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PubMed1997

Characterization of the two H1(zero)-encoding genes from Xenopus laevis.

We have analyzed the promoter and the coding sequences of the two homologous histone H1(zero)-encoding genes from Xenopus laevis, here termed H1(zero)-1 and H1(zero)-2. Both genes encode proteins of 193 amino acids and differ at just 16 amino-acid residues. Putative regulatory sequences identified in the promoter region are the same and are highly conserved. However, significant differences exist in the 5' untranslated regions (UTR) of the transcribed sequences of these two genes, such as several deletions in the 5'-UTR of the H1(zero)-2 gene in comparison with the H1(zero)-1 gene 5'-UTR. The 3'-UTR is a short sequence of about 200 bp which is unexpected compared with the long 3'-UTR of mammalian H1(zero) mRNA, but it is in the same size range as in avian H5 mRNA. Thus, the main differences between these two genes are observed in sequences potentially involved in the regulation of the H1(zero) gene expression such as the 5'-UTR. The two genes are expressed during embryogenesis and in several adult tissues. We discuss these findings in terms of the evolution of histone H1(zero) genes in vertebrates and the appearance of histone H5 in avian species.

Amino Acid Sequence↗
PubMed1979

Non-polyadenylated 22 s ribonucleoprotein particle is insensitive to translational inhibitor RNA of cryptobiotic gastrulae of Artemia salina.

A free cytoplasmic 22 S ribonucleoprotein particle exhibiting a major template activity in rabbit reticulocyte system has been identified in the cryptobiotic gastrulae of Artemia salina. This particle contains non-polyadenylated 9 S messenger RNA which codes primarily for a non-histone basic protein with an apparent molecular weight of 26 000 daltons. We have previously demonstrated the presence of a translational inhibitor RNA which is apparently responsible for transforming polyadenylated messenger (Slegers et al., FEBS Letters 80, 390-394, 1977). This inhibitor RNA was found to be completely ineffective on the template activity of non-polyadenylated 22 S messenger ribonucleoprotein, confirming the specificity of this regulatory RNA for polyadenylate sequences.

Animals↗
PubMed2026

Epigenetics and In Silico Transcriptome Analysis of Pediatric Acute Myeloid Leukemia.

Pediatric acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy that accounts for about 15%-20% of childhood leukemias. Despite therapeutic advances, relapses remain common, and survival for high-risk patients is below 60%. Unlike adult AML, pediatric AML displays distinct genetic mutations, including FLT3-ITD, NPM1, KMT2A rearrangements, and core-binding factors (CBF) fusions, as well as extensive epigenetic dysregulation. Aberrant DNA methylation, histone modifications, and altered non-coding RNA expressions disrupt hematopoietic differentiation and activate oncogenic transcriptional networks. Recent advances in silico transcriptomic analysis have transformed the study of pediatric AML by integrating gene expression and epigenetic data to identify molecular drivers and regulatory networks. Computational RNA-seq pipelines and pathway analyses have highlighted key epigenetic regulators, including DNMT3A, TET2, and HDACs, as potential therapeutic targets. Multi-omics approaches combining transcriptomic, methylomic, and chromatin accessibility data are increasingly used to define biomarkers for diagnosis, prognosis, and therapeutic response. This review provides a comprehensive overview of the molecular and epigenetic landscape of pediatric AML, emphasizing the power of in silico transcriptome analysis to uncover disease mechanisms, refine patient stratification, and guide the development of precision-based epigenetic therapies aimed at improving long-term outcomes in children with AML.

Humans↗
PubMed1981

Polysomal and nonpolysomal messenger RNA of noninduced and induced Friend erythroleukemic cells: analysis by cell-free translation.

