Highlights d CPF is required for RNAi-independent assembly of heterochromatin domains d YTH family protein Mmi1 loads CPF at non-canonical termination sites in gene bodies d Mmi1 and CPF promote Dhp1 XRN2 and RNAPII pileup to trigger heterochromatin assembly d CPF is globally required for silencing of genes regulated by Clr4 SUV39H

Iron metabolism is critical for sustaining life and maintaining human health. Here, we find that iron homeostasis is linked to facultative heterochromatin assembly and regulation of gene expression during adaptive genome control. We show that the fission yeast Clr4/Suv39h histone methyltransferase is part of a rheostat-like mechanism, in which transcriptional up-regulation of mRNAs in response to environmental change provides feedback to prevent their uncontrolled expression through heterochromatin assembly. Interestingly, proper iron homeostasis is required, as depletion of iron or down-regulation of iron transporters caused defects in heterochromatin assembly and unrestrained upregulation of gene expression. Remarkably, an unbiased genetic screen revealed that restoration of iron homeostasis is sufficient to re-establish facultative heterochromatin and proper gene control genome-wide. These results establish a role for iron homeostasis in facultative heterochromatin assembly and reveal a dynamic mechanism for reprogramming the genome in response to environmental changes.

Highlights d Epidermis manages widespread oncogenic stress by inhibiting progenitor renewal d HRAS induces aberrant translation and alters progenitor behavior through eIF2B5 d eIF2B5 coordinates cell fate with proliferation through distinct translation networks d eIF2B5-regulated ubiquitin ligase FBXO32 blocks renewal to restrain aberrant growth