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PubMed2021

Functional impact of cancer-associated cohesin variants on gene expression and cellular identity.

Cohesin is a ring-shaped protein complex that controls dynamic chromosome structure. Cohesin activity is important for a variety of biological processes, including formation of DNA loops that regulate gene expression. The precise mechanisms by which cohesin shapes local chromosome structure and gene expression are not fully understood. Recurrent mutations in cohesin complex members have been reported in various cancers, though it is not clear whether many cohesin sequence variants have phenotypes and contribute to disease. Here, we utilized CRISPR/Cas9 genome editing to introduce a variety of cohesin sequence variants into murine embryonic stem cells and investigate their molecular and cellular consequences. Some of the cohesin variants tested caused changes to transcription, including altered expression of gene encoding lineage-specifying developmental regulators. Altered gene expression was also observed at insulated neighborhoods, where cohesin-mediated DNA loops constrain potential interactions between genes and enhancers. Furthermore, some cohesin variants altered the proliferation rate and differentiation potential of murine embryonic stem cells. This study provides a functional comparison of cohesin variants found in cancer within an isogenic system, revealing the relative roles of various cohesin perturbations on gene expression and maintenance of cellular identity.

Animals↗
PubMed2026

Morphological changes and transcriptomic insights into skeletal development of embryos and larvae of the sea urchin Strongylocentrotus intermedius.

To explore morphological features and molecular dynamics underlying skeletogenesis in the sea urchin Strongylocentrotus intermedius, we conducted combined morphological observation and comparative transcriptome analyses across representative embryonic and larval developmental stages. Morphological results showed that triradiate spicules first emerged at the gastrula stage. The 8-arm pluteus stage was identified as a key phase for skeletal remodeling, during which new three-radiate crystals transformed into complex stereoscopic ossicles including tube feet, spines and test plates. Transcriptomic data indicated that most differentially expressed genes (DEGs) were downregulated from the blastula to gastrula. The altered expression of basal metabolic genes and extracellular matrix genes including Colp2α and calm may be correlated with the linear mineralization of early spicules, which potentially reflects an energy adjustment pattern in developing larvae. During the transition from 6-arm to 8-arm pluteus, expression changes of calmodulin-like, Colp2α and SISin18G001660 suggest potential associations with regional calcium deposition and modifications of skeletal matrix properties. This work systematically characterizes morphological traits and transcriptional dynamics of skeletogenesis in S. intermedius. Its early spiculogenesis follows the conserved developmental pattern of echinoderms, while massive formation of stereoscopic ossicles occurs at the 8-arm pluteus stage. Stage-specific transcriptional changes across key larval skeletogenic stages are uncovered, offering transcriptomic resources for functional verification of skeletal regulatory genes.

Animals↗
PubMed1989

Regulation of the visna virus long terminal repeat in macrophages involves cellular factors that bind sequences containing AP-1 sites.

Visna virus gene expression is highly restricted in monocytes but is induced by monocyte-macrophage differentiation in vivo. Deletion and linker-scanning mutants, gel shift assays, and DNase I footprinting were used to identify sequences in the visna virus long terminal repeat involved in the developmental regulation of gene expression in the U937 monocytic cell line. We found that an AP-1 and an AP-4 binding site were critical for basal activity and that the AP-1 site was required for phorbol ester-inducible gene expression. These results suggest that cellular factors that interact with AP-1 sites are involved in the developmental regulation of visna virus gene expression in macrophages.

Base Sequence↗
PubMed2026

Transcriptome sequencing provides novel insights into larval development and sexual dimorphism in the firefly Aquatica leii (Coleoptera: Lampyridae).

Fireflies are regarded as one of the most charismatic beetles due to their bioluminescence and ecological importance as bioindicators of freshwater quality. However, molecular mechanisms of larval development and sexual dimorphism in aquatic species remain poorly understood. Here, we performed multi-stage transcriptomic analysis of the aquatic firefly Aquatica leii across larval instars from L2 to L6, together with adult females and males, with three biological replicates per stage. Using time-series expression clustering, differential expression analysis, and weighted gene co-expression network analysis (WGCNA), we characterized the transcriptional dynamics of continuous larval development and the onset of sex-biased gene expression. We identified a critical transcriptional transition occurred at L5-L6, marked by downregulation of early morphogenetic genes and upregulation of juvenile hormone metabolism, oxidoreductase activity, and muscle contraction genes, indicating a shift from growth to metamorphic preparation. WGCNA identified a module strongly correlated with L6 (R = 0.97) enriched for the same functions, confirming a coordinated late-larval program. Notably, genes exhibiting sex-biased expression in adults were already expressed during late larval stages (L5 and L6), and 123 genes progressively upregulated from L2 to L6 showed enrichment in chitin biosynthesis, heart contraction, and ion transport; among these, six genes maintained high expression in adults with clear male-biased (Alei052192, Alei006658, and Alei087054) or female-biased (Alei003725, Alei096818, and Alei074026) patterns. These findings establish that transcriptional foundations for sexual dimorphism and adult tissue formation are laid during late larval stages, providing the first multi-stage transcriptomic resource for aquatic firefly conservation and breeding.

