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PubMed1988

Antisense oligonucleotide-directed cleavage of mRNA in Xenopus oocytes and eggs.

We have investigated the effect of specific antisense oligonucleotides on both exogenous and endogenous mRNAs in Xenopus oocytes and eggs. Injection of 19- or 20-mers complementary to 70-kd heat shock protein, histone H4 and vegetally localized Veg 1 coding sequences causes rapid cleavage and degradation of up to 96% of the target transcripts present in stage VI oocytes. Nuclear and cytoplasmic transcripts appear to be equally accessible to cytoplasmically injected oligonucleotide and efficient cleavage also occurs in mature oocytes and unfertilized eggs. The residual intact mRNA appears to be completely inaccessible, resisting cleavage by further addition of oligonucleotide. We confirm that antisense oligonucleotides appear to act specifically in vivo, as previously reported in vitro, by directing RNase H cleavage and destabilization of their complementary mRNA.

Animals↗

PubMed2025

Comparative and systems analyses of Leishmania spp. non-coding RNAs through developmental stages.

Leishmania spp. is the etiological agent of leishmaniases, neglected diseases that seek to be eradicated in the coming years. The life cycle of these parasites involves different host and stress environments. In recent years, many studies have shown that several protein-coding genes are directly involved with the development and host interactions. However, little is still known about the role of non-coding RNAs (ncRNAs) in life cycle progression. In this study, we aimed to identify the genomic structure and function of ncRNAs from Leishmania spp. and to get insights into the repertoire of ncRNAs (RNAome) of this protozoan genus. We studied 26 strains corresponding to 16 different species of Leishmania. Our RNAome analysis revealed the presence of several ncRNAs that are shared among different species, allowing us to differentiate between subgenera as well as between species that are canonically related to visceral leishmaniasis. We also studied co-expression relationships between coding genes and ncRNAs which in the amastigote developmental stage for Leishmania braziliensis and Leishmania donovani revealed the presence of miRNA-like transcripts co-expressed with several coding genes involved in starvation, survival and histone modification. This work represents the first effort to characterize the Leishmania ssp. RNAome, supporting further approaches to better understand the role of ncRNAs in gene regulation, infective process, and host-parasite interaction.

RNA, Untranslated↗

PubMed2004

[Exploration of the hidden layers of genome].

In recent years, geneticists have been exploring the less visible parts of genome more thoroughly. They are coming to realize that these much more layers of genomic information, distinct from the protein-coding genes, connect in surprisingly deep and potent ways to growth and development in the high eukaryotes. This article reviews a number of startling observations about the extent of non-protein-coding RNA transcriptions, DNA methylation and covalent histone modifications in the complex organisms.

Acetylation↗

PubMed2004

Evidence for distinct mechanisms facilitating transcript elongation through chromatin in vivo.

The mechanism and kinetics of RNA polymerase II transcription and histone acetylation were studied by chromatin immunoprecipitation in yeast. Our results indicate that a significant fraction of polymerases starting transcription never make it to the end of a long GAL-VPS13 fusion gene. Surprisingly, induction of GAL genes results in substantial loss of histone-DNA contacts not only in the promoter but also in the coding region. The loss of nucleosomes is dependent on active transcript elongation, but apparently occurs independently of histone acetylation. In contrast, histones in genes previously shown to require the histone acetyltransferases GCN5 and ELP3 for normal transcription do not lose DNA contacts, but do become acetylated as a result of transcription. Together, these results suggest the existence of at least two distinct mechanisms to achieve efficient transcript elongation through chromatin: a pathway based on loss of histone-DNA contacts, and a histone acetylation-dependent mechanism correlating with little or no net loss of nucleosomes.

Acetylation↗

PubMed1981

Vertebrate histone genes: nucleotide sequence of a chicken H2A gene and regulatory flanking sequences.

The DNA sequence of a chicken genomal fragment containing a histone H2A gene has been determined. It contains extensive 5' and 3' flanking regions and encodes a protein identical in sequence to the histone H2A protein isolated from chicken erythrocytes. In the 5' flanking region, a possible "TATA box" and three possible "cap sites" can be recognised upstream from the initiation codon. To the 5' side of the "TATA box" is found an unusual sequence of 21 A's interrupted by a central G residue. It occupies the same relative position as the P. miliaris H2A gene-specific 5' dyad symmetry sequence and the "CCAAT box" seen in other eukaryotic polymerase II genes but is clearly different from both. A significant feature of the 3' non-coding region is the presence of a 23 base-pair sequence that is nearly identical to a conserved region found in sea urchin histone genes. The coding region is extremely GC rich, with strong selection for these bases in the third position of codons. Not a single coding triplet ends in U. No intervening sequences were found in this gene.

