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PubMed1997

Binding sites for adeno-associated virus Rep proteins within the human genome.

The Rep proteins of adeno-associated virus type 2 (AAV) are known to bind to Rep recognition sequences (RRSs) in the AAV inverted terminal repeats (ITRs), the AAV p5 promoter, and the preferred AAV integration site in human chromosome 19, called AAVS1. Integration of the AAV genome into AAVS1 appears to be mediated by an interaction between the Rep proteins of AAV and Rep binding sites within the viral genome and the integration locus. In an attempt to identify potential alternate integration sites, we looked for recognition sites for AAV Rep proteins in the human genome by performing a BLASTN computerized homology search. We used the 16-mer core sequences of the RRSs in the AAV ITRs and AAVS1 separately as query sequences and identified 18 new RRSs in or flanking the genes coding for the following: tyrosine kinase activator protein 1 (TKA-1); colony stimulating factor-1; insulin-like growth factor binding protein 2 (IGFBP-2); histone H2B.1; basement membrane heparan sulfate proteoglycan, also known as perlecan; the AF-9 gene product, which is involved in the chromosomal translocation t (9:11)(p22:q23); the betaB subunit of the hormone known as inhibin; interleukin-2 enhancer binding factor; an endoplasmic reticulum-Golgi intermediate compartment resident protein called p63; a global transcription activator (hSNF2L); the beta-actin repair domain; a retinoic acid-inducible factor, also known as midkine; a breast tumor autoantigen; a growth-arrest- and DNA-damage-inducible protein called gadd45; the cyclin-dependent kinase inhibitor called KIP2, which inhibits several G1 cyclin-cyclin-dependent kinase complexes; and the hereditary breast and ovarian cancer gene (BRCA1). RRSs were also identified in a newly discovered open reading frame on chromosome 10 and in the ERCC1 locus on human chromosome 19. The ability of a maltose binding protein-Rep68 fusion protein to bind to these sequences was confirmed by electrophoretic mobility shift assays. These sites may serve as alternate integration sites for AAV or play a role in Rep-mediated effects on human cells.

Base Sequence↗

PubMed1989

Nucleotide variation and divergence in the histone multigene family in Drosophila melanogaster.

Nucleotide differences in the histone H3 gene family in Drosophila melanogaster were studied on three levels: (1) within a chromosome, (2) within a population and (3) between species (D. melanogaster and Drosophila simulans). The average difference within the H3 gene within a chromosome was 0.0040 per nucleotide site, about 52% of that within a population (0.0077). The proportion of divergent sites between the two species was 0.0575, which is about 8.5 times the difference within a species. The distribution of divergence between species was similar to that of variation within a species. Divergence and variation were noted to be greatest in the 3' noncoding region and least in the coding region. Values intermediate between these were found for the 5' noncoding region. Divergence and variation in silent sites exceeded those in the total coding region, thus indicating possible purifying selection for amino-acid-altering change. Phylogenetic relations among H3 genes and genetic differences on these three levels are evidence for the concerted evolution of the histone gene family. The molecular mechanism by which variation is produced and maintained is discussed.

Amino Acid Sequence↗

PubMed2002

Epigenetic codes for heterochromatin formation and silencing: rounding up the usual suspects.

Recent results from diverse organisms point to a self-reinforcing network of interactions among the three best-characterized covalent modifications that mark heterochromatin: histone hypoacetylation, histone H3-Lys9 methylation, and cytosine methylation. These modification systems suggest a mechanistic basis for spreading of heterochromatin over large domains and for stable epigenetic inheritance of the silent state. All three modifications used in packaging heterochromatin are also used in stable silencing of euchromatic genes.

Acetylation↗

PubMed2004

Comparative analysis of the mouse and human peptidylarginine deiminase gene clusters reveals highly conserved non-coding segments and a new human gene, PADI6.

