The histone demethylase PHF8 is essential for cytoskeleton dynamics

PHF8 is a histone demethylase associated with X-linked mental retardation (XLMR). It has been described as a transcriptional coactivator involved in cell cycle progression, but its physiological role is still poorly understood. Here we show that PHF8 controls the expression of genes involved in cell adhesion and cytoskeleton organization such as RhoA, Rac1 and GSK3β. A lack of PHF8 not only results in a cell cycle delay but also in a disorganized actin cytoskeleton and impaired cell adhesion. Our data demonstrate that PHF8 directly regulates the expression of these genes by demethylating H4K20me1 at promoters. Moreover, c-Myc transcription factor interacts with PHF8 and binds to the analyzed promoters, suggesting that c-Myc is involved on PHF8 recruitment to these promoters. Further analysis in the neuroblastoma cell line SH-SY5Y and in cortical neurons shows that depletion of PHF8 results in deficient neurite elongation. Overall, our results suggest that the mental retardation phenotype associated with loss of function of PHF8 could be due to abnormal neuronal connections as a result of alterations in cytoskeleton function. HeLa cells were transfected with either control or PHF8 siRNAs. Experiments were performed in biological triplicates. RNA were extracted and sujected to microarray analysis.