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PubMed2005

MLL associates specifically with a subset of transcriptionally active target genes.

MLL (mixed-lineage leukemia) is a histone H3 Lys-4 specific methyltransferase that is a positive regulator of Hox expression. MLL rearrangements and amplification are common in acute lymphoid and myeloid leukemias and myelodysplastic disorders and are associated with abnormal up-regulation of Hox gene expression. Although MLL is expressed throughout hematopoiesis, Hox gene expression is sharply down-regulated during differentiation, suggesting that either the activity of MLL or its association with target promoters must be regulated. Here we show that MLL associates with actively transcribed genes but does not remain bound after transcriptional down-regulation. Surprisingly, MLL is associated not only with promoter regions but also is distributed across the entire coding regions of genes. MLL interacts with RNA polymerase II (pol II) and colocalizes with RNA pol II at a subset of actively transcribed target in vivo. Loss of function Mll results in defects in RNA pol II distribution. Together the results suggest that an intimate association between MLL and RNA pol II occurs at MLL target genes in vivo that is required for normal initiation and/or transcriptional elongation.

Animals↗
PubMed2000

Functional analysis of six genes from chromosomes XIV and XV of Saccharomyces cerevisiae reveals YOR145c as an essential gene and YNL059c/ARP5 as a strain-dependent essential gene encoding nuclear proteins.

We report here basic functional analysis of strains deleted for six open reading frames (ORFs), YNL059c and YNL148c from chromosome XIV and YOR145c, YOR152c, YOR161c and YOR162c from chromosome XV of Saccharomyces cerevisiae. ORFs were replaced with the KanMX4 resistance marker using a long flanking homology PCR strategy in FY1679 and W303 diploid strains. Replacement cassettes were constructed in plasmid pUG7 and the cognate wild-type genes were recovered by gap repair. Sporulation and tetrad analysis revealed that deletion of YNL059c/ARP5 was lethal for vegetative growth in strain W303 and caused severe growth defects in strain FY1679 while YOR145c was essential for growth in both strains. Fusion of the green fluorescent protein (GFP) gene to the 3' ends of the YNL059c/ARP5 and YOR145c coding sequences created functional chimeric genes at the respective chromosomal loci. Both Arp5-GFP and Yor145-GFP localized to the nucleus, Yor145-GFP concentrating in the nucleolus. The vectors containing the deletion cassettes and the cognate wild-type genes, the oligonucleotides, and the deletant strains are available from the EUROFAN resource centre EUROSCARF (Frankfurt).

Actins↗
PubMed2004

Characterization of a CENP-C homolog in Arabidopsis thaliana.

Centromere protein C (CENP-C) is a component of the kinetochore essential for correct segregation of sister chromatids in mammals. In Arabidopsis thaliana, a single-copy gene encoding a protein homologous to CENP-C has been found by homology in the whole-genome sequence. To investigate the CENP-C homolog (AtCENP-C), we cloned cDNAs by RT-PCR and determined its full-length coding sequence. Antibodies against the synthetic peptide for the C-terminal residues of AtCENP-C detected a polypeptide in Arabidopsis cell extracts on western blots. Immunofluorescence labeling with the antibodies and fluorescence in situ hybridization demonstrated clearly that AtCENP-C is present at the centromeric regions throughout the cell cycle.

Amino Acid Sequence↗
PubMed2025

Genome-Wide Silencer Screening Reveals Key Silencer Modulating Reprogramming Efficiency in Mouse Induced Pluripotent Stem Cells.

The majority of the mouse genome is composed of non-coding regions, which harbor numerous regulatory sequences essential for gene regulation. While extensive research focuses on enhancers that activate gene expression, the role of silencers that repress gene expression remains less explored. In this study, the first genome-wide identification of silencers in the mouse genome is conducted. In mouse embryonic fibroblasts (MEFs) and embryonic stem cells (mESCs), 89 596 and 115 165 silencers are identified, respectively. These silencers are ubiquitously distributed across the genome and are predominantly associated with low-expression genes. Additionally, these silencers are mainly cell-specific and function by binding to repressive transcription factors (TFs). Further, these silencers are notably enriched with the histone modification H3K9me3. It is observed that the transformation between dual-function silencers and enhancers is correlated with intracellular transcription factor concentrations, accompanied by changes in epigenetic modifications. In terms of biological effects, we have identified silencers that can enhance the induction efficiency of MEFs and influence the pluripotency of mESCs. Collectively, this work offers the first comprehensive silencer landscape in the mouse genome and provides strong evidence for the role of silencers in the induction of induced pluripotent stem cells (iPSCs).