Peptidylarginine deiminases (PADs) convert arginine residues in proteins into citrullines. They are suspected to be involved in multiple sclerosis and rheumatoid arthritis pathophysiology, and they play a role in epidermis homeostasis and possibly in regulation of gene expression through histone modification. In humans, four isoforms encoded by the genes PADI1-4 are known so far. We here report the characterization and comparative analysis of the human (355 kb) and mouse (240 kb) PAD gene clusters on chromosomes 1p35-36 and 4E1, respectively. We characterized an as yet unknown human PADI6 gene, and cloned the corresponding cDNA encoding a 694-amino-acid protein. RT-PCR analysis showed a rather restricted pattern of tissue-specific expression, mainly in ovary, testis and peripheral blood leukocytes. Nucleotide substitution rates suggest that PADI genes are under purifying selection. Comparative analysis of the human and mouse sequences identified 251 conserved non-coding segments predominantly clustered within the promoter regions, the large (>10 kb) first intron of each of the genes PADI1-3, and an 8 kb PADI1-2 intergenic region. The presence of numerous transcription factor binding sites suggests the segments are putative regulatory elements. This study is the first description of the human PADI6 gene and encoded protein, and the first step towards a better understanding of the coordinated regulation of PADI gene expression.

Amino Acid Sequence↗

PubMed2001

The replacement H3.3 histone gene in Paracentrotus lividus sea urchin: structure and regulatory elements.

We have isolated the Paracentrotus lividus sea urchin H3.3 histone gene and characterized the nucleotide sequences of the gene and its proximal promoter. Band shift experiments showed that two cAMP/PMA responsive elements (CRE/TRE), present in the proximal promoter, bind nuclear factors present in embryos at the blastula and gastrula stages (CRE1) and at the blastula stage (CRE2). The putative H3.3 coding region activating sequences (CRAS) failed to bind nuclear factors while the corresponding elements of the two replication-dependent genes (H3L and late H3) clearly recognized nuclear proteins. These results suggest some role of the CRE/TRE elements but not CRAS elements in the transcriptional regulation of the replication-independent histone genes in invertebrates.

Animals↗

PubMed2000

Rett syndrome: analysis of MECP2 and clinical characterization of 31 patients.

UNLABELLED: Only recently have mutations in MECP2 been found to be a cause of Rett Syndrome (RTT), a neuro-developmental disorder characterized by mental retardation, loss of expressive speech, deceleration of head growth and loss of acquired skills that almost exclusively affects females. We analysed the MECP2 gene in 31 patients diagnosed with RTT. Sequencing of the coding region and the splice sites revealed mutations in 24 females (77.40%). However, no abnormalities were detected in any of the parents that were available for investigation. Eleven mutations have not been described previously. Confirming two earlier studies, we found that most mutations are truncating and only a few of them are missense mutations. Several females carrying the same mutation display different phenotypes indicating that factors other than the type or position of mutations influence the severity of RTT. Four females with RTT variants were included in the study. Three of these presented with preserved speech while the fourth patient with congenital RTT lacked the initial period of normal development. Detection of mutations in these cases reveals that they are indeed variants of RTT. They represent the mild and the severe extremes of RTT. CONCLUSIONS: mutations in MECP2 seem to be the main cause for RTT and can be expected to be found in approximately 77% of patients that fulfil the criteria for RTT. Therefore analysis of MECP2 should be performed if RTT is suspected. Three mutation hotspots (T158M, R168X and R255X) were confirmed and a further one (R270X) newly identified. We recommend screening for these mutations before analysing the coding region.

Alleles↗

PubMed2005

Prevention of early flowering by expression of FLOWERING LOCUS C requires methylation of histone H3 K36.

Flowering represents a crucial transition from a vegetative to a reproductive phase of the plant life cycle. Despite extensive studies, the molecular mechanisms controlling flowering remain elusive. Although the enzymes involved are unknown, methylation of histone H3 K9 and K27 correlates with repression of FLOWERING LOCUS C (FLC), an essential transcriptional repressor involved in flowering time control in Arabidopsis thaliana; in contrast, methylation of H3K4 correlates with FLC activation. Here we show that loss-of-function of SET DOMAIN GROUP 8 (SDG 8), which encodes a homologue of the yeast SET2 histone methyltransferase, results in reduced dimethylation of histone H3K36, particularly in chromatin associated with the FLC promoter and the first intron, regions that contain essential cis-elements for transcription. sdg8 mutants display reduced FLC expression and flower early, establishing SDG8-mediated H3K36 methylation as a novel epigenetic memory code required for FLC expression in preventing early flowering. This is the first demonstrated role of H3K36 methylation in eukaryote development.

