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PubMed2000

Identification of an alternatively spliced form of the Tat interactive protein (Tip60), Tip60(beta).

Tip60 was originally isolated as a Tat interactive protein. It was subsequently shown that Tip60 had histone acetyltransferase (HAT) activity. In studies to understand gene-expression regulation that might involve HAT activity, we PCR-amplified Tip60 from a human heart marathon-ready cDNA library. As a result, we identified an alternatively spliced form of Tip60, Tip60beta (we refer to the previously cloned Tip60 as Tip60alpha). Tip60beta cDNA is slightly smaller than Tip60alpha, and sequencing indicates that there is a deletion of 156 bp in the coding region of the gene. The predicted Tip60beta protein therefore lacks 52 amino acids when compared with Tip60alpha. The Tip60alpha gene is encoded by 14 exons, and Tip60beta is an alternatively spliced form resulting from the exclusion of exon 5 during the splicing process. Exon 5 encodes a proline-rich region that is known to be important for protein-protein interaction. Tip60beta is expressed in a variety of human tissues and cell lines, and the protein is present in both the nucleus and cytoplasm in contrast to Tip60alpha, which is entirely nuclear. The results suggest that Tip60beta may have functions additional to those of Tip60alpha in cells and tissues.

Acetyltransferases↗

PubMed1993

The gene encoding chicken chromosomal protein HMG-14a is transcribed into multiple mRNAs.

The sequence and structure of the chicken HMG14a gene encoding HMG-14a non-histone chromosomal protein suggest that it may be a unique member of the HMG (high mobility group) gene family with properties intermediate to those of the typical HMG-14 and HMG-17 genes. Genomic clones were isolated which together contain the complete chicken HMG-14a gene. The gene covers about 10 kb while coding for an mRNA of about 1000 nt in size. Primer extension, S1 mapping and further cDNA clone analysis suggest that HMG-14a codes for multiple mRNAs arising from two or more transcription start points with alternative splicing and utilization of two or more polyadenylation sites. However, no variation in the coding portion of the mRNA has been observed. The sequence of the promoter region of HMG-14a is similar to that of chicken HMG-14b and human HMG-14 in that it is very G+C rich, contains several putative Sp1-binding sequences and has an unusually high density of CpG dinucleotides. Expression studies confirm earlier results suggesting that the gene is expressed at low levels in most tissue types.

Alternative Splicing↗

PubMed2001

Spectrum of MECP2 mutations in Rett syndrome.

Mutations in the methyl-CpG-binding protein 2 gene (MECP2) are identified in the majority of females with Rett syndrome (RTT), an X-linked dominant neurodevelopmental disorder. We searched for mutations by sequencing the MECP2 coding region in 45 sporadic cases (35 with classic RTT, eight with variant forms and two males) and in seven families with two or more affected females. Following our previous report of mutations in two families and eight sporadic cases, we here present 18 additional mutations. We found 13 single nucleotide substitutions, all of which are C-->T transitions at CpG hot spots. Frameshift mutations, leading to premature termination of translation, include two single guanine (G) nucleotide deletions from a stretch of contiguous Gs, a novel four nucleotide deletion, a novel 32 nucleotide deletion in the C-terminal domain and a novel complex duplication/deletion rearrangement in the same region. When X-chromosome inactivation patterns were compared in 16 MECP2 mutation-positive and 23 mutation-negative samples, no significant differences were observed. The mutational spectrum in our subject population is similar to studies from around the world. Of over 300 MECP2 mutations reported, two-thirds are truncating mutations and one-third are missense mutations, mostly in the methyl-binding domain. Nearly 70% of all identified mutations are C-->T transitions at one of eight CpG hot spots, and about 10% are intragenic deletions or complex rearrangements that lead to frameshifts in the C-terminal region. The rate of mutation detection in the MECP2 coding region ranges from 70 to 85% in clinically diagnosed RTT and is much lower in diagnostic variants.

Adolescent↗

PubMed2001

Aggressive uterine sarcoma with rhabdoid features: diagnosis by peritoneal fluid cytology and absence of INI1 gene mutation.