Animals↗
PubMed2024

A time-resolved single-cell roadmap of the logic driving anterior neural crest diversification from neural border to migration stages.

Neural crest cells exemplify cellular diversification from a multipotent progenitor population. However, the full sequence of early molecular choices orchestrating the emergence of neural crest heterogeneity from the embryonic ectoderm remains elusive. Gene-regulatory-networks (GRN) govern early development and cell specification toward definitive neural crest. Here, we combine ultradense single-cell transcriptomes with machine-learning and large-scale transcriptomic and epigenomic experimental validation of selected trajectories, to provide the general principles and highlight specific features of the GRN underlying neural crest fate diversification from induction to early migration stages using Xenopus frog embryos as a model. During gastrulation, a transient neural border zone state precedes the choice between neural crest and placodes which includes multiple converging gene programs. During neurulation, transcription factor connectome, and bifurcation analyses demonstrate the early emergence of neural crest fates at the neural plate stage, alongside an unbiased multipotent-like lineage persisting until epithelial-mesenchymal transition stage. We also decipher circuits driving cranial and vagal neural crest formation and provide a broadly applicable high-throughput validation strategy for investigating single-cell transcriptomes in vertebrate GRNs in development, evolution, and disease.

Animals↗
PubMed1991

Developmental regulation for collagen II gene expression in transgenic mice.

In order to evaluate the involvement of the type II collagen regulatory sequences in development, we have injected a construct containing a toxin gene under the control of the rat type II collagen promoter and enhancer. The construct, pDAS10-DTA, contained the diphtheria toxin A chain gene under the control of type II collagen sequences which had been used previously to target cartilagenous tissues in transgenics. Inspection of developing fetuses at various stages of gestation revealed a high number of aborted implants as well as abnormally developing fetuses. These abnormal fetuses were of small size, had shortened and underdeveloped limbs, cleft palates, and generally resembled a phenotype similar to chondrodystrophic mice. Histological comparisons of normal and abnormal fetuses indicated a reduced amount of extracellular matrix surrounding chondrocytes, and a disorganized appearance of the tissue. These results suggest that the expression of the toxin has occurred in chondrocytes and altered the survival and development of the transgenic mice. These results also indicate that the promoter and enhancer sequences contained in the transgene controlled the developmental expression of the type II collagen gene expression.

Animals↗
PubMed1992

Cloning of an ovine 11 beta-hydroxysteroid dehydrogenase complementary deoxyribonucleic acid: tissue and temporal distribution of its messenger ribonucleic acid during fetal and neonatal development.

Glucocorticoids promote the development of many organ systems vital for extrauterine survival, and fetal cortisol provides the trigger for birth in sheep. The activity of glucocorticoids may be influenced at a cellular level by 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD), which is responsible for the interconversion of cortisol and cortisone. To examine 11 beta-HSD gene expression during fetal development, two overlapping clones which yield a 1.4 kilobase (kb) complementary DNA encoding sheep 11 beta-HSD from a liver library were isolated by using a rat 11 beta-HSD cDNA as the probe. This cDNA contains a 879 base pair open reading frame for a protein of 292 amino acids that has more than 70% sequence identity to rat and human 11 beta-HSDs. To define the tissue distribution of 11 beta-HSD messenger RNA in sheep, selected tissues were collected from one fetus at day 130 and term (approximately 145 days), and from a nonpregnant ewe. Cellular RNA was extracted and subjected to Northern blot analysis, and a single 1.8 kb transcript was detected in the fetal and adult liver, lung, hypothalamus, anterior pituitary, and placenta. This was undetectable in adrenals and kidneys, but a smaller (1.5 kb) transcript was present in fetal and adult kidney RNA. The relative abundance of 11 beta-HSD mRNA was greatest in fetal and adult livers, and it was much higher in adult liver, lung, and kidney than in the corresponding fetal tissues. To examine whether 11 beta-HSD gene expression is developmentally regulated in the fetal sheep, liver, lung, and kidney tissues were taken from fetuses at day 60-70, day 100-110, day 125-130, at term, and from newborn lambs (24-48 h old). In the lung and kidney, the relative abundance of 11 beta-HSD mRNA did not change from day 60 to term but increased in the lungs of newborn lambs. In contrast, 11 beta-HSD mRNA levels in the liver increased between day 125 and term and rose further in the newborn. Collectively, these results demonstrate that 11 beta-HSD gene expression in sheep is regulated in a tissue-specific and developmentally programmed manner.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1988

Developmentally regulated expression of the calcitonin gene related peptide (CGRP) in rat lung endocrine cells.