Arabidopsis↗

PubMed1992

Genes encoding a histone H3.3-like variant in Arabidopsis contain intervening sequences.

Two genes encoding a particular H3 histone variant were isolated from Arabidopsis thaliana. These genes differ from the H3 genes previously cloned from Arabidopsis and other plants by several interesting properties: (1) the two genes are located close to each other; (2) their coding regions are interrupted by two or three small introns, the two closest to the initiation codon being located at the same place in the two genes; (3) another, long intron is located in the 5'-untranslated region just before the initiation codon of gene I as deduced from the sequence of several corresponding cDNAs, and very likely also of gene II; (4) these genes do not show preferential expression in organs containing meristematic tissues contrary to the classical intronless replication-dependent histone genes, thus suggesting that their expression is not replication-dependent; (5) the protein encoded by both genes is the same and corresponds to a minor H3 variant highly conserved among all the plant species studied up to now. All these characteristics are common with the animal replication-independent H3.3 histone genes and it is assumed that the genes described here are the first example of the equivalent H3.3 gene family in plants. Interestingly, the promoter regions of the two genes have the same general structure as the Arabidopsis intronless genes. Possible implications on the regulation of H3 genes expression are discussed.

Amino Acid Sequence↗

PubMed1997

MLL is fused to CBP, a histone acetyltransferase, in therapy-related acute myeloid leukemia with a t(11;16)(q23;p13.3).

The recurring translocation t(11;16)(q23;p13.3) has been documented only in cases of acute leukemia or myelodysplasia secondary to therapy with drugs targeting DNA topoisomerase II. We show that the MLL gene is fused to the gene that codes for CBP (CREB-binding protein), the protein that binds specifically to the DNA-binding protein CREB (cAMP response element-binding protein) in this translocation. MLL is fused in-frame to a different exon of CBP in two patients producing chimeric proteins containing the AT-hooks, methyltransferase homology domain, and transcriptional repression domain of MLL fused to the CREB binding domain or to the bromodomain of CBP. Both fusion products retain the histone acetyltransferase domain of CBP and may lead to leukemia by promoting histone acetylation of genomic regions targeted by the MLL AT-hooks, leading to transcriptional deregulation via aberrant chromatin organization. CBP is the first partner gene of MLL containing well defined structural and functional motifs that provide unique insights into the potential mechanisms by which these translocations contribute to leukemogenesis.

Acute Disease↗

PubMed2006

Transposon-mediated expansion and diversification of a family of ULP-like genes.

Transposons comprise a major component of eukaryotic genomes, yet it remains controversial whether they are merely genetic parasites or instead significant contributors to organismal function and evolution. In plants, thousands of DNA transposons were recently shown to contain duplicated cellular gene fragments, a process termed transduplication. Although transduplication is a potentially rich source of novel coding sequences, virtually all appear to be pseudogenes in rice. Here we report the results of a genome-wide survey of transduplication in Mutator-like elements (MULEs) in Arabidopsis thaliana, which shows that the phenomenon is generally similar to rice transduplication, with one important exception: KAONASHI (KI). A family of more than 97 potentially functional genes and apparent pseudogenes, evidently derived at least 15 MYA from a cellular small ubiquitin-like modifier-specific protease gene, KI is predominantly located in potentially autonomous non-terminal inverted repeat MULEs and has evolved under purifying selection to maintain a conserved peptidase domain. Similar to the associated transposase gene but unlike cellular genes, KI is targeted by small RNAs and silenced in most tissues but has elevated expression in pollen. In an Arabidopsis double mutant deficient in histone and DNA methylation with elevated KI expression compared to wild type, at least one KI-MULE is mobile. The existence of KI demonstrates that transduplicated genes can retain protein-coding capacity and evolve novel functions. However, in this case, our evidence suggests that the function of KI may be selfish rather than cellular.

Amino Acid Sequence↗

PubMed1998

Multicomponent chimeric antigen for serodiagnosis of canine visceral leishmaniasis.