We report a primary uterine sarcoma with classic histologic, immunohistochemical, and ultrastructural features of a malignant extrarenal rhabdoid tumor (MERT). It arose in a 71-year-old woman who presented with postmenopausal bleeding, ascites, and a right pelvic mass. Malignant cells with rhabdoid morphology were identified by cytologic examination of the peritoneal fluid. Exploratory laparotomy revealed a 10-cm right adnexal mass and disseminated peritoneal tumor. Pathologic study showed diffuse expansion of the endometrial stroma by rhabdoid-like cells with transmural infiltration of the myometrium and extensive involvement of uterine serosa and right ovary by tumor. Neoplastic cells were immunoreactive for vimentin, cytokeratin, and epithelial membrane antigen, and cytoplasmic whorls of intermediate filaments were observed by electron microscopy. Fluorescence in situ hybridization (FISH) studies with chromosome 22-specific probes showed no loss of the INI1 gene, and no coding sequence mutation was identified.

Aged↗

PubMed2006

The imprinted mouse Igf2r/Air cluster--a model maternal imprinting system.

Every diploid organism inherits a complete chromosome set from its father and mother in addition to the sex chromosomes, so that all autosomal genes are available in two copies. For most genes, both copies are expressed without preference. Imprinted genes, however, are expressed depending on their parental origin, being active on the paternal or maternal allele only. To date 73 imprinted genes are known in mouse (www.mgu.har.mrc.ac.uk/research/imprinting), 37 show paternal expression while 36 show maternal expression, indicating no bias for imprinting to occur in one sex or the other. Therefore, two different parental-specific imprinting systems may have evolved in mammals, acting specifically in the paternal or maternal gamete. Similarities and differences between the two imprinting systems will be reviewed, with specific reference to the role of non-coding RNAs and chromatin modifications. The mouse Igf2r/Air cluster is presented as a model of the maternal imprinting system.

Animals↗

PubMed2005

Multiple bromodomain genes are involved in restricting the spread of heterochromatic silencing at the Saccharomyces cerevisiae HMR-tRNA boundary.

The transfer RNA gene downstream from the HMR locus in S. cerevisiae functions as part of a boundary (barrier) element that restricts the spread of heterochromatic gene silencing into the downstream region of chromosome III. A genetic screen for identifying additional genes that, when mutated, allow inappropriate spreading of silencing from HMR through the tRNA gene was performed. YTA7, a gene containing bromodomain and ATPase homologies, was identified multiple times. Previously, others had shown that the bromodomain protein Bdf1p functions to restrict silencing at yeast euchromatin-heterochromatin boundaries; therefore we deleted nonessential bromodomain-containing genes to test their effects on heterochromatin spreading. Deletion of RSC2, coding for a component of the RSC chromatin-remodeling complex, resulted in a significant spread of silencing at HMR. Since the bromodomain of YTA7 lacks a key tyrosine residue shown to be important for acetyllysine binding in other bromodomains, we confirmed that a GST-Yta7p bromodomain fusion was capable of binding to histones in vitro. Epistasis analysis suggests that YTA7 and the HMR-tRNA function independently to restrict the spread of silencing, while RSC2 may function through the tRNA element. Our results suggest that multiple bromodomain proteins are involved in restricting the propagation of heterochromatin at HMR.

Amino Acid Sequence↗

PubMed1984

Characterization of cyclic AMP-requiring yeast mutants altered in the catalytic subunit of protein kinase.

The cyr2 mutant of yeast, Saccharomyces cerevisiae, required cAMP for growth at 35 degrees C. The cyr2 mutation was suppressed by the bcy1 mutation which resulted in deficiency of the regulatory subunit of cAMP-dependent protein kinase. The DEAE-Sephacel elution profile of cyr2 cAMP-dependent protein kinase was markedly different from that observed for the wild-type enzyme. With histone as substrate, the cAMP-dependent protein kinase activity of cyr2 cells showed 100-fold greater Ka value for activation by cAMP at 35 degrees C than that of the wild-type cells, while the Kd value for cAMP of the mutant enzyme was not altered. The electrophoretic character, molecular weight, and pI value of the regulatory subunit of the mutant enzyme were the same as those of the wild-type enzyme. When histone, trehalase, and glutamate dehydrogenase were used as substrate, the free catalytic subunit of the mutant enzyme showed a markedly decreased affinity for ATP and was more thermolabile compared to that of the wild-type enzyme. The results indicated that the cyr2 phenotype was produced by a structural mutation in the cyr2 gene coding for the catalytic subunit of cAMP-dependent protein kinase in yeast.

