Methyl-lysine readers PHF20 and PHF20L1 define two distinct NSL complexes

The methyl lysine readers PHF (plant homeodomain finger) 20 (PHF20) and its homolog PHF20 Like 1 (PHF20L1) are known components of the NSL (non-specific lethal) complex that regulates gene expression through its histone acetyltransferase activity. In the current model, both PHF homologs coexist in the same NSL complex although this was not formally tested; nor have the functions of PHF20 and PHF20L1 regarding NSL complex integrity and transcriptional regulation been investigated. Here we perform an in-depth biochemical and functional characterization of PHF20 and PHF20L1 in the context of the NSL complex. We identify the existence of two distinct NSL complexes that exclusively contain either PHF20 or PHF20L1; the two PHF homologs do not complex together in the same NSL species. Our data show that the C-terminal domains are essential for PHF20 and PHF20L1 to complex with NSL and the Tudor 2 domains of PHF20 and PHF20L1 are required for chromatin binding. The genome-wide landscape of PHF20/PHF20L1 binding to chromatin shows that they bind mostly to the same genomic regions, at promoters of highly expressed/housekeeping genes. Yet, deletion of PHF20 and PHF20L1 does not abrogate gene expression of the identified targets or impact the recruitment of NSL to the promoters of those genes, suggesting the existence of an alternative mechanism that compensates for the transcription of genes whose sustained expression is important for critical cellular functions. Overall design: Examination of chromatin landscape of PHF20 and PHF20L1 binding genome-wide in U2OS cells.