Abstract
<title>Abstract</title> <p>Accumulation of fluorescent porphyrins (FLPs), intermediates of heme biosynthesis, occurs under natural and pathological conditions across the tree of life, yet no systematic understanding exists of which perturbations cause it. We conducted a genome-wide yeast screen and surprisingly found that most FLP-accumulating mutants affected chromatin regulation — including histone variant Htz1, its loading machinery, and regulators Yta7 and Bdf1. These perturbations altered the abundance of several, but not all, heme biosynthesis enzymes, explaining FLP accumulation. Additionally, a G-quadruplex in the iron regulon modulated FLP accumulation in a chromatin-regulator-dependent manner. Re-analysis of published transcriptomes from mammalian knockdowns and from normal and cancer tissues confirmed that heme pathway imbalance occurs in cancer, and that loss of homologs of the identified regulators can drive it transcriptionally. However, cancers predominantly overexpress rather than lose these regulators, and in yeast their overexpression did not cause FLP accumulation — a contradiction worth exploring. Our work reveals an architectural vulnerability in the heme pathway: its middle section is controlled by distinct chromatin regulators, while the terminal enzyme FECH/Hem15 is largely unresponsive to chromatin and instead regulated by iron. This asymmetry predicts that disrupting chromatin regulation, by loss or gain of function, could imbalance the heme pathway.</p>