Carrier Proteins↗

PubMed1990

Regulation of thyroid hormone receptor and c-erbA mRNA levels by butyrate in neuroblastoma (N2A) and glioma (C6) cells.

Butyrate produced a biphasic modulation of the thyroid hormone receptor in neuroblastoma N2A cells increasing receptor number by 20-35% at concentrations 0.25-0.75 mM and decreasing receptor levels by 30-55% at 2-4 mM. The half-life of the receptor, as assessed by its disappearance after incubation with 18 microM cycloheximide was 8.4 hr in control cells and 10.3 hr and 5.0 hr in cells incubated with 0.25 and 4 mM butyrate, respectively. This compound increased the abundance of multyacetylated forms of histone H4 from 30% in control cells to almost 70% with butyrate 4 mM. In glioma C6 cells, the fatty acid produced a dose-dependent increase of receptor levels (up to 3-4-fold with 2-5 mM butyrate) and had little effect in increasing multiacetylation (from 30% in controls to 42-46% with 2-5 mM butyrate). Recent studies have shown that the c-erbA proto-oncogen codes for the thyroid hormone receptor. In N2A and C6 cells, 2 c-erbA-related mRNAs, one measuring 2.6 kb and the other 6 kb, were detected. Both forms were differently regulated by butyrate. This compound decreased the abundance of the 2.6 kb forms in both cell types, even at the concentrations at which there was an elevation of receptor levels. Only the largest mRNA correlated with receptor concentration increasing by 2-3-fold after treatment of C6 cells with butyrate, and undergoing a smaller but biphasic change in N2A cells. Our data suggest that modification of chromatin structure probably secondary to acetylation induces changes in thyroid hormone receptor levels in neuroblastoma and glioma cells by affecting both receptor stability and receptor mRNA levels.

Animals↗

PubMed1984

Detection of mrnas in sea urchin embryos by in situ hybridization using asymmetric RNA probes.

Asymmetric RNA probes, which contain only the mRNA coding strand, provide a large increase in hybridization efficiency in situ over that observed with either symmetric (both strands represented) RNA or DNA probes. Asymmetric RNA probes are synthesized in vitro by transcription from recombinants formed between sequences encoding sea urchin mRNAs and the transcription vector R7 delta 7. Using a probe representing early variant histone mRNA sequences we have characterized hybridization to sections of sea urchin embryos with respect to thermal stability of the hybrids formed, optimum temperature, effect of sequence divergence on hybrid thermal stability, and dependence of the hybridization signals on probe concentration and hybridization time. Estimates from the observed signals indicate that a large fraction of target RNAs is both retained in sections and hybridized with probe at saturation. Coupled with measurements of nonspecific background binding of heterologous probes, these data indicate that the method has sufficient sensitivity to detect many moderately abundant mRNAs (20-75 molecules per cell in the 1500-cell pluteus). In situ hybridizations to embryos at different developmental stages show that while histone mRNAs are uniformly distributed in cleaving embryos, different cell lineages of older embryos show large differences in accumulation of these mRNAs.

Animals↗

PubMed1991

Differential gene expression in the recovery from ischemic renal injury.