Polyadenylated and nonpolyadenylated mRNA were prepared from polysomes and from the postribosomal supernatant of noninduced and DMSO-induced Friend cells. The mRNA preparations were translated in a wheat germ cell-free system and the in vitro synthesized proteins, fractionated by polyacrylamide gel electrophoresis, were compared by fluorography. The electrophoretic analysis shows that four preparations of poly (A) + RNA code for many different peptides and that most of these peptides are present in each of the poly (A) + RNA translation products. However, the electrophoretic patterns of these translation products differ in the relative amounts of peptides comigrating in the gel electrophoresis. After DMSO treatment, Friend cells show significative differences in the polysomal and nonpolysomal mRNA pools. With induction, globin becomes the most abundant product of the polysomal poly (A) + RNA, while the relative amounts of peptides coded by nonglobin polysomal poly (A) + RNA are reduced. In parallel, the electrophoretic pattern of the in vitro products on the nonpolysomal poly (A) + RNA changes in the relative amounts of the fractionated peptides; moreover, in induced cells, the nonpolysomal poly (A) + RNA codes for peptides not detected in the polysomal poly (A) + RNA of the same cells. These data were interpreted assuming that in DMSO-induced cells, protein synthesis is regulated at both the transcriptional and translational levels. Polysomal poly (A)-RNA codes mostly for the five main histone classes; with DMSO treatment the amount of H2b MRNA bound to polysomes is increased with respect to the other polysomal histone mRNA.

Animals↗
PubMed2026

Decreased H3K79 acetylation and dysregulation of neurodevelopmental genes in fetal down syndrome.

BACKGROUND: Down syndrome (DS), the most prevalent chromosomal disorder caused by trisomy 21, manifests intellectual disability and cognitive dysfunction. Cumulative studies confirm epigenetic pathways including DNA methylation and non-coding RNAs drive DS pathological progression. Histone post-translational modifications (PTMs) are core epigenetic regulators of fetal brain development. However, genome-wide PTM alterations and their downstream functions in fetal DS brains remain poorly characterized, leaving a key gap in revealing epigenetic mechanisms underlying DS neurodevelopmental defects. To address this, we aimed to establish the first comprehensive landscape of histone PTMs in fetal DS cortex and investigate whether specific PTM changes contribute to aberrant neurodevelopmental gene expression. METHODS: Fetal cortexs from control and DS groups were subjected to global histone modification profiling via high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). We detected mono-, di-, and tri-methylation, acetylation, homocysteinylation and malonylation on all four core histones (H2A, H2B, H3, H4). Chromatin immunoprecipitation sequencing (ChIP-seq) was used to map genomic binding profiles of H3 lysine 79 acetylation (H3K79ac). Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was performed to quantify mRNA levels of candidate neurodevelopmental genes. RESULTS: HPLC-MS/MS analysis identified 172 distinct histone PTMs in control fetal cortices and 168 PTMs in DS fetal cortical samples. Quantitative comparison of 22 quantifiable histone PTMs revealed that H3K79ac showed the most prominent reduction in DS samples, with a 34% decrease (P<0.05). Chromatin immunoprecipitation (ChIP)-seq verified specific H3K79ac occupancy at the genomic loci of three vital neurodevelopmental genes: TNFSF13B, NXPH1 and CAMK4. Correspondingly, qRT-PCR revealed aberrant transcription levels of these three genes in DS fetal cortices. CONCLUSIONS: This study establishes the first quantitative landscape of histone PTMs in in DS fetal cortical tissues. We demonstrate that depleted H3K79ac acts as a candidate epigenetic driver of DS neuropathology by disrupting the transcription of critical neurodevelopmental genes. This work reveals a novel epigenetic mechanism and a promising therapeutic target for DS-related neurodevelopmental disorders.

Down syndrome (DS)↗
PubMedDate not supplied

[From cytogenetics to cytogenomics of adipose tissue tumors: 1. Benign adipose tissue tumors].

