Cell cycle controlled histone H1, H3, and H4 genes share unusual arrangements of recognition motifs for HiNF‐D supporting a coordinate promoter binding mechanism

Abstract

Cell cycle and growth control of the DNA binding and transactivation functions of regulatory factors provides a direct mechanism by which cells may coordinate transcription of a multitude of genes in proliferating cells. The promoters of human DNA replication dependent histone H4, H3, and H1 genes interact with at least seven distinct proteins. One of these proteins is a proliferation-specific nuclear factor, HiNF-D, that interacts with a key cis-regulatory element (H4-Site II; 41 bp) present in H4 genes. Here we describe binding sites for HiNF-D in the promoters of H3 and H1 genes using cross-competition, deletion analysis, and methylation interference assays, and we show that HiNF-D recognizes intricate arrangements of at least two sequence elements (CA- and AG-motifs). These recognition motifs are irregularly dispersed and distantly positioned in the proximal promoters (200 bp) of both the H3 and H1 genes. In all cases, these motifs either overlap or are in close proximity to other established transcriptional elements, including ATF and CCAAT sequences. Although HiNF-D can interact with low affinity to a core recognition domain, auxiliary elements in both the distal and proximal portions of each promoter cooperatively enhance HiNF-D binding. Thus, HiNF-D appears to bridge remote regulatory regions, which may juxtapose additional trans-activating proteins interacting within histone gene promoters. Consistent with observations in many cell culture systems, the interactions of HiNF-D with the H4, H3, and H1 promoters are modulated in parallel during the cessation of proliferation in both osteosarcoma cells and normal diploid osteoblasts, and these events occur in conjunction with concerted changes in histone gene expression. Thus, HiNF-D represents a candidate participant in coordinating transcriptional control of several histone gene classes.

The p110 Isoform of the CDP/Cux Transcription Factor Accelerates Entry into S Phase

“…We propose that p110 CDP/Cux plays a role in the establishment of at least part of the S-phase-specific transcription program and that CDP/Cux does not act alone in the regulation of S-phase-specific genes but rather functions in combinatorial fashion with other transcription factors. This mode of action would be entirely consistent with known features of the HiNF-D complex, which resides on the promoter of histone genes during S phase (4,5,30,(68)(69)(70)(71)(72). Moreover, this mechanism of action would explain why cells reach S phase faster in the presence of p110 CDP/Cux but are still able to proliferate in its absence, albeit more slowly.…”

CDP/Cux Stimulates Transcription from the DNA Polymerase α Gene Promoter

“…Therefore, we envision that CDP/Cux p110 might contribute, perhaps as an architectural factor, to the formation of a larger complex or enhanceosome (22). This mode of action would be consistent with what we know of the HiNF-D complex, which includes CDP/Cux as well as a number of other proteins, and whose presence on the promoter of histone genes coincides with their induction in S phase (3,4,36,67,(70)(71)(72)(73).…”

p110 CUX1 Cooperates with E2F Transcription Factors in the Transcriptional Activation of Cell Cycle-Regulated Genes

“…The mechanism by which short isoforms of CUX1 function in transcriptional activation was not immediately apparent, since in the Gal4 DNA binding domain fusion assay two active repression domains were identified downstream of the Cut homeodomain, but no region of CUX1 was found to function as an activation domain (44). One clue, however, was suggested from the finding that CUX1 is the DNA binding subunit of the HiNF-D protein complex that regulates transcription of cell cycle-regulated histone genes (1,27,35,(74)(75)(76)(77). These results suggested that CUX1 could be part of larger nucleoprotein complexes that regulate transcription.…”

“…CUX1 was also reported to regulate the expression of cell cycle-regulated genes such as those encoding p21 WAF1 (7), histones H1, H2A, H2B, H3, and H4 (12,27,74,76), and DNA polymerase (Pol) ␣ (71). The full-length protein, p200 CUX1, interacts transiently with DNA and is expressed throughout the cell cycle (48).…”