Recovery from renal ischemia requires regeneration of damaged tubular epithelium. Previous studies have examined the expression of proto-oncogenes and growth factors after ischemia, but the response of genes coding for structural and functional genes has not been scrutinized. Rats were subjected to 40 minutes of renal artery occlusion and 60 minutes to 96 hours of reperfusion. Total RNA was isolated and mRNA for the structural protein actin, the enzymes superoxide dismutase and renin, the proto-oncogene c-fos, the nuclear protein histone H2b, and the putative marker for cell injury TRPM-2 was quantitated by Northern hybridization. Expression of the proto-oncogene c-fos was seen early but for only short duration. Histone gene expression was not markedly increased until 24 hours after ischemia, but remained increased for several days. Renin mRNA was undetectable one hour after ischemia, but was present in normal amounts at 24 and 48 hours. In contrast, superoxide dismutase mRNA was present in decreased amounts 24, 48, and 96 hours after ischemia. TRPM-2 gene expression was greatly increased 24 to 72 hours after ischemia and began decreasing at 96 hours. This selective sequence of gene expression or repression after renal ischemia might maximize the proliferative repair process. This information will be useful for designing therapies to further enhance recovery from acute renal injury.

Actins↗

PubMed1988

Universal rule for coding sequence construction: TA/CG deficiency-TG/CT excess.

Each coding sequence is a finite resource as to the number and composition of four bases. Accordingly, the excessive recurrence of one base oligomer entails the noticeable underrepresentation by the other, so that if the former is the same in most, if not all, of the coding sequences, the latter too must necessarily be the same in all. Indeed, a previous series of studies on 20-odd divergent coding sequences established CTG as one of the most frequently recurring base trimers (if not the most frequent), and this excess was compensated by the underrepresentation by CG and TA dimer-containing base trimers. In this study, I have analyzed three additional coding sequences and reanalyzed one previously studied coding sequence. These four, derived from man, a plant, and a fish, were of variously lopsided base compositions that were not at all conducive to high recurrences of either CT dimer or CT and TG. Yet, the excess of CT and TG dimers accompanied by complementary deficiency of CG and TA dimers emerged as the common rule. Thus, I propose the above as the universal rule of coding sequence construction. The underrepresentation by CG and TA dimers within coding sequences explains why regulatory signals in intergenic spacers are of two kinds: one, TA dimer rich; and the other, CG dimer rich.

Adenine↗

PubMed2026

Unraveling the c-Myc-CASC19/HDAC1-NPM1 epigenetic axis: A novel regulatory circuitry and therapeutic target in gastric carcinogenesis.

Mounting evidence implicates long non-coding RNA cancer susceptibility candidate 19 (CASC19) in the pathogenesis of diverse malignancies. However, its functional role and molecular mechanisms in gastric cancer (GC) remain elusive. Herein, we identified a novel 717-bp transcript isoform of CASC19 in GC cells. This study aimed to delineate the biological functions and underlying mechanisms of this novel CASC19 transcript in GC pathogenesis. CASC19 was significantly upregulated in GC tissues and cell lines, correlating with adverse clinicopathological features and poor prognosis in GC patients. Functional investigations demonstrated that CASC19 overexpression potentiated GC cell proliferation, metastasis, and epithelial-mesenchymal transition, whereas CASC19 knockdown attenuated these malignant phenotypes and suppressed tumorigenesis in xenograft models. Mechanistically, CASC19 functioned as a molecular scaffold by recruiting histone deacetylase 1 (HDAC1) to the nucleophosmin 1 (NPM1) promoter. This recruitment sustained H3K27 deacetylation, thereby transcriptionally repressing NPM1 promoter activity and accelerating gastric carcinogenesis. Crucially, Depletion of HDAC1 or NPM1 partial rescued CASC19-mediated oncogenic effects. Intriguingly, the transcription factor c-Myc was found to transcriptionally activate CASC19 through direct binding to its promoter region. Collectively, our findings indicate that the c-Myc-CASC19/HDAC1-NPM1 axis acts as a potential prognostic biomarker candidate for GC and may represent a therapeutic vulnerability worthy of future investigation.

Humans↗

PubMed1989

Molecular analyses of gene expression during sea star spermatogenesis.