Animals↗
PubMed2006

MSL proteins and the regulation of gene expression.

Epigenetics describes changes in genome function that occur without a change in the DNA sequence. Dosage compensation is a prime example of the regulation of gene expression by an epigenetic mechanism. Dosage compensation has evolved to balance the expression of sex-linked genes in males and females, which possess different numbers of sex chromosomes. However, the genetic sequence of the chromosomes is the same in both sexes. This mechanism therefore needs (1) to function in a sex-specific manner, (2) to target the sex chromosome from amongst the autosomes and (3) to establish and maintain through development a precise, equalised level of gene expression in one sex compared to the other. The process by which dosage compensation is orchestrated has been well characterised in fruit flies and mammals. Although each has evolved a specific dosage-compensation mechanism, these systems share some underlying themes; the molecular components that mediate dosage compensation in both include non-coding RNA molecules, which act as nucleation points for the compensation process. Both systems utilise chromatin-modifying enzymes to remodel large domains of a chromosome. This review will discuss the mechanism of dosage compensation in Drosophila in light of recent developments that have brought into question the previous model of dosage compensation.

Animals↗
PubMed2006

Comparison of dot chromosome sequences from D. melanogaster and D. virilis reveals an enrichment of DNA transposon sequences in heterochromatic domains.

BACKGROUND: Chromosome four of Drosophila melanogaster, known as the dot chromosome, is largely heterochromatic, as shown by immunofluorescent staining with antibodies to heterochromatin protein 1 (HP1) and histone H3K9me. In contrast, the absence of HP1 and H3K9me from the dot chromosome in D. virilis suggests that this region is euchromatic. D. virilis diverged from D. melanogaster 40 to 60 million years ago. RESULTS: Here we describe finished sequencing and analysis of 11 fosmids hybridizing to the dot chromosome of D. virilis (372,650 base-pairs) and seven fosmids from major euchromatic chromosome arms (273,110 base-pairs). Most genes from the dot chromosome of D. melanogaster remain on the dot chromosome in D. virilis, but many inversions have occurred. The dot chromosomes of both species are similar to the major chromosome arms in gene density and coding density, but the dot chromosome genes of both species have larger introns. The D. virilis dot chromosome fosmids have a high repeat density (22.8%), similar to homologous regions of D. melanogaster (26.5%). There are, however, major differences in the representation of repetitive elements. Remnants of DNA transposons make up only 6.3% of the D. virilis dot chromosome fosmids, but 18.4% of the homologous regions from D. melanogaster; DINE-1 and 1360 elements are particularly enriched in D. melanogaster. Euchromatic domains on the major chromosomes in both species have very few DNA transposons (less than 0.4 %). CONCLUSION: Combining these results with recent findings about RNAi, we suggest that specific repetitive elements, as well as density, play a role in determining higher-order chromatin packaging.

Animals↗
PubMed2006

A large deletion on chromosome 11 in acute intermittent porphyria.

Acute intermittent porphyria (AIP) is an autosomal disorder caused by molecular abnormalities in the gene coding for hydroxymethylbilane synthase (HMBS), the third enzyme in the heme biosynthetic pathway. So far, more than 242 different mutations responsible for AIP have been identified in this gene. In an Italian family with typical clinical and biochemical signs of AIP, no mutation was found by direct sequencing of the entire hydroxymethylbilane synthase gene (HMBS). All the symptomatic patients showed apparent homozygosity and absence of mendelian segregation for eleven common polymorphisms along the gene. Excluding interference of polymorphisms in the primer sites, we assumed the presence of a complete HMBS gene deletion. In order to identify the size of this deletion, single nucleotide polymorphisms (SNPs) analysis was extended to flanking genes, H2A Histone Family member X (H2AFX) and Dolichyl-Phosphate N-Acetylglucosamine Phosphotransferase 1 (DPAGT1), downstream and Vacuolar protein sorting 11 (VPS11), upstream. Heterozygous polymorphisms in the VPS11 and DPAGT1 genes were found. Thus, we performed a Long-PCR with primers situated in regions outside the homozygous polymorphisms and we identified a double deletion with inversion on chromosome 11 (g22516974_22524062del7088, g22524062_22524278inv216, g22524278_22531093del6815). Even if the deletions include the entire HMBS and H2AFX genes and 1463 bp of the final portion of DPAGT1 gene, our patients had no other symptoms than AIP.

Chromosome Deletion↗
PubMed2002

The bacterial histone-like protein HU specifically recognizes similar structures in all nucleic acids. DNA, RNA, and their hybrids.

