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PubMed2002

Comparative sequence analysis of the X-inactivation center region in mouse, human, and bovine.

We have sequenced to high levels of accuracy 714-kb and 233-kb regions of the mouse and bovine X-inactivation centers (Xic), respectively, centered on the Xist gene. This has provided the basis for a fully annotated comparative analysis of the mouse Xic with the 2.3-Mb orthologous region in human and has allowed a three-way species comparison of the core central region, including the Xist gene. These comparisons have revealed conserved genes, both coding and noncoding, conserved CpG islands and, more surprisingly, conserved pseudogenes. The distribution of repeated elements, especially LINE repeats, in the mouse Xic region when compared to the rest of the genome does not support the hypothesis of a role for these repeat elements in the spreading of X inactivation. Interestingly, an asymmetric distribution of LINE elements on the two DNA strands was observed in the three species, not only within introns but also in intergenic regions. This feature is suggestive of important transcriptional activity within these intergenic regions. In silico prediction followed by experimental analysis has allowed four new genes, Cnbp2, Ftx, Jpx, and Ppnx, to be identified and novel, widespread, complex, and apparently noncoding transcriptional activity to be characterized in a region 5' of Xist that was recently shown to attract histone modification early after the onset of X inactivation.

Animals↗
PubMed2005

Variation in exon 1 coding region and promoter of MECP2 in Rett syndrome and controls.

Mutations in MECP2 are a cause of Rett syndrome. Recently, a new isoform of MeCP2 was described, which has an alternative N-terminus, transcribed from exon 1. We screened exon 1 and the promoter region of MECP2 in 97 mutation-negative Rett syndrome cases. We found two sequence variants, but there was no evidence that they are pathogenic. Mutations in exon 1 and the promoter of MECP2 are not a common cause of Rett syndrome.

Case-Control Studies↗
PubMed1996

Identification, purification, and molecular cloning of autonomously replicating sequence-binding protein 1 from fission yeast Schizosaccharomyces pombe.

Autonomously replicating sequence (ARS) elements of the fission yeast Schizosaccharomyces pombe contain multiple imperfect copies of the consensus sequence reported by Maundrell et al. [Maundrell K., Hutchison, A. & Shall, S. (1988) EMBO J. 7, 2203-2209]. When cell free extracts of S. pombe were incubated with a dimer or tetramer of an oligonucleotide containing the ARS consensus sequence, several complexes were detected using a gel mobility-shift assay. The proteins forming these complexes also bind ars3002, which is the most active origin in the ura4 region of chromosome III of S. pombe. One protein, partly responsible for the binding activity observed with crude extracts, was purified to near homogeneity. It is a 60-kDa protein and was named ARS-binding protein 1 (Abp1). Abp1 preferentially binds to multiple sites in ARS 3002 and to the DNA polymer poly[d(A.T)]. The cloning and sequence of the gene coding for Abp1 revealed that it encodes a protein of 59.8 kDa (522 amino acids). Abp1 has significant homology (25% identity, 50% similarity) to the N-terminal region (approximately 300 amino acids) of the human and mouse centromere DNA-binding protein CENP-B. Because centromeres of S. pombe contain a high density of ARS elements, Abp1 may play a role connecting DNA replication and chromosome segregation.

Amino Acid Sequence↗
PubMed2001

RIZ, the retinoblastoma protein interacting zinc finger gene, is mutated in genetically unstable cancers of the pancreas, stomach, and colorectum.

The retinoblastoma protein interacting zinc finger (RIZ) gene is a candidate tumor suppressor gene on 1p36, a region frequently rearranged in a wide variety of human tumors. As the RIZ gene harbors several microsatellites within its coding region, it is a candidate for an inactivating mutation in microsatellite instability (MSI) mediated carcinogenesis. In this study, we examined mutations of two poly adenine tracts, A(8) and A(9), within the coding region of the RIZ gene, in MSI-high (MSI-H) primary cancers occurring in the pancreas, stomach, and colorectum. Frameshift mutations were found in one (10%) of 10 pancreatic, four (36%) of 11 gastric, and two (25%) of eight colorectal cancers. These results indicate that mutations of the RIZ gene play an important role in the pathogenesis of some MSI-H cancers.