We have investigated actin gene expression during the annual spermatogenic cycle of Pisaster ochraceus by Northern blot analyses of testes RNAs pooled from defined spermatogenic stages. Specific probes for cytoplasmic (Cy) and muscle (M) actin gene products detect 2.3 and 2.1 kb transcripts, respectively. In addition, actin-coding sequence probes detect a third, much larger (3.5 kb) transcript designated FAT. Preliminary sequence analyses of two cDNAs representing portions of the FAT transcript show over 90% homology to Pisaster Cy actin at the amino acid level but only 80% nucleotide identity. The expression patterns of these three transcripts, plus two spermiogenic indicator transcripts (H3 histone and beta-tubulin), were determined over the cycle. The Cy transcript is seen at all stages but is ten- to 100-fold higher early in the cycle when mitotic activity predominates. The M transcript appears at the onset of gonadal growth and is maintained at constant levels through spermatogenesis consistent with the expansion of the muscular sheath surrounding the testes. The FAT, H3 histone, and beta-tubulin transcripts reach their highest levels in ripe testes when spermiogenic activity is maximal. The homology of the FAT transcript to actin, and its pattern of expression, suggest the hypothesis that this transcript may encode acrosomal actin.

Actins↗

PubMed1994

Genetic mapping of two new blood pressure quantitative trait loci in the rat by genotyping endothelin system genes.

The endothelin system, consisting of a series of potent vasoconstrictor peptides and their receptors, is potentially important in the control of blood pressure. We found that the gene coding for endothelin-2 (ET2), also known as vasoctive intestine peptide, cosegregated strongly with systolic blood pressure in a F2 population [F2(S x LEW)] derived from a cross of the Dahl salt-sensitive (S) rat and the Lewis (LEW/NCrlBR) (LEW) rat. The ET2 locus was assigned to rat chromosome 5. The testis-specific histone (HITH) locus also strongly cosegregated with blood pressure in the F2(S x LEW) population and was assigned to rat chromosome 17. Genetic maps of the regions containing the quantitative trait loci (QTL) for blood pressure on chromosomes 5 and 17 were constructed and the QTL were localized using the MAPMAKER/QTL program. The rat genes for endothelin-1, endothelin-3, and endothelin receptor A did not cosegregate with blood pressure in several F2 populations tested and were assigned to rat chromosomes 17, 3, and 19, respectively. Endothelin receptor B cosegregated weakly with blood pressure and was provisionally assigned to rat chromosome 15. We conclude that, in the rat, one new blood pressure QTL is located on chromosome 5 marked by the ET2 locus and another new QTL is located on chromosome 17 near the HITH locus.

Animals↗

PubMed1992

Presence of distinct transcriptional regulatory elements in the 5'-flanking region shared by the chicken H3 histone gene homopair.

The chicken H3 histone gene family contains nine members belonging to two major histone gene clusters. Six of these genes have been sequenced and shown to encode two different H3 protein variants. Five H3 genes (H3-I, -II, -IV, -V, and -VI) encode the same amino acid sequence (class I) and another H3 gene (H3-III) differs from class I in a single amino acid (IIe113-Met) (class II). H3-II and H3-III have inverted orientations and share a 5' intergenic region of about 900 bp. To understand the regulation of expression of these two genes, we fused the 5'-flanking region to the CAT gene in inverted orientations to generate two chimeric plasmids, pH3-II-900 and pH3-III-900. Transient CAT assays using these constructs indicated that the promoter of H3-III is more active than that of H3-II. CAT assays with deletion mutants showed that H3-II and H3-III each possess a particular transcription regulatory sequence 5' adjacent to their coding sequence. In addition, the functional sequences of H3-II have no effect on expression of H3-III and vice versa. These results suggest that the regulations of expression of the two H3 genes are distinct.

3T3 Cells↗

PubMed2002

RNA polymerase II elongation factors of Saccharomyces cerevisiae: a targeted proteomics approach.