Animals↗

PubMed1981

Monocistronic transcription is the physiological mechanism of sea urchin embryonic histone gene expression.

We have examined histone gene expression during the early stages of sea urchin embryogenesis. The five histone genes expressed at that time are contained in tandem repetitive segments. It has been suggested that adjacent coding regions and their intervening spacer sequences are transcribed into large polycistronic messenger ribonucleic acid (RNA) precursors. We have subcloned into pBR322 deoxyribonucleic acid (DNA) sequences mapping either in the coding region, the 5' spacer, or the 3' spacer of the H2B histone gene. These clones were used to produce radioiodinated hybridization probes. We measured the steady-state quantity of H2B messenger RNA as well as spacer-specific RNA in the total RNA from embryos taken at various stages of development from fertilization to hatching of blastulae (0 to 22 h post-fertilization). Small amounts of RNA hybridizing to both spacer probes could be found. However, we show that these RNAs form mismatched hybrids with the spacer DNA and therefore cannot originate from the spacers present in the histone genes. We conclude that there is no detectable transcription of the spacer regions on either side of the H2B histone gene. The detection limit for RNA complementary to the 5' spacer sequence corresponds to a maximum of about three RNA molecules per cell, an amount shown to be far less than the projected steady-state pool size of a putative polycistronic transcript, if such a precursor were to be the obligatory transcript of the histone genes. (This conclusion was derived by using the known rates of production of H2B mRNA throughout early development [R. E. Maxson and F. H. Wilt, Dev. Biol., in press].) The physiologically relevant transcript of the histone genes in early development is therefore monocistronic and probably identical to the messenger RNA itself.

Animals↗

PubMed1987

The stem-loop structure at the 3' end of histone mRNA is necessary and sufficient for regulation of histone mRNA stability.

Chimeric genes were made by fusing mouse histone genes with a human alpha-globin gene. The genes were introduced into mouse L cells and the stability of the chimeric mRNAs was measured when DNA synthesis was inhibited. An mRNA containing all the globin coding sequences and the last 30 nucleotides of the histone mRNA was degraded at the same rate as histone mRNA.

Animals↗

PubMed2004

On the mechanism of constitutive Pdr1 activator-mediated PDR5 transcription in Saccharomyces cerevisiae: evidence for enhanced recruitment of coactivators and altered nucleosome structures.

Drug resistance as a result of overexpression of drug transporter genes presents a major obstacle in the treatment of cancers and infections. The molecular mechanisms underlying transcriptional up-regulation of drug transporter genes remains elusive. Employing Saccharomyces cerevisiae as a model, we analyzed here transcriptional regulation of the drug transporter gene PDR5 in a drug-resistant pdr1-3 strain. This mutant bears a gain-of-function mutation in PDR1, which encodes a transcriptional activator for PDR5. Similar to the well studied model gene GAL1, we provide evidence showing that PDR5 belongs to a group of genes whose transcription requires the Spt-Ada-Gcn5 acetyltransferase (SAGA) complex. We also show that the drugindependent PDR5 transcription is associated with enhanced promoter occupancy of coactivator complexes, including SAGA, Mediator, chromatin remodeling SWI/SNF complex, and TATA-binding protein. Analyzed by chromatin immunoprecipitations, loss of contacts between histones and DNA occurs at both promoter and coding sequences of PDR5. Consistently, micrococcal nuclease susceptibility analysis revealed altered chromatin structure at the promoter and coding sequences of PDR5. Our data provide molecular description of the changes associated with constitutive PDR5 transcription, and reveal the molecular mechanism underlying drug-independent transcriptional up-regulation of PDR5.

ATP-Binding Cassette Transporters↗

PubMed2002

[Effect of products of germ-line and somatic gene mutations on chromatin remodeling].

Chromatin remodeling is engaged in basic cell functions as DNA replication, recombination, DNA repair and transcription of genes. Chromatin is remodeled by ATP-dependent chromatin remodeling complexes and protein complexes covalently modifying histones. Germ-line mutations of the genes coding for proteins which participate in chromatin remodeling cause severe developmental diseases and they increase a risk of cancer development. Somatic mutations and translocations of such genes are associated with cancer development of certain tumors. Chromatin remodeling mechanisms can thus be targeted by special strategy of cancer therapy.