Colorectal Neoplasms↗
PubMed1990

Primary structure of non-histone chromosomal protein HMG2 revealed by the nucleotide sequence.

The isolation and sequencing of a cDNA clone for the entire sequence of pig thymus non-histone protein HMG2 are described. cDNA the size of 1153 nucleotides contains an open reading frame of 627 nucleotides. The 5'-untranslated region of 146 nucleotides is extremely rich in GC residues whereas the 3'-untranslated region of 380 nucleotides is rich in AT residues. The open reading frame encodes 209 amino acids, which contain a unique continuous run of 23 acidic amino acids at the C-terminal. The deduced amino acid sequence is 79% homologous to that of HMG1 protein from the same source which we reported [Tsuda, K., Kikuchi, M., Mori, K., Waga, S., & Yoshida, M. (1988) Biochemistry 27, 6159-6163]. In addition, the hydropathy index profiles of both proteins are very similar, supporting that they have similar structural features. Northern analysis of poly(A+) RNA reveals that a single-sized mRNA codes for HMG2 protein. Southern analysis suggests that the HMG2 coding gene is homogeneous within the pig thymus genome.

Amino Acid Sequence↗
PubMed1996

A specific deletion in the breakpoint cluster region of the ALL-1 gene is associated with acute lymphoblastic T-cell leukemias.

A variety of chromosomal translocations to the ALL-1 gene are regularly observed in acute leukemias and are thought to play a key role in the leukemogenic process. Chimeric proteins are encoded by the breakpoint regions of the derivative chromosomes have been proposed to be the relevant oncogenic agents. In addition, internal duplications of the ALL-1 gene have been observed in patients with specific acute myeloid leukemias. Thus, it has been hypothesized that oncogenic variants of the ALL-1 protein may be generated by both chimerization and self-fusion, but the critical structural features endowing the altered proteins with their oncogenic potential are still unknown. Here a novel structural alteration of the ALL-1 gene was observed in three patients presenting with acute T-cell leukemia (ALL) without chromosomal translocations or self-fusions of the ALL-1 gene. These unrelated patients carried an internal deletion in one of the two alleles of the ALL-1 gene that eliminated parts of introns 7 and 8, together with exon 8. The deletion was found in 3 of 74 ALL patients, but not in acute myeloid leukemias, follicular lymphomas, or peripheral blood leukocytes from healthy donors. One ALL patient showed the deletion at diagnosis but no longer at remission or at 9 months after remission. These findings support the hypothesis that the ALL-1 protein may be converted to an oncogenic variant, not only by chimerization or self-fusion, but also by deletion of sequences coded by exon 8. They further suggest that these three different types of structural alterations of the ALL-1 protein may each cause a distinct disease phenotype. Alternatively spliced mRNA species omitting exon 8 were observed in 14 of 24 ALL patients without detectable macroscopic alterations of the ALL-1 gene and also in peripheral blood leukocytes from healthy donors.

Adolescent↗
PubMed2001

Rett syndrome in Spain: mutation analysis and clinical correlations.

Rett syndrome (RTT) is an X-linked neurodevelopmental disease that affects girls almost exclusively. In a high proportion of patients the disease is caused by de novo mutations at the MECP2 gene, encoding methyl-CpG-binding protein 2. With the aim to characterize the spectrum of mutations in a series of sporadic RTT patients, including an affected male, and to relate the genetic results to the clinical features of the disease, a clinical checklist and a score system were elaborated to evaluate the clinical severity of the disease. Mutation analysis of the MECP2 coding region was done by direct sequencing. De novo mutations were found in 60% of the patients, including both classic and atypical forms. The change R133H was identified in a 13-year-old boy showing a classic RTT phenotype and normal karyotype. Significant differences were observed among missense and truncating mutations regarding disease severity, age of onset of stereotypies, and the ability of the patients to sit alone and to walk.

