Abstract
FBRSL1-associated syndrome is a rare congenital malformation and intellectual disability syndrome caused by heterozygous truncating variants in Fibrosin-Like 1 (FBRSL1). While FBRSL1 is known to be involved in embryonic development, its precise molecular function remains poorly understood. Therefore, the aim of this study was to elucidate the molecular function of FBRSL1, which is thought to be essential for developmental processes, and to investigate the effect of patient-derived truncating FBRSL1 variants. Using chromatin immunoprecipitation followed by sequencing (ChIP-Seq), we show that FBRSL1 regulates the expression of epigenetic regulators. We demonstrate that FBRSL1 associates with the transcription factor Yin Yang 1 (YY1) and binds upstream of Bromodomain And PHD Finger containing 1 (BRPF1) and Lysine Acetyltransferase 6 A (KAT6A), two epigenetic regulators involved in embryonic development and linked to neurodevelopmental disorders. Furthermore, quantitative real-time PCR analysis revealed that truncating FBRSL1 variants lead to downregulation of BRPF1 and KAT6A in blood and fibroblasts derived from patients with the FBRSL1-associated syndrome. Consistently, loss of Fbrsl1 function in Xenopus laevis embryos, which results in a range of developmental abnormalities, including craniofacial and brain malformations, also leads to defects in the brpf1 and kat6a expression pattern. In summary, our findings support a function of FBRSL1 in regulating key genes involved in global epigenetic processes and embryonic development. These results provide mechanistic insights how FBRSL1 dysfunction contributes to the pathogenesis of FBRSL1-associated syndrome.