Benign lipomatous tumors are characterized at the genetic level by different types of chromosomal abnormalities. A rearrangement of the HMGIC (HMGA2) gene, localized in 12q15 and coding for an architectural non-histone DNA protein, is observed in a majority of solitary superficial lipomas. Alterations of HMGIC are often resulting from reciprocal translocations, such as t(3;12)(q27-28;q15) that fuses LPP with HMGIC, but a variety of chromosomal anomalies, such as deletions, inversions or insertions are also observed. Rearrangements of chromosomal regions 6p21-22, 13q, 11q13, 12q13 or others are described in approximately one third of superficial lipoma cases with abnormal karyotypes. The genes involved in these alterations remain to be determined. Lipoblastomas are pediatric neoplasms that are characterized by rearrangements of PLAG1, located in 8q11-12 whereas hibernomas, that resemble brown fat, are associated with 11q13 rearrangements together with often complex chromosomal alterations. Deletions of 13q and 16q have been identified in spindle cell lipomas. A t(11;16)(q13;p12-13) have been described in the two published karyotypes of chondroid lipomas. The chromosomal features of other rare benign lipomatous tumors, the differential diagnosis of which is occasionally difficult, such as infiltrating intra-muscular lipomas, organic deep-seated lipomas, or angiomyolipomas, myolipomas, myxolipomas are still poorly defined. Although the genetic characterization of benign lipomatous tumors has been dramatically in progress over the last ten years, many aspects remain obscure and warrant future investigations for a better comprehension of underlying molecular mechanisms.

Chromosome Aberrations↗
PubMed1977

Coupled transcription-translation of DNA injected into Xenopus oocytes.

A previous report from this laboratory showed that purified DNAs are transcribed after injection into the nucleus of Xenopus laevis oocytes (Mertz and Gurdon, 1977). Here we demonstrate that at least some of the RNA synthesized is translated within these injected cells to produce the correct protein products. Injection of Simian Virus 40 DNA into oocytes induces the synthesis of at least two proteins not normally synthesized in these cells. Using two-dimensional polyacrylamide gel electrophoresis and well characterized deletion mutants of SV40 that produce proteins of smaller size, we show that these two proteins are, indeed, the virus-coded proteins VP1 and VP3. Synthesis of VP1 and VP3 is inhibited by alpha-amanitin and, therefore, presumably mediated by a type II RNA polymerase. We also present evidence indicating that a histone-like protein is induced after the injection of a cloned plasmid DNA that codes for the Drosophila melanogaster histone proteins. This in vivo coupled transcription-translation system should be useful for identifying and mapping proteins coded by cloned eucaryotic DNAs.

Amanitins↗
PubMed2004

Modulation of heat shock gene expression by the TAC1 chromatin-modifying complex.

Rapid induction of the Drosophila melanogaster heat shock gene hsp70 is achieved through the binding of heat shock factor (HSF) to heat shock elements (HSEs) located upstream of the transcription start site (reviewed in ref. 3). The subsequent recruitment of several other factors, including Spt5, Spt6 and FACT, is believed to facilitate Pol II elongation through nucleosomes downstream of the start site. Here, we report a novel mechanism of heat shock gene regulation that involves modifications of nucleosomes by the TAC1 histone modification complex. After heat stress, TAC1 is recruited to several heat shock gene loci, where its components are required for high levels of gene expression. Recruitment of TAC1 to the 5'-coding region of hsp70 seems to involve the elongating Pol II complex. TAC1 has both histone H3 Lys 4-specific (H3-K4) methyltransferase (HMTase) activity and histone acetyltransferase activity through Trithorax (Trx) and CREB-binding protein (CBP), respectively. Consistently, TAC1 is required for methylation and acetylation of nucleosomal histones in the 5'-coding region of hsp70 after induction, suggesting an unexpected role for TAC1 during transcriptional elongation.

Animals↗
PubMed1990

Introns in histone genes alter the distribution of 3' ends.

Chimeric genes were constructed which contained either a histone or globin promoter, a human alpha-globin coding region as a cDNA or containing one or both intervening sequences, and the 3' end of a mouse histone H2a gene. The genes were introduced into mouse L cells or Chinese Hamster Ovary cells. The genes containing at least one intervening sequence produced two mRNAs in about equal amounts, one which ended at a cryptic polyadenylation site 33 nucleotides 3' to the normal histone mRNA 3' end and one which ended at the normal histone 3' end. In contrast, the same construct containing a globin cDNA yielded mRNA ending only at the correct histone 3' end. Similar proportions of polyadenylated and non-polyadenylated mRNA were obtained when the cryptic polyadenylation signal was replaced with the globin polyadenylation signal. More than 90% of the transcripts were accurately spliced. All of the unspliced transcripts had histone 3' ends.

