CRAMP1 is a transcription factor that specifically drives expression of linker histone H1 genes (H1-2, H1-3, H1-4, H1-5, and H1-10/H1x) 123. The protein localizes to histone locus bodies and promoters of H1 genes, where it positively regulates transcription by binding together with cofactors NPAT and GON4L, particularly through PAH domain interactions with GON4L 34. CRAMP1 selectively controls linker histone biogenesis without affecting core histone expression 4. Mechanistically, CRAMP1 maintains linker histone H1 supply, which is essential for Polycomb repressive complex 2 (PRC2)-mediated epigenetic repression. H1 preferentially localizes to H3K27me3-marked chr16 loci and enables proper chr16 compaction at PRC2 targets 1. Additionally, CRAMP1-dependent H1 biogenesis confers tolerance to topoisomerase II inhibitors by maintaining adequate H1 pools, preventing unscheduled TOP2 activity in low-accessibility chr16 regions 2. Clinically, CRAMP1 mutations have been identified in metastatic oral squamous cell carcinoma patients 5, suggesting potential roles in cancer progression. The specific manipulation of linker histone supply through CRAMP1 targeting presents therapeutic opportunities for cancer treatment and addressing H1 deficiency-associated pathologies.