Chromatin↗

PubMed1984

Evidence for a human histone gene cluster containing H2B and H2A pseudogenes.

Not all members of the human histone gene family are functional. We have isolated a human H2B pseudogene that contains alterations in the protein-coding sequences as well as in the 3' and 5' flanking sequences that preclude expression of a functional H2B histone protein. There are three modifications in the amino acid-coding region: a single-base deletion producing a frame shift, a single-base substitution resulting in a codon change from serine to tryptophan (an amino acid not present in histones), and the absence of a stop codon. Analysis of nucleotide sequences upstream from the AUG start signal indicates the absence of a "TATA" box and other putative consensus regulatory sequences. In the 3' flanking region, a highly conserved block of 22 nucleotides that exhibits hyphenated dyad symmetry is displaced downstream. Within the same genomic segment, the adjacent H2A histone gene is missing 12 nucleotides, resulting in a deletion of four amino acids in a highly conserved region of the protein.

Amino Acid Sequence↗

PubMed2005

Domain-wide displacement of histones by activated heat shock factor occurs independently of Swi/Snf and is not correlated with RNA polymerase II density.

We show that histone-DNA interactions are disrupted across entire yeast heat shock genes upon their transcriptional activation. At HSP82, nucleosomal disassembly spans a domain of approximately 3 kb, beginning upstream of the promoter and extending through the transcribed region. A kinetic analysis reveals that histone H4 loses contact with DNA within 45 s of thermal upshift. Nucleosomal reassembly, prompted by temperature downshift, is also rapid, detectable within 60 s. Prior to their eviction, promoter-associated histones are transiently hyperacetylated, while those in the coding region are not. An upstream activation sequence mutation that weakens the binding of heat shock factor obviates domain-wide remodeling, while deletion of the TATA box that nearly abolishes transcription is permissive to 5'-end remodeling. The Swi/Snf complex is rapidly recruited to HSP82 upon heat shock. Nonetheless, domain-wide remodeling occurs efficiently in Swi/Snf mutants despite a sixfold reduction in transcription; it is also seen in gcn5Delta, set1Delta, and paf1Delta mutants. Contrary to current models, we demonstrate that a high density of RNA polymerase (Pol) is insufficient to elicit histone displacement. This finding suggests that histone eviction is modulated by factors that are not linked to elongating Pol II. It further suggests that histone depletion plays a causal role in mediating vigorous transcription in vivo and is not merely a consequence of it.

3' Untranslated Regions↗

PubMed1978

Histone gene transcripts in the cleavage and mesenchyme blastula embryo of the sea urchin, S. purpuratus.

Two distinct populations of histone gene transcripts have been identified in the sea urchin embryo. Both late cleavage and mesenchyme blastula stages contain histone transcripts which hybridize to a full-length histone repeat recombinant DNA, pCO1. The histone RNAs of the two stages, however, are dissimilar in sequence. While the transcripts of the cleavage embryo form well matched hybrids with the plasmid DNA which are relatively resistant to RNAase, the hybrids containing the mesenchyme blastula transcripts melt some 10 degrees C lower and are twice as sensitive to RNAase. Hybridization of the two RNA samples to the Hha I fragments of the histone DNA, or to segments of the histone repeat subcloned in other plasmids, shows that many regions scattered along the repeat are complementary to widely diverged transcripts in the mesenchyme blastula RNA. The two RNA populations consist predominantly of polysomal RNA sequences and are most probably mRNAs for the five histones. The mesenchyme blastula RNA sequences in both S. purpuratus and L. pictus form hybrids with pCO1 DNA that are less stable than those containing L. pictus cleavage RNA, indicating the wide divergence of the two histone RNA populations. The bulk of the histone genes in S. purpuratus appear to be of the type coding for the early mRNAs. Only a small percentage of the several hundred gene copies are candidates for the type coding for the late mRNAs. The melting characteristics of the hybrids and the sensitivity of RNAase provide an assay for the late embryonic histone genes. Of the total RNA labeled during a 10 min pulse in the cleavage embryo, histone transcripts represent approximately 9.7 and 6.5% of the radioactivity in S. purpuratus and L. pictus, respectively. These values fall to 0.57 and 1.4%, respectively, at the mesenchyme blastula stage. Although histone genes are transcribed during these two periods, the type of gene which is active is switched at some point prior to the mesenchyme blastula stage.