In this work, we describe the assembly of a synthetic gene coding for several antigenic determinants found in different Leishmania infantum antigens. Selected epitopes were derived from the ribosomal proteins LiP2a, LiP2b, and LiP0 and from the histone H2A. The resulting gene was overexpressed in Escherichia coli either as a fusion protein (with the vector pMAL-c2) or alone (with the vector pQE). In both cases, high-level bacterial production of the recombinant protein was achieved and the products were found to be stable. Enzyme-linked immunosorbent assay (ELISA) and Western blotting experiments confirmed that the corresponding epitopes are present in the engineered protein. Finally, a serological evaluation of this multiple-epitope protein by Falcon assay screening test-ELISA revealed a sensitivity of 79 to 93% and a specificity of 96 to 100% in diagnosis of canine visceral leishmaniasis, indicating that this protein represents a valuable tool for serodiagnosis.

Amino Acid Sequence↗

PubMed1991

Molecular cloning and immunolocalization of two variants of the major basic nuclear protein (HCc) from the histone-less eukaryote Crypthecodinium cohnii (Pyrrhophyta).

Two clones that encode variants (HCc1 and HCc2) of the major basic nuclear protein of the dinoflagellate Crypthecodinium cohnii, were identified by immunoscreening of a cDNA expression library. The first clone carries a full-length cDNA with an open reading frame (HCc1) encoding 113 amino acids. The cDNA from the second clone lacks some of the 5' end, and the coding sequence is only 102 residues. The two proteins display 77% sequence similarity and their NH2-ends are homologous to the NH2-peptide of the HCc protein determined by P. Rizzo. The amino acid composition, which confirms the basic nature of lysine-rich HCc proteins, differs markedly from other known DNA-binding proteins such as histones, HMGs or prokaryotic histone-like proteins. No convincing homology was found with other proteins. HCc antigens were localized on C. cohnii by immunofluorescence, and by electron microscopy (EM) with immunogold labelling. HCc proteins are mainly detected at the periphery of the permanently condensed chromosomes, where active chromatin is located, as well as in the nucleolar organizing region (NOR). This suggests that these basic, non-histone proteins, with a moderate affinity for DNA, are involved at some level in the regulation of gene expression.

Amino Acid Sequence↗

PubMed1985

The conserved CAAGAAAGA spacer sequence is an essential element for the formation of 3' termini of the sea urchin H3 histone mRNA by RNA processing.

Analysis of cDNA sequences obtained from the small nuclear RNA U7 has previously suggested specific contacts, by base pairing, between the conserved stem-loop structure and CAAGAAAGA sequence of the histone pre-mRNA and the 5'-terminal sequence of the U7 RNA during RNA processing. In order to test some aspects of the model we have created a series of linker scan, deletion and insertion mutants of the 3' terminus of a sea urchin H3 histone gene and have injected mutant DNAs or in vitro synthesized precursors into frog oocyte nuclei for interpretation. We find that, in addition to the stem-loop structure of the mRNA, the CAAGAAAGA spacer transcript within the histone pre-mRNA is required absolutely for RNA processing, as predicted from our model. Spacer sequences immediately downstream of the CAAGAAAGA motif are not complementary to U7 RNA. Nevertheless, they are necessary for obtaining a maximal rate of RNA processing, as is the ACCA sequence coding for the 3' terminus of the mature mRNA. An increase of distance between the mRNA palindrome and the CAAGAAAGA by as little as six nucleotides abolishes all processing. It may, therefore, be useful to regard both these sequence motifs as part of one and the same RNA processing signal with narrowly defined topologies. Interestingly, U7 RNA-dependent 3' processing of histone pre-mRNA can occur in RNA injection experiments only when the in vitro synthesized pre-mRNA contains sequence extensions well beyond the region of sequence complementarities to the U7 RNA. In addition to directing 3' processing the terminal mRNA sequences may have a role in histone mRNA stabilization in the cytoplasmic compartment.

Animals↗

PubMed1996

The HIR protein family: isolation and characterization of a complete murine cDNA.