HU, a major component of the bacterial nucleoid, shares properties with histones, high mobility group proteins (HMGs), and other eukaryotic proteins. HU, which participates in many major pathways of the bacterial cell, binds without sequence specificity to duplex DNA but recognizes with high affinity DNA repair intermediates. Here we demonstrate that HU binds to double-stranded DNA, double-stranded RNA, and linear DNA-RNA duplexes with a similar low affinity. In contrast to this nonspecific binding to total cellular RNA and to supercoiled DNA, HU specifically recognizes defined structures common to both DNA and RNA. In particular HU binds specifically to nicked or gapped DNA-RNA hybrids and to composite RNA molecules such as DsrA, a small non-coding RNA. HU, which modulates DNA architecture, may play additional key functions in the bacterial machinery via its RNA binding capacity. The simple, straightforward structure of its binding domain with two highly flexible beta-ribbon arms and an alpha-helical platform is an alternative model for the elaborate binding domains of the eukaryotic proteins that display dual DNA- and RNA-specific binding capacities.

Bacterial Proteins↗
PubMed2003

Analysis of the transcription regulator, CNOT7, as a candidate chromosome 8 tumor suppressor gene in colorectal cancer.

Loss of heterozygosity (LOH) on the short arm of chromosome 8 occurs at high frequencies in many tumor types, including colorectal carcinoma. We have previously used microcell-mediated chromosome transfer (MMCT) to map an approximately 7.7 Mb colorectal cancer suppressor region (CRCSR) at 8p22-23.1. We have now taken a candidate gene approach to identify the putative tumor suppressor gene located within the CRCSR. CNOT7 encodes a subunit of the CCR4-Not transcription complex and is located at 8p22. We showed that CNOT7 is expressed in normal colonic mucosa and in colonic crypt cells, as well as in colorectal cell lines and primary tumors. We assembled a panel of 88 primary colorectal tumors comprising 20 MSI-high (high microsatellite instability), 19 MSI-low and 49 MSS (microsatellite stable) tumors for mutation analysis of the CNOT7 gene. Denaturing high-performance liquid chromatography (DHPLC) analysis of the entire coding region of the CNOT7 gene revealed only one somatic missense mutation in an MSS tumor. The rarity of somatic mutations in CNOT7, and its expression in primary colorectal tumors and cell lines, suggests that CNOT7 is not the target tumor suppressor gene in the 8p22-23.1 CRCSR.

Carcinoma, Squamous Cell↗
PubMed2004

The canine HMGA1.

Due to the emerging advantages of numerous canine diseases as a genetic model for their human orthologs, the dog could join the mouse as the species of choice to unravel genetic mechanisms, e.g. of cancer predisposition, development and progression. However, precondition for such studies is the characterisation of the corresponding canine genes. Human and murine HMGA1 non-histone proteins participate in a wide variety of cellular processes including regulation of inducible gene transcription, integration of retroviruses into chromosomes, and the induction of neoplastic transformation and promotion of metastatic progression of cancer cells. Chromosomal aberrations affecting the human HMGA1 gene at 6p21 were described in several tumours like pulmonary chondroid hamartomas, uterine leiomyomas, follicular thyroid adenomas and others. Over-expression of the proteins of HMGA1 is characteristic for various malignant tumours suggesting a relation between high titer of the protein and the neoplastic phenotype. In this study, we characterised the molecular structure of the canine HMGA1 cDNA, its splice variants and predicted proteins HMGA1a and HMGA1b. Furthermore, we compared the coding sequence(s) (CDS) of both splice variants for 12 different breeds, screened them for single nucleotide polymorphisms (SNPs) and characterised a basic expression pattern.

Alternative Splicing↗
PubMed1999

Epigenetic regulation of gelsolin expression in human breast cancer cells.

Gelsolin is a multifunctional, actin-binding protein that is greatly decreased in many transformed cell lines and tumor tissues, including breast cancers. Downregulation of gelsolin RNA occurs in most breast cancers of rats, mice, and humans, but gross mutations of the gelsolin gene have not been found. Here we demonstrate by PCR and RT-PCR analysis that there are no point mutations in putative regulatory regions or the entire coding region of the cytoplasmic isoform of the gelsolin gene in human breast cancer cells (BCC). To determine if epigenetic modification is involved in downregulating gelsolin expression in MDA-MB-231 (MDA231), MCF7, and T47D BCC, we have used Southern blot analysis, 5-azacytidine (5aza) treatment, and trichostatin A (TSA) treatment. Southern blot analysis performed on genomic DNA demonstrated altered CpG methylation within intron 1 in DNA from all BCC compared to normal, mortal human mammary epithelial cells (HMEC). Treatment of the BCC with 5aza converted the DNA restriction pattern to that seen in untreated HMEC genomic DNA and caused modest increases in gelsolin RNA and protein. Incubation with TSA, an inhibitor of histone deacetylase, induced a dramatic upregulation of gelsolin RNA and protein levels which preceded apoptotic death of all BCC within 48-60 h. Our data support a role for epigenetic changes in chromatin structure leading to downregulation of gelsolin expression in human breast cancer. To our knowledge, this is the first example of a tumor suppressor gene downregulated in human breast cancer by changes in histone acetylation.