Calcitonin (CT) and the calcitonin gene-related peptide (CGRP) are generated by alternative RNA processing from a single CT/CGRP gene. Recently, we reported the existence of CGRP-immunoreactivity and CGRP mRNA in endocrine cells or Kulchitsky (K) cells of human and rat lung [Wada et al. 1987b]. In this report, an examination was made of developmental changes in the expression of the CGRP gene in rat lungs by immunohistochemistry, radioimmunoassay (RIA) and Northern hybridization. CGRP-positive K-cells in lung tissue appeared on the 18th day of gestation. Their number was greatest on the 20th day of gestation and then decreased postnatally. The level of CGRP in rat lung was found to be highest in a 1-day-old neonate by RIA. In the Northern hybridization of rat lung using the CGRP 3' non-coding region (exon 6) of the first human CT/CGRP gene as the probe, 1.0 kilobase (kb) CGRP mRNA was found to be abundant on the 20th day of gestation and in a 1 day-old neonate. It thus appears that CGRP in rat lung is essential for pulmonary adaptation at birth and/or from the last intrauterine stage to the early neonatal period.

Animals↗
PubMed1990

Promoter structure and protein sequence of msp130, a lipid-anchored sea urchin glycoprotein.

The early fate specification of primary mesenchyme cells in sea urchin embryos makes them an attractive system for studying alterations in gene expression and protein synthesis during cell lineage determination and differentiation. To analyze the developmental regulation of gene expression in Strongylocentrotus purpuratus, we have isolated and sequenced genomic and cDNA clones encoding msp 130, a mesenchyme-specific cell surface glycoprotein. We have located the transcription initiation site of the msp130 gene and sequenced several kilobases of the promoter region. The region of the gene that encodes the protein is divided into numerous small (less than 500 base pairs) exons. The msp130 protein possesses two novel glycine-rich domains and a signal peptide, but apparently lacks a transmembrane domain. The carboxyl-terminal sequence suggests that msp130 may be phosphatidylinositol-linked to the cell membrane, and experiments with phospholipases support this conclusion. The implications of the msp130 sequence for its possible functions are discussed.

Amino Acid Sequence↗
PubMed1989

Developmental regulation of P-45017 alpha gene expression in fetal bovine adrenal.

Among the multifactorial aspects of regulation of steroid hydroxylase gene expression, it is the developmental process which leads to imprinting of expression of particular steroid hydroxylases in specific cell types. We have begun to investigate the ontogeny of steroidogenesis in fetal bovine tissues. Expression of most steroid hydroxylases and related enzymes is detectable in adrenals of the smallest fetuses studied and continues throughout fetal life. Like the other steroid hydroxylases, P-450(17)alpha is detectable in the earliest fetal adrenals studied. However, following an increase in expression, P-450(17)alpha disappears from the fetal adrenal by 100 days gestational age and remains absent until about 230 days gestational age. The absence of P-450(17)alpha is correlated with the absence of cortisol in the fetal adrenal and the absence of ACTH in fetal plasma. Thus expression of P-450(17)alpha in bovine fetal adrenal appears to be strictly dependent on cAMP while expression of other steroid hydroxylases appears to involve both cAMP-dependent and cAMP-independent mechanisms. Furthermore, P-450(17)alpha is expressed in fetal testis at gestational times when it is absent in fetal adrenal. We have begun to examine binding of nuclear proteins from adrenals of various gestational ages to the 5'-flanking region of the bovine P-450(17)alpha gene. Preliminary evidence indicates the presence of a protein in nuclei of fetal adrenals not expressing P-450(17)alpha that is not present in fetal adrenals of other gestational ages.

Adrenal Glands↗
PubMed1991

Developmental regulation of gap junction gene expression during mouse embryonic development.

