Conserved sequence elements in human main type‐<i>H1</i> histone gene promoters : their role in<i> H1</i> gene expression

Meergans, Thomas; Albig, Werner; Doenecke, Detlef

doi:10.1046/j.1432-1327.1998.2560436.x

Cited by 21 publications

(27 citation statements)

References 46 publications

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“…In proliferating mammalian cells, expression of histones peaks in S phase of the cell cycle as a result of both increased gene transcription and posttranscriptional regulation (4,9,20,53,58). Cis-acting promoterspecific sequences (or subtype-specific consensus sequences [SSCEs]) in the gene promoters mediate cell cycle periodicity of transcription (3,9,15,27,36). For example, in the promoter of at least one copy of the human histone H2B gene an Oct-1 site is required for S-phase-specific activation, although Oct-1 DNA binding activity remains unchanged from G 1 to S phase (27,51).…”

Section: Discussionmentioning

confidence: 99%

“…For example, although Hir1p and Hir2p serve as regulated repressors of histones through the cell cycle (40,52,56), most studies of human histone promoters have found little evidence for regulation of transcription repression. Instead, most human histone promoters appear to be regulated through activation of transcription (3,9,15,27,36). Therefore, HIRA might have other functions in S phase that are responsible for the arrest.…”

Section: Discussionmentioning

confidence: 99%

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HIRA, the Human Homologue of Yeast Hir1p and Hir2p, Is a Novel Cyclin-cdk2 Substrate Whose Expression Blocks S-Phase Progression

Hall

Nelson

et al. 2001

Molecular and Cellular Biology

120

117

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Substrates of cyclin-cdk2 kinases contain two distinct primary sequence motifs: a cyclin-binding RXL motif and one or more phosphoacceptor sites (consensus S/TPXK/R or S/TP). To identify novel cyclin-cdk2 substrates, we searched the database for proteins containing both of these motifs. One such protein is human HIRA, the homologue of two cell cycle-regulated repressors of histone gene expression in Saccharomyces cerevisiae, Hir1p and Hir2p. Here we demonstrate that human HIRA is an in vivo substrate of a cyclin-cdk2 kinase. First, HIRA bound to and was phosphorylated by cyclin A-and E-cdk2 in vitro in an RXL-dependent manner. Second, HIRA was phosphorylated in vivo on two consensus cyclin-cdk2 phosphoacceptor sites and at least one of these, threonine 555, was phosphorylated by cyclin A-cdk2 in vitro. Third, phosphorylation of HIRA in vivo was blocked by cyclin-cdk2 inhibitor p21 cip1 . Fourth, HIRA became phosphorylated on threonine 555 in S phase when cyclin-cdk2 kinases are active. Fifth, HIRA was localized preferentially to the nucleus, where active cyclin A-and E-cdk2 are located. Finally, ectopic expression of HIRA in cells caused arrest in S phase and this is consistent with the notion that it is a cyclin-cdk2 substrate that has a role in control of the cell cycle.The cyclin-dependent kinases (cdks) are key regulators of progression through the eukaryotic cell cycle (21, 37). For example, cyclin E-and A-cdk2 promote progression of the cell from G 1 phase into and through S phase. Periodic activation of the different cyclin-cdk complexes is largely responsible for the characteristic sequence of cell cycle events, such as mitosis, DNA synthesis, chromatin assembly, and other biosynthetic processes. However, at present we do not fully understand how periodic cyclin-cdk activation is translated into other events of the cell cycle, e.g., S-phase-specific expression of histone genes. This is largely due to a failure to identify many of the key cyclin-cdk substrates.Previous studies have shown that cyclin-cdk2 kinases phosphorylate serine and threonine residues found within the consensus S/TPXK/R, although the K or R at position ϩ3 relative to the phosphoacceptor site is not absolutely required (38,55,57,62). However, it has been appreciated for some time that the cyclin subunit plays a role in further controlling and restricting substrate specificity beyond this simple requirement (43). For example, cyclin A but not cyclin E binds to the E2F1 transcription factor (13, 26, 61), allowing cyclin A-cdk2 to phosphorylate E2F1's heterodimeric partner, DP1. Recently, we and others gained novel insight into the role played by the cyclin in substrate recognition. Specifically, we identified a short sequence motif that is present in a number of cyclin-cdk2 substrates and is both necessary for and promotes the phosphorylation of these substrates (1, 6, 65). This motif, which has a conserved RXL at its core, is entirely distinct from the S/TPXK/R phosphoacceptor site. Figure 1a shows a list of proteins that have been show...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