Adolescent↗
PubMed2003

Molecular pathogenesis of non-Hodgkin's lymphoma: the role of Bcl-6.

Non-Hodgkin's lymphomas (NHL) form a heterogeneous group of diseases, with diffuse large B-cell lymphoma (DLBCL) comprising the largest subgroup. The commonest chromosomal translocations found in DLBCL are those affecting band 3q27. In 35% of DLBCL cases, as well as in a small fraction of follicular lymphomas, the normal transcriptional regulation of Bcl-6 is disrupted by these chromosomal translocations. In addition, about three-quarters of cases of DLBCL display multiple somatic mutations in the 5' non-coding region of Bcl-6, which occur independently of chromosomal translocations and appear to be due to the IgV-associated somatic hypermutation process. Bcl-6 is a 95-kD nuclear phosphoprotein belonging to the BTB/POZ (bric-a-brac, tramtrack, broad complex/Pox virus zinc finger) zinc finger family of transcription factors. It has been suggested that Bcl-6 is important in the repression of genes involved in the control of lymphocyte activation, differentiation, and apoptosis within the germinal center, and that its down-regulation is necessary for normal B-cells to exit the germinal center. Bcl-6 remains constitutively expressed in a substantial proportion of B-cell lymphomas. Recently, acetylation has been identified as a mode for down-regulating Bcl-6 activity by inhibition of the ability of Bcl-6 to recruit complexes containing histone deacetylases (HDAC). The pharmacologic inhibition of two recently identified deacetylation pathways, HDAC- and silent information regulator (SIR)-2-dependent deacetylation, results in the accumulation of inactive acetylated Bcl-6 and thus in cell cycle arrest and apoptosis in B-cell lymphoma cells. These results reveal a new method of regulating Bcl-6, with the potential for therapeutic exploitation. These studies also indicate a novel mechanism by which acetylation promotes transcription, not only by modifying histones and activating transcriptional activators, but also by inhibiting transcriptional repressors.

Acetylation↗
PubMed2000

RNA polymerase II elongation through chromatin.

The machinery that transcribes protein-coding genes in eukaryotic cells must contend with repressive chromatin structures in order to find its target DNA sequences. Diverse arrays of proteins modify the structure of chromatin at gene promoters to help transcriptional regulatory proteins access their DNA recognition sites. The way in which disruption of chromatin structure at a promoter is transmitted through a whole gene has not been defined. Recent breakthroughs suggest that the passage of an RNA polymerase through a gene is coupled to mechanisms that propagate the breakdown of chromatin.

Acetylation↗
PubMed2004

Pharmacological inhibition of fatty acid synthase (FAS): a novel therapeutic approach for breast cancer chemoprevention through its ability to suppress Her-2/neu (erbB-2) oncogene-induced malignant transformation.

We designed our experiments to evaluate whether fatty acid synthase (FAS), a lipogenic enzyme linked to tumor virulence in population studies of human cancer, is necessary for the malignant transformation induced by Her-2/neu (erbB-2) oncogene, which is overexpressed not only in invasive breast cancer but also in premalignant atypical duct proliferations and in ductal carcinoma in situ of the breast. To avoid the genetic complexities associated with established breast cancer cell lines, we employed NIH-3T3 mouse fibroblasts engineered to overexpress human Her-2/neu coding sequence. NIH-3T3/Her-2 cells demonstrated a significant upregulation of FAS protein expression, which was dependent on the upstream activation of mitogen-activated protein kinase and phosphatidylinositol 3'-kinase/AKT pathways. Remarkably, pharmacological FAS blockade using the mycotoxin cerulenin or the novel small compound C75 completely suppressed the state of Her-2/neu-induced malignant transformation by inhibiting the ability of NIH-3T3/Her-2 cells to grow under either anchorage-independent (i.e., to form colonies in soft agar) or low-serum monolayer conditions. Moreover, NIH-3T3/Her-2 fibroblasts were up to three times more sensitive to chemical FAS inhibitors relative to untransformed controls as determined by MTT-based cell viability assays. In addition, pharmacological FAS blockade preferentially induced apoptotic cell death of NIH-3T3/Her-2 fibroblasts, as determined by an ELISA for histone-associated DNA fragments and by the terminal deoxynucleotidyltransferase (TdT)-mediated nick end labeling assay (TUNEL). Interestingly, the degree of Her-2/neu oncogene expression in a panel of breast cancer cell lines was predictive of sensitivity to chemical FAS inhibitors-induced cytotoxicity, while low-FAS expressing and chemical FAS inhibitors-resistant MDA-MB-231 breast cancer cells became hypersensitive to FAS blockade when they were engineered to overexpress Her-2/neu. Our observations strongly suggest that inhibition of FAS activity may provide a new molecular avenue for chemotherapeutic prevention and/or treatment of Her-2/neu-related breast carcinomas.