The expression of products from three different gap junction genes (alpha 1, beta 1 and beta 2) was studied in pre- and postimplantation mouse embryos, during organogenesis, during differentiation of F9 teratocarcinoma cells, and in cultured embryonic stem (ES) cells. In this analysis, the following results were obtained. 1) Pre- and postimplantation mouse embryos. The alpha 1 transcript was the earliest gap junction RNA detected (in the 4 cell stage embryo) and its abundance increased significantly throughout subsequent development. 2) Organogenesis. Evidence was obtained for developmental expression of these three different gap junction genes during early embryogenesis and throughout the late stages of organogenesis. The expression patterns for these genes may be related to differences in gap junctional communication requirements for fetal organ development versus neonatal and adult organ function, or the utilization of different genes by different cell types during organogenesis. 3) During the differentiation of F9 cells in culture, expression of these three genes was modulated. Thus, this is the first evidence for modulation of gap junction gene expression during the differentiation of a single cell type in culture. 4) In an ES cell culture line, alpha 1 was the only gap junction gene product detected. This is consistent with the findings of alpha 1 expression in the embryonic inner cell mass region and in undifferentiated teratocarcinoma cells.

Amino Acid Sequence↗
PubMed1985

Tissue specific expression and developmental regulation of two genes coding for rat fatty acid binding proteins.

We have examined the tissue distribution and developmental regulation of two low molecular weight cytosolic fatty acid binding proteins. Based on their initial site of isolation, they have been referred to as liver and intestinal fatty acid binding proteins (FABP). Cloned cDNAs were used to probe blots of RNAs extracted from a wide variety of adult rat tissues as well as small intestine and liver RNA obtained from fetal, suckling, and weaning animals. The highest concentrations of "liver" FABP mRNA were found in small intestine and liver. "Intestinal" FABP mRNA is most abundant in small bowel RNA while only trace amounts were encountered in liver. Both mRNAs were detectable in stomach, colon, pancreas, spleen, lung, heart, testes, adrenal, and brain RNA at 1-8% the concentrations observed in small intestine. Accumulation of both mRNAs in the small intestinal epithelium increases during development. The mRNAs are first detectable between the 19th and 21st day of gestation. They undergo a coordinated 3-4-fold increase in concentration within the first 24 h after birth. Thereafter, gut levels of intestinal FABP mRNA remain constant during the suckling period while liver FABP mRNA increases an additional 2-fold. Liver FABP mRNA levels are also induced in hepatocytes during the first postnatal day but subsequently do not change during the suckling and weaning phase, despite marked alterations in hepatic fatty acid metabolism. These observations support the concept that the major role of these proteins is to facilitate the entry of lipids into cells and/or their subsequent intracellular transport and compartmentalization. The data also raise questions about the identity of extragastrointestinal FABPs.

Aging↗
PubMed2025

A Balanced Inversion Polymorphism Exhibits a Dominance Reversal at the Gene Expression Level that Depends on Developmental Context.

How genetic variance for fitness is maintained is incompletely understood. Mutation-selection balance and single-locus overdominance cannot account for the large variance observed. Recent work suggests that antagonistic balancing selection, favoring different alleles in different contexts and involving beneficial dominance reversals, might contribute to maintaining fitness variance. However, while this mechanism is plausible, evidence for dominance reversals remains scarce. Here, we study how In(3R)Payne, a balanced inversion polymorphism in Drosophila melanogaster, affects gene expression and chromatin accessibility by using RNA-seq and ATAC-seq (assay for transposase-accessible chromatin with sequencing). We find that, in embryos, the inverted (INV) arrangement tends to have dominant effects, while the standard (STD) arrangement behaves like a recessive Mendelian allele. Yet, in wing discs, this pattern is reversed: STD has mostly dominant effects, whereas INV behaves recessively. Since this shift in the dominance of the INV "allele" between developmental contexts affects the expression of suites of genes in a concerted manner, it might be mediated by a dominance modifier, for example, a transcription factor. In favor of this idea, 25% of the differentially expressed genes between INV and STD encode transcription factors. Interestingly, while only four differentially expressed genes are shared between embryos and wing discs, one of them is HP1c, a chromatin-binding protein and major transcriptional regulator, and thus a promising candidate for mediating the context-dependent change in dominance. Although the relationship between these patterns and fitness is presently unknown, our observations are consistent with a potential role of reversals (or, more generally, shifts) of dominance in maintaining inversion polymorphism.

Animals↗
PubMed1992

Circadian and developmental regulation of Oct-2 gene expression in the suprachiasmatic nuclei.

Oct-2 is a transcriptional activating factor that is expressed in the suprachiasmatic nuclei (SCN), the site of a biological clock. We examined in rats whether Oct-2 gene expression is regulated by the circadian pacemaker or by light using quantitative in situ hybridization. The ontogeny of Oct-2 gene expression in the SCN was also studied. Oct-2 mRNA levels remained constant throughout the circadian cycle. In contrast to c-fos mRNA levels which are acutely induced by acute light exposure at night, Oct-2 mRNA levels were not increased by light exposure at night. At gestational day 18, the first age the SCN are anatomically distinct, a prominent Oct-2 hybridization signal was present in the SCN. Our results suggest that Oct-2 is constitutively expressed in the SCN and is present from the time the SCN are discernible as discrete nuclei in fetal brain.

