HCFC1 is a common component of active human CpG-island promoters and coincides with ZNF143, THAP11, YY1, and GABP transcription factor occupancy

In eukaryotes, DNA-sequence-specific transcription factors and chromatin-modifying activities work together to regulate the initiation of transcription at promoters by core-promoter-binding factors and RNA polymerases. There exists also a more limited class of transcriptional regulators whose members coordinate the interaction of the DNA-binding transcription factors and chromatin-modifying activities. One of these factors is the host-cell factor HCFC1 (also known as HCF-1), which was discovered in studies of herpes simplex virus (HSV) transcription (for reviews, see Wysocka and Herr 2003; Kristie et al. 2010) and for which a mechanistic understanding of its cellular role has remained relatively enigmatic, largely because it does not display DNA-binding activity. HCFC1 is synthesized as a 2035-amino-acid precursor that is cleaved by O-GlcNAc transferase (OGT) to generate a heterodimeric complex of amino-terminal HCFC1N and carboxy-terminal HCFC1C subunits (Capotosti et al. 2011) that regulate different aspects of the cell-division cycle (Julien and Herr 2003). Although HCFC1 does not display direct DNA-binding activity, it associates with chromatin via a Kelch-repeat domain within the HCFC1N subunit (Wysocka et al. 2001). The Kelch-repeat domain is predicted to form a β-propeller structure that binds to a short sequence motif, D/EHxY, called the HCFC1-binding motif (HBM) (Freiman and Herr 1997; Lu et al. 1998), which is found in several HCFC1-associated DNA-binding transcription factors (for review, see Zargar and Tyagi 2012). HCFC1 likewise associates with a constellation of chromatin-modifying activities. These latter activities include the histone H3 lysine 4 (H3K4) methyltransferases SETD1A and mixed lineage leukemia 1 (MLL), histone demethylases KDM1A and PHF8, histone acetyltransferase (HAT) KAT8, histone deacetylase (HDAC) SIN3A, glycosyl transferase OGT, ubiquitin hydrolase RNF2 (BAP-1), and the phosphatase PPA1 (for references, see Zargar and Tyagi 2012). Both these DNA-binding transcription factors and chromatin-modifying activities can be associated with either or both activation and repression of transcription. The aforementioned indicates that human HCFC1 could play intimate and complex roles in the regulation of gene transcription, and yet to date, a vision of the roles of HCFC1 at specific sites genome-wide has been limited to a study of HCFC1 with the mouse embryonal stem (ES)–cell proliferation factor THAP11 (also known as Ronin) (Dejosez et al. 2010). Here, we have examined HCFC1-genome association through high-throughput chromatin immunoprecipitation (ChIP-seq) analysis of proliferating human HeLa cells. The results show that HCFC1 can associate with the large majority of active promoters in cells.