4-Butyrolactone↗
PubMed1997

Genetic testing for male infertility: a postulated role for mutations in sperm nuclear matrix attachment regions.

Numerous reports have suggested that disturbances in nuclear condensation may result in male infertility. This notion has been supported by the observation of infertile individuals with a decrease or absence of the male sperm-specific chromatin packaging protamine proteins. To date, no correlation between the absence of protamine proteins and a mutation within the coding regions of the protamine genes has been documented. To address this issue, PCR-based mutation scanning analysis has been performed across the human male haploid expressed PRM1-->PRM2-->TNP2 domain in several oligozoospermic infertile individuals. This analysis identified a candidate mutation in a region of contact with the sperm nuclear matrix from 2 of 5 affected individuals. This is the first report of a mutation scan covering the entire PRM1-->PRM2-->TNP2 locus in affected individuals.

Chromosomal Proteins, Non-Histone↗
PubMed1991

Estrogen-induced ribonuclease activity in Xenopus liver.

Estrogen administration to male Xenopus causes the cytoplasmic destabilization of the hepatic serum protein coding mRNAs, most notably, albumin, yet has little effect on mRNAs encoding intracellular proteins such as ferritin. This report describes an estrogen-inducible ribonuclease activity found in liver polysomes that degrades albumin mRNA 4 times faster in vitro than it degrades ferritin mRNA. This differential rate of degradation was observed upon incubation of polysome extract with free liver RNA, isolated liver mRNPs, or transcripts from plasmid vectors. A cleavage fragment consisting of a doublet of approximately 194 nucleotides in length was consistently observed upon digestion of transcripts for the full length or 5' half of albumin mRNA. The generation of this cleavage fragment was used as an assay to study properties of the polysome nuclease activity. The 194 doublet is produced by the action of a Mg(2+)-independent endonuclease. This distinguishes the Xenopus liver enzyme from the enzymes that degrade histone or c-myc mRNA in vitro. It is inactivated by 400 mM NaCl or heating at 90 degrees C, but not by placental ribonuclease inhibitor or N-ethylmaleimide. Finally, the polysomal nuclease activity does not degrade double-stranded RNA. We believe the estrogen-induced nuclease activity contains an enzyme(s) that may mediate hormone-regulated changes in mRNA stability in this tissue.

Animals↗
PubMed1997

Analysis of mutation rates in the SMCY/SMCX genes shows that mammalian evolution is male driven.

Mammalian evolution is believed to be male driven because the greater number of germ cell divisions per generation in males increases the opportunity for errors in DNA replication. Since the Y Chromosome (Chr) replicates exclusively in males, its genes should also evolve faster than X or autosomal genes. In addition, estimating the overall male-to-female mutation ratio (alpha m) is of great importance as a large alpha m implies that replication-independent mutagenic events play a relatively small role in evolution. A small alpha m suggests that the impact of these factors may, in fact, be significant. In order to address this problem, we have analyzed the rates of evolution in the homologous X-Y common SMCX/SMCY genes from three different species--mouse, human, and horse. The SMC genes were chosen because the X and Y copies are highly homologous, well conserved in evolution, and in all probability functionally interchangeable. Sequence comparisons and analysis of synonymous substitutions in approximately 1kb of the 5' coding region of the SMC genes reveal that the Y-linked copies are evolving approximately 1.8 times faster than their X homologs. The male-to-female mutation ratio alpha m was estimated to be 3. These data support the hypothesis that mammalian evolution is male driven. However, the ratio value is far smaller than suggested in earlier works, implying significance of replication-independent mutagenic events in evolution.