Animals↗
PubMed1986

Developmentally regulated expression of Drosophila chorion genes introduced at diverse chromosomal positions.

Drosophila chorion genes are organized into two clusters that are selectively amplified in the ovarian follicle cells. During oogenesis the transcription of individual genes is temporally regulated, resulting in distinct, stage-specific profiles of chorion mRNA accumulation. P element-mediated gene transfer was used to study the regulation of genes encoding the major chorion proteins s15-1 and s38-1. Transformed chorion genes integrated at diverse chromosomal locations exhibited proper tissue-specific and stage-specific expression, despite separation from the gene clusters. Qualitatively normal expression was not dependent on the ability of the inserted DNA to undergo amplification. However, chromosome position quantitatively influenced the RNA produced by the transformed genes. The level of RNA per gene copy produced by individual transformed genes varied approximately tenfold, after correction for differences in gene dosage due to the amplification of some inserted sequences. Transformation experiments with an s38-1-lacZ fusion gene demonstrated that cis-regulatory sequences sufficient for the stage-specific program of s38-1 expression were confined to a 1.3 X 10(3) base-pair segment between -748 and +573 relative to the s38-1 initiation site. Finally, egg chamber-specific amplification was induced at the site of two s38-1 insertions, suggesting that an amplification control element resides near this gene.

Animals↗
PubMed1986

Developmentally regulated rearrangement and expression of genes encoding the T cell receptor-T3 complex.

Human leukemic cells corresponding to the earliest identifiable stages of intrathymic T cell differentiation lack cell surface expression of the T cell receptor(TCR alpha/beta)-T3 complex but transcribe TCR beta mRNA from either germ-line configuration (1/13) or partially (DJ) or fully (VDJ) rearranged (12/13) genes. These cells do not produce TCR alpha mRNA, but do contain T3 delta and T3 epsilon mRNA and accumulate T3 polypeptides, primarily in the perinuclear envelope. Equivalent normal T cells isolated from thymus have a predominantly germ-line configuration of TCR beta but contain intracellular T3 proteins. T3 gene expression is therefore a very early event in T cell differentiation. TCR alpha chain production appears to be the limiting maturation-linked event in the transport, assembly, and cell surface membrane insertion of the TCR alpha/beta-T3 complex.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1991

Developmental regulation of creatine kinase gene expression by myogenic factors in embryonic mouse and chick skeletal muscle.

The B isoform of creatine kinase (BCK), which is expressed at a high level in embryonic neural tissues, is also expressed abundantly in developing striated muscle and is an early marker for skeletal myogenesis. Using isoform-specific 35S-labeled antisense cRNA probes for in situ hybridization, we have detected BCK mRNAs in embryonic mouse and chick myotomes, the first skeletal muscle masses to form in developing embryos. These transcripts are detectable as soon as myotomes are morphologically distinguishable. BCK is expressed at high levels in both skeletal and cardiac muscle in mouse and chick embryos. In the mouse, BCK transcript levels fall of rapidly in striated muscle shortly after the onset of MCK gene expression. The M isoform of creatine kinase (MCK), the striated muscle-specific isoform, is expressed later than BCK. In the mouse, BCK transcripts are expressed in myotomes at 8.5 days post coitum (p.c.), but MCK transcripts are not detected before 13 days p.c. In the chick, BCK mRNAs are present at Hamburger-Hamilton stage 13, but MCK mRNAs are not detected before stage 19. We have compared the patterns of expression of the CK genes with those of myogenic differentiation factor genes, which are thought to regulate skeletal muscle-specific gene expression. In the chick, both CMD1, first detected at stage 13, and myogenin, first detected at stage 15, are present prior to MCK, which begins to be expressed at stage 19. Unlike the mouse embryo, CMD1, the chick homologue of MyoD1, is expressed before chick myogenin. In the mouse, myogenin, first detected at 8.5 days p.c., is expressed at the same time as BCK in myotomes. Both myogenin and MyoD1, which begins to be detected two days later than myogenin, are expressed at least two days before MCK. It has been proposed that the myogenic factors, MyoD1 and myogenin, directly regulate MCK gene expression in the mouse by binding to its enhancer. However, our results show that MCK transcripts are not detected until well after MyoD1 and myogenin mRNAs are expressed, suggesting that these factors by themselves are not sufficient to initiate MCK gene expression.

Animals↗