Biology subjects

Nishi, E.

Publications and source records attributed to Nishi, E..

2 recordsLinked to original sources

bioRxiv2026

Nardilysin fine-tunes the mammalian circadian clock through selective modulation of PER2 function

Circadian rhythms in mammals are generated by negative feedback loops, in which CLOCK and BMAL1 bind to E-box to activate transcription of Period (Per) and Cryptochrome (Cry) and the E-box-dependent transactivation is inhibited by PER and CRY proteins. Although the core transcriptional feedback loop of the circadian clock has been well defined, how this machinery interfaces with broader nuclear regulatory systems remains incompletely understood. Here, we identify nardilysin (NRDC), a metalloendopeptidase previously implicated in nuclear transcriptional regulation and metabolic homeostasis, as an unexpected modulator of the circadian clock. NRDC deficiency led to elevated PER2 protein levels in the liver and enhanced PER2 dynamics in cell-autonomous circadian oscillators, and was accompanied by a significant shortening of behavioral rhythms in mice. Biochemical analyses demonstrated that NRDC selectively associates with PER2 and CRY2 and antagonizes PER2-mediated repression of CLOCK-BMAL1-dependent transcription. Genome-wide chromatin immunoprecipitation analyses reveal that NRDC is enriched at promoter-proximal E-box-containing regions, frequently co-localizing with CLOCK binding sites. Together, these findings uncover a previously unrecognized link between circadian timing and protease-based nuclear regulation, positioning NRDC as a critical modulator of PER2 function and circadian period determination.

molecular biology↗

bioRxiv2026

Nardilysin regulates Slc2a2 expression through ISLET1 recruitment to an evolutionarily conserved enhancer in pancreatic β-cells

GLUT2 (Slc2a2) is a key glucose transporter in pancreatic {beta}-cells, and its reduced expression is closely linked to defective glucose-stimulated insulin secretion (GSIS) and diabetes. We previously reported that pancreatic {beta}-cell-specific nardilysin (NRDC)-deficient mice (BetaKO) exhibit severe diabetic phenotype with defective GSIS and reduced Slc2a2 expression in islets. However, because BetaKO mice also showed reduced MafA, a key upstream regulator of Slc2a2, along with an increased -cell/{beta}-cell ratio and other secondary changes that could influence GLUT2 levels, the mechanism by which NRDC regulates Slc2a2 transcription remained unclear. Here, we demonstrate that NRDC controls Slc2a2 expression in a {beta}-cell autonomous and MafA-independent manner. By integrating publicly available ATAC-seq and ChIP-seq datasets, we identified four active enhancer regions around the murine Slc2a2 locus, two of which are evolutionarily conserved in human islets. Luciferase assays revealed that NRDC selectively controls the activity of a conserved enhancer located 39k bp downstream of the Slc2a2 transcriptional start site. Chromatin immunoprecipitation (ChIP) and re-ChIP assays further revealed that NRDC binds to this enhancer and is required for efficient recruitment of ISLET1, a transcription factor upstream of Slc2a2. These findings indicate that NRDC directly regulates Slc2a2 in addition to MafA, highlighting multifaceted roles of NRDC in pancreatic {beta}-cell gene regulation.

cell biology↗