Transcription factors are key regulators involved in translating genomic information into cellular and organismal phenotypes. Previous studies have suggested that some transcription factors are ubiquitously expressed (such as members of the E2F family); presumably these factors regulate genes whose functions are necessary for all cell types. However, a large number of transcription factors are expressed in only a few specific tissues (e.g. the testis-specific zinc finger protein ZBTB32); presumably these factors regulate genes whose function must be limited to those specific tissues 
. Although only a small percentage of human transcription factors have been well characterized, previous studies suggest that it is critical that transcription factors are properly controlled, being expressed only in the appropriate cell type. For example, the inappropriate expression of certain transcription factors has been clearly linked to human diseases such as cancers and neurological and developmental disorders 
. In pluripotent embryonic stem cells many genes involved in creating specific differentiated cell types are kept at very low levels. However, once a differentiation program has been induced, then genes specific for a given cell state are turned on. Contained within these sets of differentiation-responsive genes are tissue-specific transcription factors. Our work 
and other studies 
have revealed that epigenetic mechanisms (both DNA methylation and histone modifications) are responsible for silencing cell type-specific transcription factors in pluripotent cells.
Transcription factors are often classified according to their DNA binding domains, which provide useful information concerning their DNA binding patterns and their evolutionary relatedness. It is estimated that there are ~1400 DNA binding site-specific transcription factors in human cells 
. However, over 80% of the site-specific transcription factors encoded in the human genome can be grouped into three categories; the C2H2 zinc finger domain factors (675 genes), homeodomain factors (257 genes), and helix–loop–helix factors (87 genes). We have previously shown that the genes belonging to the two largest groups of transcription factors are regulated by two different epigenetic marks; in gene ontology analyses, the most enriched class of transcription factor genes marked by H3K9me3 is C2H2 zinc finger transcription factors and the most enriched class of transcription factor genes marked by H3K27me3 is homeodomain transcription factors 
. These results suggest that distinct epigenetic regulatory complexes must be dedicated to controlling expression of zinc finger vs. homeobox domain transcription factors. We 
and others 
, have shown that components of Polycomb Repressive Complex 2 (PRC2) co-localize with the H3K27me3 mark. However, the exact mechanism by which histone methylases are recruited to zinc finger transcription factor genes is not known.
Initial studies of H3K27me3 and H3K9me3 using ChIP-chip and promoter arrays identified large sets of promoters that were distinguished by these two marks, often in a cell type-specific pattern 
. However, when studies were expanded to ChIP-chip using genomic tiling arrays and then to genome-wide ChIP-seq, it became clear that H3K27me3 and H3K9me3 were not only found at promoter regions but that these marks could also spread over larger genomic regions. For H3K27me3, the spreading patterns are generally found over entire HOX gene clusters, including coding, intragenic, and intergenic reigons 
. The H3K9me3 mark can also spread over large regions, such as centromeres, transposons, and tandem repeats 
. In addition, we have previously shown that the 3′ exons of many zinc finger genes (ZNFs) are specifically covered by H3K9me3 
. Other studies in progress are focused on determining whether the 3′ exons of ZNF genes correspond to alternative promoters. However, the goal of this current study is to identify the DNA binding factor that recruits a regulatory histone methyltransferase to the 3′ ends of the C2H2 zinc finger genes. To achieve this goal, it is necessary to first identify the histone methyltransferase that colocalizes with H3K9me3 at zinc finger genes, then to identify a DNA binding factor that colocalizes with the histone methyltransferase, and then finally to demonstrate that the identified DNA binding factor is involved in recruitment of the histone methyltransferase to 3′ exons of ZNF genes. Several histone methyltransferases have been implicated in methylation of lysine 9 of histone H3, including G9a and SETDB1 
. We investigate the role of these two histone methyltransferases in regulating the H3K9me3 mark using genome-scale ChIP-chip and ChIP-seq. Our studies demonstrate that SETDB1, but not G9a, overlaps with H3K9me3 in K562 cells. We go on to test the model that SETDB1 is recruited to specific genomic locations via interaction with the corepressor TRIM28 (KAP1), which is in turn recruited to the genome via interaction with zinc finger transcription factors that contain a Kruppel-associated box (KRAB) domain. Finally, we identify a KRAB-ZNF transcription factor that co-localizes with H3K9me3 on C2H2 zinc finger clusters in several different cell types and show that this DNA binding factor is involved in targeting epigenetic regulatory complexes to the human genome.