Amino Acid Sequence↗
PubMed1997

The retinoblastoma interacting zinc finger gene RIZ produces a PR domain-lacking product through an internal promoter.

The PR domain is a newly recognized protein motif that characterizes a subfamily of Krüppel-like zinc finger genes. Members of the PR domain family have been shown to play important roles in cell differentiation and malignant transformation. The RIZ gene is the founding member of this family; it was isolated because its gene products can bind to the retinoblastoma tumor suppressor protein. Here, we have studied the RIZ gene structure and expression. By immunoprecipitation and immunoblot analysis we identified two different RIZ protein products of 280 and 250 kDa, designated RIZ1 and RIZ2, respectively. The 280-kDa RIZ1 product comigrated with the RIZ cDNA-derived polypeptide. The 250-kDa RIZ2 product lacked the NH2-terminal PR domain of RIZ1; it comigrated with a truncated RIZ1 polypeptide that was initiated from an internal ATG codon. Both the full-length and the truncated RIZ1 polypeptide were located in the nucleus as shown by transfection and immunofluorescence analysis. We identified the RIZ2 transcripts and showed that they were produced by an internal promoter located at the 5' boundary of coding exon 5. RNase protection analysis revealed similar ratios of RIZ1 and RIZ2 transcripts in most adult rat tissues except in testis, where RIZ1 was more abundant than RIZ2. These observations were strikingly similar to those described for the MDS1-EVI1 cancer gene, which also normally gives rise to a PR domain-lacking product, EVI1, because of an internal promoter.

Amino Acid Sequence↗
PubMed1995

Treatment with propionic and butyric acid enhances expression variegation and promoter methylation in plant transgenes.

Two phenotypic marker genes (A1 and GUS) were employed to monitor the influence of small chain fatty acids on transgene expression in petunia and tobacco. In plants homozygous with respect to the A1 transgene, which normally carry red flowers due to A1 expression, fatty acid treatment induced a range of variegated and white pigmentation patterns which persisted for several months after terminating the treatment. The inhibitory effect was clearly less pronounced for heterozygous plants of the same transgenic line. In all cases the reduction of transgene activities correlated with an increase in transgene promoter methylation. Contrary to evidence reported for mammals and Drosophila, we do not observe an increase in gene expression, but an enhancement of DNA methylation and epigenetic variegation. The inhibition of transgene activity was also observed in several tobacco transformants cultured on fatty acid containing media. Some tobacco transformants carrying Gus-coding regions driven by either 35S or 1'2' promoters responded with a significant reduction in GUS activity. This study suggests that, rather than exerting a general response on all chromatin regions, fatty acids appear to affect genes in a labile epigenetic surrounding or all genes in a susceptible chromatin configuration. Thus, application of these agents may be useful to screen and monitor transgenes prone to epigenetic instabilities.

Acetylation↗
PubMed2025

CDACHIE: chromatin domain annotation by integrating chromatin interaction and epigenomic data with contrastive learning.

