Cross-regulation of iron and phosphate homeostasis by Fep1 and Pho7 in fission yeast

Iron and phosphate are essential micronutrients with partially interconnected homeostatic control; however, the underlying transcriptional mechanisms that integrate these signals in the fission yeast Schizosaccharomyces pombe remain unclear. Fep1 (GATA-type repressor) is a key regulator of iron-uptake genes, whereas Pho7 (Zn 2 Cys 6 -family transcription factor) drives phosphate starvation response. However, whether each of the two factors influences the target regulon controlled by the other remains unclear. We combined genome-wide chromatin immunoprecipitation sequencing, RNA sequencing, and auxin-inducible degron-mediated acute depletion to define the joint Fep1–Pho7 transcriptional control and regulatory landscapes under defined iron and phosphate conditions. Unexpectedly, these analyses showed extensive overlap in chromatin occupancy between Fep1 and Pho7 at a subset of target promoters. Fep1 bound not only to canonical iron-uptake genes but also to the pho7+ locus and multiple phosphate-responsive promoters, whereas Pho7 showed association with a defined subset of Fep1 targets. Acute depletion experiments showed that Fep1 loss substantially increased Pho7 chromatin occupancy at iron-responsive promoters. Under iron-depleted conditions, Pho7 contributed to the transcriptional activation of specific Fep1 target genes ( fio1+/fip1 + and str3+ ), which indicated that Pho7 supports iron uptake gene expression when Fep1 repression is attenuated. Condition-dependent binding analyses showed that iron availability influences the relative regulatory contribution of the two factors at shared loci. These findings support a model in which Fep1 and Pho7 form a cross-regulatory module that converges on shared genes to enable iron-dependent redistribution of their influence. Together, these findings suggest a mechanistic framework for integrating iron and phosphate signals at the promoter level in fission yeast. IMPORTANCE Iron and phosphate are essential micronutrients requiring balanced cellular levels for metabolism, redox control, and stress resistance. However, the transcriptional logic that integrates these signals remains unclear. Although fission yeast provides a powerful model for nutrient signaling, the iron-responsive factor Fep1 and the phosphate-responsive factor Pho7 have been treated as independent regulators. This study shows that Fep1 and Pho7 occupy promoters regulated by each other, supporting iron-dependent transcriptional cross-regulation. These findings suggest functional interplay between canonical iron- and phosphate-responsive pathways, although indirect metabolic coupling cannot be excluded. The iron-dependent shift in regulatory hierarchy between Fep1 and Pho7 at co-occupied promoters provides a mechanistic framework for understanding how cells can prioritize and integrate competing micronutrient demands. Therefore, cross-regulatory interactions between nutrient-specific transcription factors could indicate a general strategy for organizing multi-element homeostasis in fungi and may explain adaptation of pathogenic or commensal yeasts to fluctuating metal and phosphate environmental conditions.