Animals↗

PubMed1988

Cloning and characterization of a core histone gene tandem repeat in Urechis caupo.

A Urechis caupo histone gene tandem repeat has been isolated from a 5.0-kilobase EcoRI genomic library in lambda gtWES.lambda B. Genomic reconstruction experiments indicate that the cloned sequence is repeated approximately 100 times per haploid genome. Unique restriction fragments from the cloned sequence hybridize with individual core histone genes from a histone gene tandem repeat of the sea urchin, Strongylocentrotus purpuratus. No hybridization is detected when restriction digests are probed with a sea urchin H1 histone gene. Hybrid selection and in vitro translation of embryo mRNAs demonstrate that the clone contains sequences complementary to all four core histones; however, no H1 histone is detected among the translation products. Based on a restriction site map of the clone and the subcloned sequences which hybridize to the histone mRNAs, the order of the core histone genes in the clone is shown to be H3 H2A H2B H4. S1 nuclease hybrid protection mapping is used to locate the coding regions and to determine the transcript lengths of the core histone mRNAs. The transcript lengths of H2A, H2B, H3, and H4 mRNAs are approximately 464, 438, 494, and 397 bases, respectively. The S1 nuclease mapping also demonstrates that H2A and H4 are transcribed from one DNA strand while H2B and H3 are transcribed from the other strand. In the tandem repeat, the genes are organized so that transcription of the H2A-H2B and H3-H4 gene pairs is divergent.

Animals↗

PubMed1982

The two yeast histone H2A genes encode similar protein subtypes.

The sequences of the two histones H2A genes in the yeast Saccharomyces cerevisiae have been determined. These genes encode two histone H2A subtypes which are 131 amino acids in length but differ at 2 amino acid positions: an Ala leads to Thr and a Thr leads to Ala change at positions 124 and 125. Thus, the two histone H2A subtypes have identical amino acid compositions. The coding regions of the two H2A genes are homologous at 369 of 393 bases (94%), with all but 2 of the 24 changes being silent. There is only 30% homology in the 5' flanking sequences of the two H2A genes. Like other eukaryotic histone genes, the yeast H2A genes are not interrupted by intervening sequences. When the yeast H2A histones are compared to those from other eukaryotes, there is at least 80% homology in amino acid sequence.

Amino Acid Sequence↗

PubMed1983

Evolution of alpha q- and beta-tubulin genes as inferred by the nucleotide sequences of sea urchin cDNA clones.

Evolutionary studies on the tubulin multigene families were initiated by nucleotide sequence analysis of cDNA clones complementary to sea urchin (Lytechinus pictus) testis alpha- and beta-tubulin cDNA clones (p beta 1, p beta 2, p beta e) demonstrated the existence of tubulin mRNA heterogeneity. p beta 2 and p beta 3 contain identical tubulin-coding regions and extremely similar 3' untranslated sequences, including a polyadenylation signal (AAUAAA). However, p beta 2 contains an additional region of 3' untranslated sequence which includes a second polyadenylation signal. These two sequences may be allelic, representing products of alternative transcription termination or processing pathways. p beta 1 and p beta 2 (or p beta 3) cDNAs almost certainly correspond to transcripts of distinct but evolutionarily related genes. Examination of the available coding portions showed that they differ only by a few silent nucleotide substitutions and the deletion/insertion of one codon; most of the differences are clustered within the last 15 3'-end codons. In contrast, their 3' untranslated sequences are considerably divergent. Nucleotide alignment in this region was feasible by considering specific point and segmental mutations, mainly T in equilibrium or formed from C transitions and small deletions/insertions associated with small direct repeats. The sea urchin alpha- and beta-tubulin cDNA and corresponding protein sequences were compared with previously described tubulin cDNA and protein sequences from other organisms. Both alpha and beta tubulins are very conserved proteins, evolving with a rate comparable to that of histones. Analysis of the nucleotide divergence of the coding cDNA regions showed that replacement sites have changed with a rate 20-175 times lower than that of the silent sites. Among the 177 codons compared between the sea urchin testis and chick brain beta-tubulin cDNAs, there are 7 conservative amino acid replacements and the deletion/insertion of two codons. Most of these changes are clustered near the C-terminus. The 161-amino acid portion of chick brain, rat and porcine alpha-tubulin sequences differs by 3 conservative amino acid replacements from the corresponding sea urchin testis alpha-tubulin sequence. The compared interspecies 3' untranslated sequences are very divergent.