MOTIVATION: Chromatin domain annotation identifies functional genomic regions, such as active and inactive zones, based on epigenomic features like histone modifications, DNA methylation, and chromatin accessibility. While recent methods have utilized both chromatin interaction data (e.g. Hi-C) and epigenomic data, they often overlook the direct relationship between these data types. RESULTS: In this study, we introduce Chromatin Domain Annotation using Contrastive Learning for Hi-C and Epigenomic Data (CDACHIE), a method for identifying chromatin domains from Hi-C and epigenomic data. Our approach leverages contrastive learning to generate aligned representative vectors for both data types at each genomic bin. The concatenated vectors are then clustered using K-means to classify distinct chromatin domain types. CDACHIE achieves superior performance in Variance Explained, evaluated across gene expression, replication timing, and ChIA-PET data. This highlights its robust ability to integrate semantic associations between Hi-C and epigenomic features within the embedding space. AVAILABILITY AND IMPLEMENTATION: The source code is available at GitHub: https://github.com/maruyama-lab-design/CDACHIE. An archival snapshot of the code used in this study is available on Zenodo: https://doi.org/10.5281/zenodo.15751780.

Chromatin↗
PubMed2006

Semi-quantitative fluorescent PCR analysis identifies PRKAA1 on chromosome 5 as a potential candidate cancer gene of cervical cancer.

OBJECTIVE: Comparative genomic hybridization has frequently detected amplification of chromosome 5p in cervical cancer, but candidate cancer genes within the region are rarely known. Therefore, we pursued to identify potential candidate gene related to cervical cancer development. METHODS: A series of 128 cervical tumor samples were examined by semi-quantitative fluorescent differential PCR for copy number changes on three candidate genes (PRKAA1, CTNND2 and POLS) mapped to chromosome 5p and one gene (ERBIN) mapped to chromosome 5q12.3. The impact of gene copy number was later analyzed in relation to HPV infection, tumor stage or tumor radiosensitivity. RESULTS: DNA copy numbers of PRKAA1, CTNND2 and ERBIN were significantly different from normal controls (P < 0.05). DNA copy number changes did not correlate with HPV infection, tumor stages or tumor radiosensitivity. Using RT-PCR, PRKAA1 mRNA expression in seven tumor samples with known 5p amplification was amplified from 3- to 15-fold. Over-expression of PRKAA1 was further confirmed by immunohistochemical staining on 125 paraffin-embedded cervical cancer tissues. The expression level in cervical tumor was significantly higher than that in normal epithelium (P < 0.001). CONCLUSIONS: PRKAA1 gene codes for the catalytic alpha 1 subunit of the AMP-activated protein kinase which is an important cellular metabolic stress regulator. It might assist tumor cells growth under stress. Thus, PRKAA1 may be one of the potential candidate genes for cervical carcinogenesis.

AMP-Activated Protein Kinases↗
PubMed2000

Two novel Drosophila TAF(II)s have homology with human TAF(II)30 and are differentially regulated during development.

TFIID is a multiprotein complex composed of the TATA binding protein (TBP) and TBP-associated factors (TAF(II)s). The binding of TFIID to the promoter is the first step of RNA polymerase II preinitiation complex assembly on protein-coding genes. Yeast (y) and human (h) TFIID complexes contain 10 to 13 TAF(II)s. Biochemical studies suggested that the Drosophila (d) TFIID complexes contain only eight TAF(II)s, leaving a number of yeast and human TAF(II)s (e.g., hTAF(II)55, hTAF(II)30, and hTAF(II)18) without known Drosophila homologues. We demonstrate that Drosophila has not one but two hTAF(II)30 homologues, dTAF(II)16 and dTAF(II)24, which are encoded by two adjacent genes. These two genes are localized in a head-to-head orientation, and their 5' extremities overlap. We show that these novel dTAF(II)s are expressed and that they are both associated with TBP and other bona fide dTAF(II)s in dTFIID complexes. dTAF(II)24, but not dTAF(II)16, was also found to be associated with the histone acetyltransferase (HAT) dGCN5. Thus, dTAF(II)16 and dTAF(II)24 are functional homologues of hTAF(II)30, and this is the first demonstration that a TAF(II)-GCN5-HAT complex exists in Drosophila. The two dTAF(II)s are differentially expressed during embryogenesis and can be detected in both nuclei and cytoplasm of the cells. These results together indicate that dTAF(II)16 and dTAF(II)24 may have similar but not identical functions.

Amino Acid Sequence↗