A full-length cDNA has been isolated for the murine homolog of the human HIRA protein, a member of the HIR family of nuclear proteins that is encoded from the chromosome 22 region critical for the DiGeorge syndrome. This family also contains Hir1p and Hir2p, two proteins identified as regulators of histone gene transcription in yeast. The murine and human amino acid sequences are 95.3% identical, with a striking 99.2% identity in the N-terminal WD repeat domain that is characteristic of the family. The two cDNAs are highly conserved within the coding regions, but also in the entire 5' untranslated region and in a strikingly long stretch of nucleotides in the 3' untranslated region.

Amino Acid Sequence↗

PubMed2005

Prospects: histone deacetylase inhibitors.

Histone deacetylase (HDAC), inhibitors represent a new class of targeted anti-cancer agents. Several of these compounds are in clinical trials with significant activity against a spectrum of both hematologic and solid tumors at doses that are well tolerated by the patients. The HDAC inhibitors are a structurally diverse group of molecules that can induce growth arrest, differentiation, apoptosis, and autophagocytic cell death of cancer cells. While the base sequence of DNA provides the genetic code for proteins, the expression of genes is regulated, in large part, by the structure of the chromatin proteins around which the DNA is wrapped (epigenetic gene regulation). The acetylation and deacetylation of the lysines in the tails of the core histones, among the most extensively studied aspects of chromatin structure, is controlled by the action of two families of enzymes, histone deacetylases (HDACs) and histone acetyltransferases (HATs). Protein components of transcription factor complexes and many other non-histone proteins are also substrates for HDACs and HATs. The structure and activity of these non-histone proteins may be altered by acetylation/deacetylation with consequent effects on various cell functions including gene expression, cell cycle progression, and cell death pathways. This review focuses on several key questions with respect to the mechanism of action of HDACi, including, what are the different cell phenotypes induced by HDACi, why are normal cells compared to transformed cells relatively resistant to HDACi induced cell death, why are certain tumors more responsive to HDACi than others, and what is the basis of the selectivity of HDACi in altering gene expression. The answers to these questions will have therapeutic importance since we will identify targets for enhancing the efficacy and safety of HDACi.

Animals↗

PubMed1990

Structure of a mouse histone-encoding gene cluster.

In addition to a previously described histone (H)-encoding H4 gene [Meier et al., Nucleic Acids Res. 17 (1989) 795], the mouse genomic DNA clone 53 contains two H3 genes, one functional and one partially deleted H2A gene, and one H2B gene. Clone 53 overlaps for 3 kb with MH143, another previously isolated mouse H-encoding clone [Yang et al., J. Biol. Chem. 262 (1987) 17118-17125], thus defining a 32-kb region of mouse chromosome 13 with a total of seven H-encoding genes. We have determined the nucleotide sequences and transcription start points of two genes coding for the H2A.1 and H3.2 proteins.

Amino Acid Sequence↗

PubMed1987

Chromatin from transcribed genes contains HMG17 only downstream from the starting point of transcription.

Monoclonal antibodies specific for the non-histone chromosomal protein HMG17 were used to isolate oligonucleosomes from the transcriptionally active chromatin of chicken liver and oviduct. The distribution of HMG17 with respect to the coding region of three genes was analyzed in these oligonucleosomes by employing two independent experimental approaches. In the vitellogenin II gene (active in liver) and the lysozyme and ovalbumin genes (active in oviduct) HMG17 was found only downstream from the respective starting points of transcription. The transition from HMG17-free to HMG17-containing chromatin is located at the transcription start. This directly demonstrates that the distribution of an abundant nuclear protein correlates with the observation of moderate DNase I-sensitivity in upstream regions and of high sensitivity in the coding regions of active genes.

Animals↗

PubMed1976

Translation of nonpolyadenylylated messenger RNA of sea urchin embryos.

A large proportion of newly synthesized polyribosomal RNA of sea urchin blastulae is not polyadenylylated. The size distributions of the polyadenylylated and nonpolyadenylylated RNA are indistinguishable (mean size of 26 S). Upon translation of sea urchin polyribosomal RNA containing poly(A) and that without poly(A) in a wheat embryo cell-free protein-synthesizing system, where polypeptide synthesis is dependent on added messenger, both classes of RNA support peptide synthesis to the same extent. A preliminary analysis of the proteins synthesized in response to added mRNA (polyadenylylated and nonpolyadenylylated) indicates that these classes of mRNA molecules may code for different populations of proteins.

Animals↗