Animals↗
PubMed2003

The transcriptional enhancer of the pea plastocyanin gene associates with the nuclear matrix and regulates gene expression through histone acetylation.

The influence of the transcriptional enhancer of the pea plastocyanin gene (PetE) on the acetylation of histones was examined with chromatin immunoprecipitation (ChIP) experiments using antibodies that recognize acetylated or nonacetylated histones H3 and H4. In transgenic tobacco plants containing the pea PetE promoter fused to uidA, both acetylated and nonacetylated histones H3 and H4 were present on the integrated transgene. Linking the PetE enhancer to the transgene resulted in increased beta-glucuronidase activity and increased amounts of acetylated histones H3 and H4 present on the promoter, suggesting that the enhancer may increase transcription by mediating the acetylation of histones. Trichostatin A and sodium butyrate, which are potent inhibitors of histone deacetylases (HDAs), activated expression from the PetE promoter by fourfold, with a concomitant increase in the acetylation states of histones H3 and H4, as determined by ChIP, indicating that the acetylation of histones has a direct positive effect on transcription. The HDA inhibitors did not increase expression from the PetE promoter when it was linked to the enhancer, consistent with preexisting hyperacetylated histones on the transgene. Mapping of histone acetylation states along the reporter gene indicated that the histones H3 and H4 associated with the promoter and the 5' region of uidA were hyperacetylated in the presence of the PetE enhancer. The PetE enhancer bound to isolated tobacco nuclear matrices in vitro and was associated with the nuclear matrix in nuclei isolated from transgenic tobacco plants. These results suggest that the pea PetE enhancer activates transcription by associating with the nuclear matrix, mediating the acetylation of histones on the promoter and the nearby coding region and resulting in an altered chromatin structure.

Acetylation↗
PubMed1999

Mytilus edulis histone gene clusters containing only H1 genes.

We isolated five different phage clones containing histone gene clusters with up to five H1 genes per phage clone from a Mytilus edulis genomic library. Among these H1 genes, nine gene types coding for five different H1 proteins have been identified. All H1 histone genes were located on repetitive restriction fragments with only slightly different sizes. The H1 coding regions show highly related sequences, suggesting that the multitude of H1 genes has evolved by gene duplication events. Core histone genes could not be found on these five Mytilus edulis genome fragments.

Amino Acid Sequence↗
PubMed2005

Naturally occurring antisense RNA of histone H2a in mouse cultured cell lines.

BACKGROUND: An antisense transcript of histone H2a that has no significant protein-coding region has been cloned from a mouse full-length cDNA library. In the present study, we evaluated this transcript by using RT-PCR and compared the expression patterns of the sense and antisense transcripts by using quantitative RT-PCR (qRT-PCR). RESULTS: This antisense RNA was expressed in three mouse cell lines. We call it ASH2a. ASH2a includes not only the complementary sequence of the transcript of Hist2h2aa2 (a replication-dependent histone H2a gene), but also that of the promoter of Hist2h2aa2. The upstream genomic sequence of the transcription start site of the ASH2a-coding gene (ASH2a) lacks both CCAAT and TATA boxes. This absence suggests that the regulation of ASH2a is different from that of the replication-dependent histone H2a genes. Findings from qRT-PCR indicated that the expression pattern of ASH2a was different from that of Hist2h2aa2. Expression of Hist2h2aa2 peaked at 2 to 4 h during S-phase, but that of ASH2a peaked at 1 h. CONCLUSION: We showed the existence of ASH2a, a histone H2a antisense RNA, in mouse cultured cells. The expression pattern of ASH2a is different from that of the sense RNA.

Animals↗