Acetylation↗
PubMed2002

[Genetic alterations of transcription cofactors in solid tumors].

Many hormones exert their effects through specific nuclear receptors which belong to a superfamily of ligand-activated transcription factors. These receptors control target gene expression through the recruitment of different cofactors acting as transcription activation or repression mediators, generally as parts of multiprotein complexes. The importance and the role in physiopathology of these different cofactors only begin to be defined. Different types of alterations affecting genes coding nuclear receptor transcription cofactors have indeed been described in cancer. The most important examples are gene amplification that leads to overexpression and gene mutations or translocations introducing qualitative modifications. This paper aims at bringing together the corresponding literature and focuses on gene alterations observed in solid tumors.

Breast Neoplasms↗
PubMed2006

Noncoding RNA synthesis and loss of Polycomb group repression accompanies the colinear activation of the human HOXA cluster.

The ratio of noncoding to protein coding DNA rises with the complexity of the organism, culminating in nearly 99% of nonprotein coding DNA in humans. Nevertheless, a large portion of these regions is transcribed, creating the alleged paradox that noncoding RNA (ncRNA) represents the largest output of the human genome. Such a complex scenario may include epigenetic mechanisms where ncRNAs would be involved in chromatin regulation. We have investigated the intergenic, noncoding transcriptomes of mammalian HOX clusters. We show that "opposite strand transcription" from the intergenic spacer regions in the human HOXA cluster correlates with the activity state of adjacent HOXA genes. This noncoding transcription is regulated by the retinoic acid morphogen and follows the colinear activation pattern of the cluster. Opening of the cluster at sites of activation of intergenic transcripts is accompanied by changes in histone modifications and a loss of interaction with Polycomb group (PcG) repressive complexes. We propose that noncoding transcription is of fundamental importance for the opening and maintenance of the active state of HOX clusters.

Animals↗
PubMedDate not supplied

HU and IHF: similarities and differences. In Escherichia coli, the lack of HU is not compensated for by IHF.

HU is one of the most abundant DNA binding proteins in Escherichia coli. Like the histones, HU is able to condense DNA in vitro and to introduce negative super-coiling in covalently closed circular, relaxed DNA molecules in the presence of topoisomerase I. HU is well conserved in all prokaryotes but surprisingly, it is also homologous to another E. coli DNA-binding protein, IHF. Contrary to HU, IHF shows sequence specificity and is much less abundant that HU. Both are heterodimers and all four polypeptide chains probably arose from a common ancestor. The question we raised was whether IHF could supply the main functions of HU in its absence. The answer seems to be negative for the following reasons. We did not observe any significant regulation of expression of the genes coding for HU by IHF, or vice-versa. The structures that these two proteins form with double-stranded or single-stranded DNA are completely different. Finally, overexpression of IHF does not relieve the growth defects observed in HU-less mutants. However, it can be speculated from our results that even if the two proteins are not equivalent and cannot replace one another, both could stimulate (or inhibit) some specific protein-DNA interactions or affect the DNA-binding properties of one another.

Bacterial Proteins↗
PubMed2005

Modulation of differential transcription of tRNA genes through chromatin organization.

In higher eukaryotes, tRNA multigene families comprise several copies encoding the same tRNA isoacceptor species. Of the 11 copies of a tRNA1Gly family from the mulberry silkworm Bombyx mori, individual members are differentially transcribed in vivo in the B. mori-derived BmN cell lines and in vitro in silk gland nuclear extracts. These genes have identical coding regions and hence harbour identical internal control sequences (the A and B boxes), but differ significantly in their 5' and 3' flanking regions. In the present study, we demonstrate the role of chromatin structure in the down-regulation of the poorly expressed copy, tRNA1Gly-6,7. Distinct footprints in the 5'-upstream region of the poorly transcribed gene in vitro as well as in vivo suggested the presence of nucleosomes. A theoretical analysis of the immediate upstream sequence of this gene copy also revealed a high propensity of nucleosome formation. The low transcription of tRNA1Gly-6,7 DNA was further impaired on assembly into chromatin and this inhibition was relieved by externally supplemented TFIIIC with an associated histone acetyltransferase activity. The inhibition due to nucleosome assembly was absent when the 5'-upstream region beyond -53 nt was deleted or entirely swapped with the 5'-upstream region of the highly transcribed gene copy, which does not position a nucleosome. Footprinting of the in vitro assembled tRNA1Gly-6,7 chromatin confirmed the presence of a nucleosome in the immediate upstream region potentially masking TFIIIB binding. Addition of TFIIIC unmasked the footprints present on account of the nucleosome. Our studies provide the first evidence for nucleosomal repression leading to differential expression of individual members from within a tRNA multigene family.

