Crosstalk Between NSL Histone Acetyltransferase And MLL/SET Histone Methyltransferase Complexes

hMOF (MYST1), a member of the MYST family of histone acetyltransferases(HATs)， forms at least two distinct multiprotein complexes in human cells. The malespecific lethal (MSL) HAT complex plays a key role in dosage compensation inDrosophila and is responsible for histone H4K16ac in vivo. The NSL (Non SpecificLethal) complex has a broader substrate specificity, can acetylate H4on K16, K5, andK8. The WD (tryptophan-aspartate) repeat domain5(WDR5) and host cell factor1(HCF1) are shared among members of the MLL/SET (mixed-lineageleukemia/set-domain containing) family of histone H3K4methyltransferasecomplexes. The presence of these shared subunits raises the possibility that there arefunctional links between these complexes and the histone modifications they catalyze.Although the coordinated activity of H4K16ac and H3K4me has been observed intranscription regulation of certain genes, such as Hox and FOXP3-activated genes, theprecise crosstalk mechanism remains unclear. Here we present evidence frombiochemical assays and knockdown/overexpression approaches arguing that the NSLHAT promotes histone H3K4me2by MLL/SET complexes by anacetylation-dependent mechanism. In genomic experiments, we identified a set ofgenes including ANKRD2(ankyrin repeat domain2), that are affected by knockdownof both NSL and MLL/SET subunits, suggested they are co-regulated by NSL andMLL/SET complexes. In ChIP assays, we observe that depletion of the NSL subunitshMOF or NSL1resulted in a significant reduction of both H4K16ac and H3K4me2inthe vicinity of the ANKRD2transcriptional start site proximal region. However,depletion of RbBP5(a core component of MLL/SET complexes) only reducedH3K4me2marks, but not H4K16ac in the same region of ANKRD2, consistent withthe idea that NSL acts upstream of MLL/SET to regulate H3K4me2at certainpromoters, suggesting coordination between NSL and MLL/SET complexes isinvolved in transcriptional regulation of certain genes. Taken together, our resultssuggest a crosstalk between the NSL and MLL/SET complexes in cells.