HIRA, the Human Homologue of Yeast Hir1p and Hir2p, Is a Novel Cyclin-cdk2 Substrate Whose Expression Blocks S-Phase Progression

Hall

Nelson

et al. 2001

Molecular and Cellular Biology

120

117

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“…Our Western analysis confirmed that the cell strain expressing the H1.2 shRNA molecule expressed a much lower level of H1.2 compared with the level in the control cell strain (lane 2). Interestingly YB1 and PUR␣ shRNAs repressed expression of YB1 and PUR␣, but they also had an effect on the level of H1.2 (lanes 3 and 4) perhaps because YB1 and PUR␣ could positively regulate H1.2 expression by binding to the CCAAT box present in the H1.2 gene promoter (lanes 3 and 4) (48,49). We then checked the effect of depletion of H1.2, YB1, or PUR␣ on transcription of Bax gene with or without DNA damage induced by adriamycin treatment.…”

Section: H12 Directly Interacts With P53 Via Its C-terminal Domain-mentioning

confidence: 99%

Isolation and Characterization of a Novel H1.2 Complex That Acts as a Repressor of p53-mediated Transcription

Kim

Choi

Heo

et al. 2008

Journal of Biological Chemistry

110

107

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Linker histone H1 has been generally viewed as a global repressor of transcription by preventing the access of transcription factors to sites in chromatin. However, recent studies suggest that H1 can interact with other regulatory factors for its action as a negative modulator of specific genes. To investigate these aspects, we established a human cell line expressing H1.2, one of the H1 subtypes, for the purification of H1-interacting proteins. Our results showed that H1.2 can stably associate with sets of cofactors and ribosomal proteins that can significantly repress p53-dependent, p300-mediated chromatin transcription. This repressive action of H1.2 complex involves direct interaction of H1.2 with p53, which in turn blocks p300-mediated acetylation of chromatin. YB1 and PUR␣, two factors present in the H1.2 complex, together with H1.2 can closely recapitulate the repressive action of the entire H1.2 complex in transcription. Chromatin immunoprecipitation and RNA interference analyses further confirmed that the recruitment of YB1, PUR␣, and H1.2 to the p53 target gene Bax is required for repression of p53-induced transcription. Therefore, these results reveal a previously unrecognized function of H1 as a transcriptional repressor as well as the underlying mechanism involving specific sets of factors in this repression process.Histones are the major protein components to compact genomic DNA into the limited volume of the nucleus as a highly organized chromatin structure. The basic element of chromatin is the nucleosome, which consists of 146 base pairs of DNA wrapped around an octameric core of histones containing two molecules each of H2A, H2B, H3, and H4 (1-4). This repeating unit of chromatin is associated with another type of histone called linker histone H1 to achieve an additional level of compaction, making genes inaccessible to transcription factors and preventing their expression (5-9). Mammalian cells have at least eight histone H1 subtypes including H1.1 through H1.5 and somatic cell-specific H1o as well as germ cell-specific H1t and H1oo, all consisting of a highly conserved globular domain and less conserved N-and C-terminal domains (6,8,10). The existence of multiple H1 subtypes and the diversity of their amino acid sequences raise the possibility that individual subtypes have nonredundant functions in various cellular processes. In addition, the expression of each H1 subtype depends on the tissue, phase of the cell cycle, and developmental stage, further suggesting the specific contribution of linker histone subtypes for regulation of various cellular processes (6,8,11).Although most studies have focused on the contribution of H1 as a structural component of the nucleosome, it is becoming apparent that H1 also acts as a repressor for specific gene transcription (12)(13)(14)(15). This repressive capacity of H1 on transcription appears to be accomplished by its localization at particular chromosomal domains with specific transcription regulators. Msx1 recruits a linker histone H1 to the MyoD gene,...