Amino Acid Sequence↗

PubMed2002

Crosstalk between CARM1 methylation and CBP acetylation on histone H3.

BACKGROUND: Dynamic changes in the modification pattern of histones, such as acetylation, phosphorylation, methylation, and ubiquitination, are thought to provide a code for the correct regulation of gene expression mostly by affecting chromatin structure and interactions of non-histone regulatory factors with chromatin. Recent studies have suggested the existence of an interplay between histone modifications during transcription. The CBP/p300 acetylase and the CARM1 methyltransferase can positively regulate the expression of estrogen-responsive genes, but the existence of a crosstalk between lysine acetylation and arginine methylation on chromatin has not yet been established in vivo. RESULTS: By following the in vivo pattern of modifications on histone H3, following estrogen stimulation of the pS2 promoter, we show that arginine methylation follows prior acetylation of H3. Within 15 min after estrogen stimulation, CBP is bound to chromatin, and acetylation of K18 takes place. Following these events, K23 is acetylated, CARM1 associates with chromatin, and methylation at R17 takes place. Exogenous expression of CBP is sufficient to drive the association of CARM1 with chromatin and methylation of R17 in vivo, whereas an acetylase-deficient CBP mutant is unable to induce these events. A mechanism for the observed cooperation between acetylation and arginine methylation comes from the finding that acetylation at K18 and K23, but not K14, tethers recombinant CARM1 to the H3 tail and allows it to act as a more efficient arginine methyltransferase. CONCLUSION: These results reveal an ordered and interdependent deposition of acetylation and arginine methylation during estrogen-regulated transcription and provide support for a combinatorial role of histone modifications in gene expression.

Acetylation↗

PubMed2025

Genetic and chromatin regulation of Pvt1 monoallelic expression.

While most genes are equivalently expressed on both alleles, genes with random monoallelic expression (RME) stably maintain expression from only one allele, but the mechanisms and consequences of RME remain unclear. We performed allele-specific RNA sequencing (RNA-seq) on ∼100 F1 hybrid neural progenitor cell (NPC) clonal lines to reveal the extent of autosomal RME (aRME). Of the 287 aRME genes, Pvt1, an oncogenic long non-coding RNA, is an aRME with a genetic bias. In the absence of genetic differences, Pvt1 undergoes balanced aRME. Pvt1 monoallelic expression is maintained by allele-specific active and repressive histone modifications, opposed to DNA methylation. Additionally, we provide a two-step mechanism for the initiation of aRME and demonstrate that Pvt1 monoallelic expression results in a growth phenotype due to the interplay with Myc. These findings provide insight into how genetic differences can skew a stochastic process, resulting in monoallelic expression with a phenotypic consequence in early development.

Chromatin↗

PubMed2003

Methylation of histone H3 by Set2 in Saccharomyces cerevisiae is linked to transcriptional elongation by RNA polymerase II.

Set2 methylates Lys36 of histone H3. We show here that yeast Set2 copurifies with RNA polymerase II (RNAPII). Chromatin immunoprecipitation analyses demonstrated that Set2 and histone H3 Lys36 methylation are associated with the coding regions of several genes that were tested and correlate with active transcription. Both depend, as well, on the Paf1 elongation factor complex. The C terminus of Set2, which contains a WW domain, is also required for effective Lys36 methylation. Deletion of CTK1, encoding an RNAPII CTD kinase, prevents Lys36 methylation and Set2 recruitment, suggesting that methylation may be triggered by contact of the WW domain or C terminus of Set2 with Ser2-phosphorylated CTD. A set2 deletion results in slight sensitivity to 6-azauracil and much less beta-galactosidase produced by a reporter plasmid, resulting from a defect in transcription. In synthetic genetic array (SGA) analysis, synthetic growth defects were obtained when a set2 deletion was combined with deletions of all five components of the Paf1 complex, the chromodomain elongation factor Chd1, the putative elongation factor Soh1, the Bre1 or Lge1 components of the histone H2B ubiquitination complex, or the histone H2A variant Htz1. SET2 also interacts genetically with components of the Set1 and Set3 complexes, suggesting that Set1, Set2, and Set3 similarly affect transcription by RNAPII.

Chromatin↗