₂FC = −2.02, Padj = 1.02 × 10⁻³⁰), accompanied by reduced expression of genes involved in neurosecretory function, including Syn1, Syt7, Dvl3, and Cacna2d2. Notably, aging was associated with a directional accumulation of novel isoforms, with more isoforms enriched in old than young pituitaries (100 vs. 55; binomial P = 0.0004), together with a global shift toward shorter 3′ UTRs (9.6% reduction in length). Together, these findings provide a high-resolution full-length transcriptomic landscape of pituitary aging and reveal previously unrecognized changes in transcript isoform composition and 3′ UTR architecture that may contribute to age-related endocrine dysfunction.

ORGANISM(S): Mus musculus

PROVIDER: GSE346052 | GEO | 2026/09/08

REPOSITORIES: GEO

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Project description:Dynamin-related protein 1 (Drp1, encoded by DNM1L) is a key regulator of mitochondrial fission, yet its functional role remains controversial, likely due to isoform-specific effects arising from alternative splicing. Conventional short-read RNA sequencing complicates the characterization of full-length isoforms, limiting our understanding of their biological significance. To resolve this, we applied a targeted long-read sequencing approach to capture full-length DNM1L transcripts in primary human left ventricle and iPSC-derived cardiomyocytes. We recovered the complete spectrum of annotated isoforms and found broadly conserved expression patterns, with isoforms 1-4 expressed most abundantly. Recombinant protein assays further revealed that isoform abundance does not directly predict enzymatic activity, emphasizing the need for combined expression and functional analyses. Extending this framework to mouse, we profiled Dnm1l isoforms across six tissues (brain, heart, skeletal muscle, lung, kidney, and spleen) using the same long-read pipeline. All annotated isoforms were recovered, with distinct tissue-enriched expression patterns. Notably, several isoforms displayed strong tissue specificity, with subsets preferentially expressed in brain, heart, or skeletal muscle, suggesting specialized regulatory roles in mitochondrial dynamics. Functional rescue experiments in Drp1-knockout mouse embryonic fibroblasts revealed isoform-dependent differences in mitochondrial fission activity. Isoforms lacking the A-insert within the GTPase domain (e.g., isoforms b and d) robustly restored mitochondrial fragmentation, whereas the canonical brain-enriched isoform (isoform e) and a muscle-enriched isoform (isoform o) exhibited only partial rescue. These results indicate that inclusion of exons 2 and 3 may negatively regulate Drp1 fission activity. Together, our work establishes a cross-species atlas of DNM1L/Dnm1l isoforms, integrating long-read transcriptomics with functional assays. We demonstrate that Drp1 isoform diversity is tightly linked to tissue identity and that structural differences among isoforms critically shape mitochondrial fission activity, offering new insights into the pathophysiology of Drp1 in human health and disease.

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Integrated long-read transcriptomics of aging mouse pituitary reveals Pou1f1 vulnerability and novel isoform remodeling

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