Animals↗
PubMed1985

Isolation and sequence of cDNA clones coding for a member of the family of high mobility group proteins (HMG-T) in trout and analysis of HMG-T-mRNA's in trout tissues.

A specific oligonucleotide has been used to isolate a cDNA prepared from the mRNA for a trout High Mobility Group (HMG) protein closely related to trout HMG-T and bovine HMG 1 and 2 proteins. The sequence isolated more closely resembles bovine HMG-1 than the previously sequenced HMG-T protein in regions corresponding to the N terminal half of the protein. Northern blot analysis at low stringency indicated that 2 related sequences are expressed in total trout testis mRNA. Southern blots of total trout DNA indicate that several different forms of the homologous sequence are present in the trout genome and an estimate of copy number by dot-blot shows 4 HMG-T genes per trout sperm DNA equivalent. Analysis of mRNA from several trout tissues, including testis, liver and kidney indicates that expression of genes for histones and the larger HMG proteins in trout is not closely coupled.

Amino Acid Sequence↗
PubMed2001

Comparative analysis of a BAC contig of the porcine RN region and the human transcript map: implications for the cloning of trait loci.

The poorly developed transcript maps and the limited resources for genome analysis hamper positional cloning of trait loci in farm animals. This study demonstrates that this will now be easier by the combined use of BAC contigs and the import of the near complete human transcript map. The conclusion was obtained by a comparative analysis of a 2.4-Mb BAC contig of the RN region in pigs. The contig was constructed as part of a successful positional cloning project, which identified PRKAG3 as the causative gene for the RN phenotype. A comparative map including the corresponding regions on human chromosome 2q35 and mouse chromosome 1 (region 36-44 cM) is reported. Sixteen coding sequences were mapped on the BAC contig. The majority of these were identified by BLAST searches of BAC end sequences and BAC shotgun sequences generated during the positional cloning project. Map data for the orthologues in humans were available for 12 of the 16 coding sequences, and all 12 have been assigned to 2q35. Furthermore, no evidence for any rearrangement in gene order was obtained. The extensive linkage conservation indicates that the near complete human transcript map will be an invaluable resource for positional cloning projects in pigs and other domestic animals.

Animals↗
PubMed2005

Molecular insight into the effects of hypothyroidism on the developing cerebellum.

Despite the recognized importance of thyroid hormones for normal brain development, little is known about the critical molecular events underlying this role. We investigated the molecular basis of thyroid hormone action on the developing brain by comparing genome-wide gene expression patterns in the cerebellum between euthyroid and hypothyroid juvenile mice using microarrays. Pregnant dams were treated with 0.1% or 0.04% 6-propyl-2-thiouracil (PTU) in drinking water continuously from day 13 post conception until weaning to produce hypothyroid pups. Cerebella were collected from vehicle and 0.1% PTU treated pups at post-natal day (PND) 15, and mRNA from these was subjected to microarray analysis using Agilent high-density oligonucleotide chips. Statistical analysis (MAANOVA) revealed significant differential expression in 2940 genes including 1357 up- and 1583 down-regulated genes. Further analysis (combined MAANOVA and ANOVA) identified 204 significantly altered genes. Hypothyroidism had a greater effect on gene expression in male than in female pups. Transcriptional changes in several genes [Syt12 (Synaptotagmin 12), Rcor (RE1-silencing transcription factor co-repressor), Bag3 (Bcl-associated athanogene 3), p21, cyclin D, Bax (Bcl2-associated X protein), and Pcp2 (Purkinje cell protein 2)] were confirmed using real-time (RT) PCR analysis. Significantly altered expression of Bag3 in cerebella from PND 15 and PND 60 pups exposed to PTU suggests permanent functional alterations in the hypothyroid brain. The thyroid hormone negative regulation of Rcor expression was confirmed in vitro using HepG2 cells. In addition to Rcor, expression of several other genes that code for critical components of the REST (RE1-silencing transcription factor) pathway was shown to be altered in hypothyroid animals. These results suggest that modification of this pathway may have a significant role in causing impaired development in the hypothyroid brain.

Animals↗