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Identification of a second conserved element within the coding sequence of a mouse H3 histone gene that interacts with nuclear factors and is necessary for normal expression.

ABSTRACT: Replication-dependent histone genes of all four nucleosomal classes are coordinately up-regulated at the beginning of S phase of the eukaryotic cell cycle. The universality and importance of this process in eukaryotic cells suggest that common regulatory mechanisms are involved in controlling the high level of expression of these histone genes. We have previously identified the alpha element within mouse H2a.2 and H3.2 coding region activating sequences (CRAS), which is involved in regulation of these two replication-dependent genes. Here we report the identification of a second element within the mouse histone CRAS, the omega element. This element interacts with nuclear proteins and we present in vivo evidence that this sequence is required for normal expression. Omega nucleotides involved in interaction with nuclear proteins have been precisely mapped by menas of DNase I footprinting and methylation interference assays. A naturally occurring mutation in the omega sequence is found in a replication-independent H3.3 gene. Mutation of the H3.2 omega element to that of the H3.3 sequence (3 nt changes) caused a 4-fold drop in in vivo expression of the H3.2 gene in stably transfected CHO cells, equally the effect of mutation of all 7 nt of the element. By UV cross-linking we have determined the approximate molecular weight of the omega binding protein to be 45 kDa. Finally, we identify putative omega sequences in the coding region of mouse H2B and H4 histone genes.

SUBMITTER: Kaludov NK

PROVIDER: S-EPMC145646 | biostudies-other | 1996 Feb

REPOSITORIES: biostudies-other

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Identification of a second conserved element within the coding sequence of a mouse H3 histone gene that interacts with nuclear factors and is necessary for normal expression.

Kaludov N K NK Pabón-Peña L L Hurt M M MM

Nucleic acids research 19960201 3

Replication-dependent histone genes of all four nucleosomal classes are coordinately up-regulated at the beginning of S phase of the eukaryotic cell cycle. The universality and importance of this process in eukaryotic cells suggest that common regulatory mechanisms are involved in controlling the high level of expression of these histone genes. We have previously identified the alpha element within mouse H2a.2 and H3.2 coding region activating sequences (CRAS), which is involved in regulation of ...[more]

PMID: 8602367

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Project description:BackgroundNASP is an essential protein in mammals that functions in histone transport pathways and maintenance of a soluble reservoir of histones H3/H4. NASP has been studied exclusively in Opisthokonta lineages where some functional diversity has been reported. In humans, growing evidence implicates NASP miss-regulation in the development of a variety of cancers. Although a comprehensive phylogenetic analysis is lacking, NASP-family proteins that possess four TPR motifs are thought to be widely distributed across eukaryotes.ResultsWe characterize the molecular evolution of NASP by systematically identifying putative NASP orthologs across diverse eukaryotic lineages ranging from excavata to those of the crown group. We detect extensive silent divergence at the nucleotide level suggesting the presence of strong purifying selection acting at the protein level. We also observe a selection bias for high frequencies of acidic residues which we hypothesize is a consequence of their critical function(s), further indicating the role of functional constraints operating on NASP evolution. Our data indicate that TPR1 and TPR4 constitute the most rapidly evolving functional units of NASP and may account for the functional diversity observed among well characterized family members. We also show that NASP paralogs in ray-finned fish have different genomic environments with clear differences in their GC content and have undergone significant changes at the protein level suggesting functional diversification.ConclusionWe draw four main conclusions from this study. First, wide distribution of NASP throughout eukaryotes suggests that it was likely present in the last eukaryotic common ancestor (LECA) possibly as an important innovation in the transport of H3/H4. Second, strong purifying selection operating at the protein level has influenced the nucleotide composition of NASP genes. Further, we show that selection has acted to maintain a high frequency of functionally relevant acidic amino acids in the region that interrupts TPR2. Third, functional diversity reported among several well characterized NASP family members can be explained in terms of quickly evolving TPR1 and TPR4 motifs. Fourth, NASP fish specific paralogs have significantly diverged at the protein level with NASP2 acquiring a NNR domain.

Dataset Information

Identification of a second conserved element within the coding sequence of a mouse H3 histone gene that interacts with nuclear factors and is necessary for normal expression.

Publications

Identification of a second conserved element within the coding sequence of a mouse H3 histone gene that interacts with nuclear factors and is necessary for normal expression.

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