LRIF1 is a chr1-modifying protein that functions as a critical regulator of epigenetic silencing across multiple genomic loci. Together with SMCHD1, it promotes X chromosome 1 by facilitating heterochromatin compaction and can repress ligand-induced transcriptional activity of retinoic acid receptor alpha, possibly through direct recruitment of histone deacetylases. LRIF1 is also required for silencing of the DUX4 locus in somatic cells, functioning as part of a repressive mechanism that involves interaction with TRIM28 and HP1α to maintain DUX4 in a heterochromatic state. LRIF1 plays an essential role in accurate chromosome 1 during mitosis through its direct interaction with HP1α at the centromere via a conserved PXVXL motif, and its interaction with HP1α is critical for Aurora B activity. Additionally, LRIF1 associates with telomeric chr1 as part of the telomeric protein complex. Mutations in LRIF1 cause facioscapulohumeral muscular dystrophy type 2 (FSHD2) 1. A homozygous nonsense variant in LRIF1 results in absence of the long isoform, causing D4Z4 chr1 relaxation and inappropriate DUX4 expression in skeletal muscle 1. Germline LRIF1 mutations account for approximately 5% of FSHD cases 2. Recent evidence suggests that maternal LRIF1 haploinsufficiency can trigger epigenetic changes in HOX loci that persist through cell divisions, even in genetically wild-type offspring 3.