To physically characterize the web of interactions connecting the Saccharomyces cerevisiae proteins suspected to be RNA polymerase II (RNAPII) elongation factors, subunits of Spt4/Spt5 and Spt16/Pob3 (corresponding to human DSIF and FACT), Spt6, TFIIF (Tfg1, -2, and -3), TFIIS, Rtf1, and Elongator (Elp1, -2, -3, -4, -5, and -6) were affinity purified under conditions designed to minimize loss of associated polypeptides and then identified by mass spectrometry. Spt16/Pob3 was discovered to associate with three distinct complexes: histones; Chd1/casein kinase II (CKII); and Rtf1, Paf1, Ctr9, Cdc73, and a previously uncharacterized protein, Leo1. Rtf1 and Chd1 have previously been implicated in the control of elongation, and the sensitivity to 6-azauracil of strains lacking Paf1, Cdc73, or Leo1 suggested that these proteins are involved in elongation by RNAPII as well. Confirmation came from chromatin immunoprecipitation (ChIP) assays demonstrating that all components of this complex, including Leo1, cross-linked to the promoter, coding region, and 3' end of the ADH1 gene. In contrast, the three subunits of TFIIF cross-linked only to the promoter-containing fragment of ADH1. Spt6 interacted with the uncharacterized, essential protein Iws1 (interacts with Spt6), and Spt5 interacted either with Spt4 or with a truncated form of Spt6. ChIP on Spt6 and the novel protein Iws1 resulted in the cross-linking of both proteins to all three regions of the ADH1 gene, suggesting that Iws1 is likely an Spt6-interacting elongation factor. Spt5, Spt6, and Iws1 are phosphorylated on consensus CKII sites in vivo, conceivably by the Chd1/CKII associated with Spt16/Pob3. All the elongation factors but Elongator copurified with RNAPII.

Amino Acid Sequence↗

PubMed2004

No germline mutations in the histone acetyltransferase gene EP300 in BRCA1 and BRCA2 negative families with breast cancer and gastric, pancreatic, or colorectal cancer.

INTRODUCTION: Mutations in BRCA1, BRCA2, ATM, TP53, CHK2 and PTEN account for many, but not all, multiple-case breast and ovarian cancer families. The histone acetyltransferase gene EP300 may function as a tumour suppressor gene because it is sometimes somatically mutated in breast, colorectal, gastric and pancreatic cancers, and is located on a region of chromosome 22 that frequently undergoes loss of heterozygosity in many cancer types. We hypothesized that germline mutations in EP300 may account for some breast cancer families that include cases of gastric, pancreatic and/or colorectal cancer. METHODS: We screened the entire coding region of EP300 for mutations in the youngest affected members of 23 non-BRCA1/BRCA2 breast cancer families with at least one confirmed case of gastric, pancreatic and/or colorectal cancer. These families were ascertained in Australia through the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer. RESULTS: Denaturing HPLC analysis identified a heterozygous alteration at codon 211, specifically a GGC to AGC (glycine to serine) alteration, in two individuals. This conservative amino acid change was not within any known functional domains of EP300. The frequency of the Ser211 variant did not differ significantly between a series of 352 breast cancer patients (4.0%) and 254 control individuals (2.8%; P = 0.5). CONCLUSION: The present study does not support a major role for EP300 mutations in breast and ovarian cancer families with a history of gastric, pancreatic and/or colorectal cancer.

Acetyltransferases↗

PubMed1998

Comparative analysis of evolution in a rodent histone H2a pseudogene.

Sequences were obtained from five species of rodents that are orthologous to an H2a histone pseudogene from Mus musculus. The pseudogene is part of the cluster of replication-dependent histone genes found on Mus musculus chromosome 13. Comparative analysis of these five sequences together with the previously published sequence from M. musculus shows that this gene has likely been a pseudogene throughout the evolution of the genus Mus, while the gene from Rattus norvegicus is likely functional. Three large (> 20 bp) deletions were found among the Mus pseudogenes, a feature that is very unusual compared to surveys of processed pseudogenes. In addition, there are two single-base deletions and one 4-bp insertion among the Mus pseudogenes. The species distributions of one of the large deletions and the 4-bp insertion require either independent insertions of an identical sequence, independent deletions with identical boundaries, or a deletion followed by precise reintegration of the original sequence. The evidence favors the hypothesis of multiple deletions with identical boundaries. The "coding" regions of the Mus pseudogenes show a much reduced level of among-species variability in the 3' half of the pseudogene, compared both to the 5' half and to flanking sequences. This supports a hypothesis that the 3' end of the pseudogene is the target of frequent gene conversion by functional H2a genes.

Animals↗