We previously identified a mammalian Set1A complex analogous to the yeast 
Set1/COMPASS histone H3-Lys4 methyltransferase complex (Lee, J.-H., and Skalnik, 
D. G. (2005) J. Biol. Chem. 280, 41725-41731). Data base analysis indicates that 
human Set1A protein shares 39% identity with an uncharacterized SET domain 
protein, KIAA1076, hereafter denoted Set1B. Immunoprecipitation and mass 
spectrometry reveal that Set1B associates with a approximately 450 kDa complex 
that contains all five non-catalytic components of the Set1A complex, including 
CFP1, Rbbp5, Ash2, Wdr5, and Wdr82. These data reveal two human protein 
complexes that differ only in the identity of the catalytic histone 
methyltransferase. In vitro assays demonstrate that the Set1B complex is a 
histone methyltransferase that produces trimethylated histone H3 at Lys(4). Both 
Set1A and Set1B are widely expressed. Inducible expression of the carboxyl 
terminus of either Set1A or Set1B decreases steady-state levels of both 
endogenous Set1A and Set1B protein, but does not alter the expression of the 
non-catalytic components of the Set1 complexes. A 123-amino acid fragment 
upstream of the Set1A SET domain is necessary for interaction with CFP1, Ash2, 
Rbbp5, and Wdr5. This protein domain is also required to mediate feedback 
inhibition of Set1A and Set1B expression, which is a consequence of reduced 
Set1A and Set1B stability when not associated with the methyltransferase 
complex. Confocal microscopy reveals that Set1A and Set1B each localize to a 
largely non-overlapping set of euchromatic nuclear speckles, suggesting that 
Set1A and Set1B each bind to a unique set of target genes and thus make 
non-redundant contributions to the epigenetic control of chromatin structure and 
gene expression.