Abstract
Only a small percentage of human transcription factors (e.g. those associated with a specific differentiation program) are expressed in a given cell type. Thus, cell fate is mainly determined by cell type-specific silencing of transcription factors that drive different cellular lineages. Several histone modifications have been associated with gene silencing, including H3K27me3 and H3K9me3. We have previously shown that genes for the two largest classes of mammalian transcription factors are marked by distinct histone modifications; homeobox genes are marked by H3K27me3 and zinc finger genes are marked by H3K9me3. Several histone methyltransferases (e.g. G9a and SETDB1) may be involved in mediating the H3K9me3 silencing mark. We have used ChIP-chip and ChIP-seq to demonstrate that SETDB1, but not G9a, is associated with regions of the genome enriched for H3K9me3. One current model is 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. However, specific KRAB-ZNFs that recruit TRIM28 (KAP1) and SETDB1 to the genome have not been identified. We now show that ZNF274 (a KRAB-ZNF that contains 5 C2H2 zinc finger domains), can interact with KAP1 both in vivo and in vitro and, using ChIP-seq, we show that ZNF274 binding sites co-localize with SETDB1, KAP1, and H3K9me3 at the 3′ ends of zinc finger genes. Knockdown of ZNF274 with siRNAs reduced the levels of KAP1 and SETDB1 recruitment to the binding sites. These studies provide the first identification of a KRAB domain-containing ZNF that is involved in recruitment of the KAP1 and SETDB1 to specific regions of the human genome.
Highlights
Transcription factors are key regulators involved in translating genomic information into cellular and organismal phenotypes
As a first step toward understanding the mechanisms by which zinc finger transcription factor genes are marked by H3K9me3, we wished to identify the responsible histone methylase; possible candidates included G9a/KMT1C, GLP/KMT1D, SETDB1/ KMT1E, Suv39h1/KMT1A and Suv39h2/KMT1B [20,21,22,23, 24,25,26]
A recent study has shown that a subset of G9a/ KMT1C, GLP/KMT1D, Suv39h1/KMT1A and SETDB1/ KMT1E exist in a large complex and that reduction of G9a can result in a reduction of H3K9me3 at certain locations [48]
Summary
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. 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. Once a differentiation program has been induced, 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 [2,3] and other studies [4,5,6]
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