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“…For others, NF-Y-binding was more than suspected. (i) The divergent promoters of the H2B-H3 and of H2A-H4 loci belong to the wide family of histone genes; detailed mutational analysis of other histone promoters clearly evidenced the importance of NF-Y (45,46). (ii) Functional analysis of the NKX6.1 promoter pointed to a double CCAAT region as essential (47).…”

Section: Fig 1 Validation Of the Nf-yb Probes For The Chip On Chipsmentioning

confidence: 99%

Chromatin Immunoprecipitation (ChIP) on Chip Experiments Uncover a Widespread Distribution of NF-Y Binding CCAAT Sites Outside of Core Promoters

Testa

Donati

Yan

et al. 2005

Journal of Biological Chemistry

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The CCAAT box is a prototypical promoter element, almost invariably found between ؊60 and ؊100 upstream of the major transcription start site. It is bound and activated by the histone fold trimer NF-Y. We performed chromatin immunoprecipitation (ChIP) on chip experiments on two different CpG islands arrays using chromatin from hepatic HepG2 and pre-B cell leukemia NALM-6 cell lines, with different protocols of probe preparation and labeling. We analyzed and classified 239 known or predicted targets The CCAAT box is a DNA element that controls transcriptional initiation in eukaryotic promoters; recent bioinformatic studies unambiguously identify it as one of the most widespread. The analysis on 1031 human promoters isolated through unbiased determination of mRNA start sites suggested that the CCAAT box or its reverse ATTGG is present in as many as 67% of promoters (1). A statistical, unbiased analysis of random octanucleotides on a large 13,000-promoter data set confirmed that the CCAAT is second only to the Sp1-binding GC box in terms of abundance, despite the fact that the percentage of CCAAT promoters was inferior, 7.5% (2). Furthermore, analysis of cell cycle-regulated genes identified the CCAAT box as specifically present in promoters of G 2 /M genes (3). Most importantly, specific flanking nucleotides emerging from these studies matched specifically the consensus of the NF-Y transcription factor. A combination of EMSAs and transfections with highly diagnostic dominant negative vectors implicated NF-Y as the CCAAT activator (4). It is composed of three subunits, NF-YA, NF-YB, and NF-YC, all necessary for sequence-specific binding to a G/A, G/A, C, C, A, A, T, C/G, A/G, G/C consensus. NF-YB and NF-YC contain evolutionarily conserved histone fold motifs common to all core histones, mediating dimerization, a feature strictly required for NF-YA association and sequence-specific DNA binding (5, 6). In essentially all cases described so far, the binding of the trimer is important or essential for transcriptional regulation (7).NF-Y is considered as a general promoter organizer: thanks to its histone-like nature, it presets chromatin structure locally (8), interfacing well with nucleosomes (9), it helps the binding of neighboring factors (reviewed in Refs. 4 and 5) and attracts coactivators, such as p300/CREB-binding protein (8,10). The location of the CCAAT box is far from random, being positioned between Ϫ60 and Ϫ100 in the vast majority of the promoters analyzed. In general, our knowledge of the anatomy of NF-Ybinding sites in terms of flanking sequences, position with respect to transcriptional start sites, and promoter context (6,11,12) enables us to make predictions as to whether a gene will be regulated by NF-Y.Chromatin Immunoprecipitation (ChIP) 1 experiments determined that NF-Y is bound in vivo before gene activation (10 -13); NF-Y is bound to a transcribing cyclin B1 promoter during mitosis in HeLa cells (14). Indeed, binding to cell cycle-regulated promoters is not constitutive but is time-regulated, b...

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Conserved sequence elements in human main type‐H1 histone gene promoters : their role in H1 gene expression

Cited by 21 publications

References 46 publications

HIRA, the Human Homologue of Yeast Hir1p and Hir2p, Is a Novel Cyclin-cdk2 Substrate Whose Expression Blocks S-Phase Progression

HIRA, the Human Homologue of Yeast Hir1p and Hir2p, Is a Novel Cyclin-cdk2 Substrate Whose Expression Blocks S-Phase Progression

Isolation and Characterization of a Novel H1.2 Complex That Acts as a Repressor of p53-mediated Transcription

Chromatin Immunoprecipitation (ChIP) on Chip Experiments Uncover a Widespread Distribution of NF-Y Binding CCAAT Sites Outside of Core Promoters

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