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PubMed2026

Enhancer-promoter interaction maps in pig implantation tissue identify candidate cis-regulatory elements and regulatory variants.

Due to the polygenic nature of pig reproductive traits, most variants accounting for the phenotypic variation remain poorly characterized. It is well established that trait-associated variants are often enriched in regulatory elements of relevant tissues, and coordinated endometrial-conceptus crosstalk is critical for implantation success. Accordingly, this study aimed to investigate the chromatin landscape in pig endometrium-conceptus tissues and identify regulatory variants associated with reproductive traits. Combining RNA-seq and ChIP-seq, we uncovered cis-regulatory elements whose histone modification patterns correlate with gene expression. H3K27ac-based chromatin interaction profiling further resolved 2137 cis-regulatory elements involved in enhancer-promoter (E-P) interactions. Subsequent analyses identified candidate variants within these regulatory regions that associate with reproductive traits, in which the enhancer SNP rs346038249 likely affects transcriptional activity through allele-dependent transcription factor binding. Collectively, our findings provide mechanistic insights into pig embryo implantation and nominate candidate regulatory variants that merit further functional validation for their potential role in pig genetic improvement.

Embryo implantation↗
PubMed2002

A chromosome RNAissance.

In RNA-mediated interference (RNAi), double-stranded RNAs (dsRNAs) target complementary mRNAs for degradation. New work demonstrates that essential chromosomal functions are mediated through RNAi protein components and short RNAs, which alter chromosome function at specific DNA loci via histone modification.

Animals↗
PubMed2002

Epigenetic consequences of nucleosome dynamics.

Current models for epigenetic gene silencing envision a static relationship between histone modifications and transcription. However, evidence for nucleosome mobility and replacement favors a dynamic model that may explain phenomena ranging from variegation to the neural restriction of Rett syndrome.

Animals↗
PubMed2002

Transcript elongation on a nucleoprotein template.

Chromatin forms a general, repeating barrier to elongation of transcripts by eukaryotic RNA polymerases. Recent studies of nucleosome structure and histone modifications reveal a set of likely mechanisms for control of elongation through chromatin. Genetic and biochemical studies of transcription have identified a set of accessory factors for transcript elongation by RNA polymerase II (Pol II) that appear to function in the context of chromatin. The C-terminal repeated domain (CTD) of Pol II may also play a role in regulating elongation through chromatin.

Chromatin↗
PubMed2003

Transcriptional regulation by the MAP kinase signaling cascades.

A major function of the mitogen-activated protein kinase (MAPK) pathways is to control eukaryotic gene expression programmes in response to extracellular signals. MAPKs directly control gene expression by phosphorylating transcription factors. However, it is becoming clear that transcriptional regulation in response to MAPK signaling is more complex. MAPKs can also target coactivators and corepressors and affect nucleosomal structure by inducing histone modifications. Furthermore, multiple inputs into individual promoters can be elicited by MAPKs by targeting different components of the same coregulatory complex or by triggering different events on the same transcription factor. "Postgenomic approaches" are beginning to impact on our understanding of these gene regulatory networks. In this review, we summarise the current knowledge of MAPK-mediated gene regulation, and focus on how complexities in signaling outcomes are achieved and how this relates to physiological processes.

Animals↗
PubMed2003

Molecular links between X-inactivation and autosomal imprinting: X-inactivation as a driving force for the evolution of imprinting?

In classical Mendelian inheritance, each parent donates a set of chromosomes to its offspring so that maternally and paternally encoded information is expressed equally. The phenomena of X-chromosome inactivation (XCI) and autosomal imprinting in mammals violate this dogma of genetic equality. In XCI, one of the two female X chromosomes is silenced to equalize X-linked gene dosage between XX and XY individuals. In genomic imprinting, parental marks determine which of the embryo's two autosomal alleles will be expressed. Although XCI and imprinting appear distinct, molecular evidence now shows that they share a surprising number of features. Among them are cis-acting control centers, long-distance regulation and differential DNA methylation. Perhaps one of the most intriguing similarities between XCI and imprinting has been their association with noncoding and antisense RNAs. Very recent data also suggest the common involvement of histone modifications and chromatin-associated factors such as CTCF. Collectively, the evidence suggests that XCI and genomic imprinting may have a common origin. Here, I hypothesize that the need for X-linked dosage compensation was a major driving force in the evolution of genomic imprinting in mammals. I propose that imprinting was first fixed on the X chromosome for XCI and subsequently acquired by autosomes.

Animals↗
PubMed2003

Dynamic alterations of replication timing in mammalian cells.

BACKGROUND: The eukaryotic genome is divided into distinct replication timing domains, which are activated during S phase in a strictly conserved order. Cellular differentiation can alter replication timing in some loci, but recent experiments yielded conflicting data regarding the relationship between gene expression and replication timing. The genetic and epigenetic determinants of replication timing in mammalian cells have yet to be elucidated. RESULTS: We developed a mammalian experimental system in which the timing of DNA replication can be altered in a controlled manner. This system utilizes sequences from the human beta-globin locus that exhibit orientation-dependent transcriptional silencing when inserted into the murine genome. We found that before insertion, the murine target site replicated late during S phase. After insertion, replication timing depended on the orientation of the transgene. In a transcription-permissive orientation, the transgene and flanking sequences replicated early. In the reverse (silencing-prone) orientation, these sequences replicated late. Early replication correlated with histone modifications of the transgene chromatin but could be observed in the absence of the beta-globin promoter. Importantly, the replication timing switch did not require a replication origin within the transgene. CONCLUSIONS: Transgene insertions into mammalian heterochromatin can alter the timing of DNA replication at the insertion site. This differentiation-independent replication timing switch did not necessitate insertion of an active promoter or a replication origin. These observations suggest that the timing of DNA replication can be manipulated by changes in DNA sequence, but that the determinants of replication timing are distinct from the sequences that specify replication initiation sites.

Animals↗
PubMed1999

Influence of nucleosome structure on the three-dimensional folding of idealized minichromosomes.

BACKGROUND: The closed circular, multinucleosome-bound DNA comprising a minichromosome provides one of the best known examples of chromatin organization beyond the wrapping of the double helix around the core of histone proteins. This higher level of chain folding is governed by the topology of the constituent nucleosomes and the spatial disposition of the intervening protein-free DNA linkers. RESULTS: By simplifying the protein-DNA assembly to an alternating sequence of virtual bonds, the organization of a string of nucleosomes on the minichromosome can be treated by analogy to conventional chemical depictions of macromolecular folding in terms of the bond lengths, valence angles, and torsions of the chain. If the nucleosomes are evenly spaced and the linkers are sufficiently short, regular minichromosome structures can be identified from analytical expressions that relate the lengths and angles formed by the virtual bonds spanning the nucleosome-linker repeating units to the pitch and radius of the organized quaternary structures that they produce. CONCLUSIONS: The resulting models with 4-24 bound nucleosomes illustrate how a minichromosome can adopt the low-writhe folding motifs deduced from biochemical studies, and account for published images of the 30 nm chromatin fiber and the simian virus 40 (SV40) nucleohistone core. The marked sensitivity of global folding to the degree of protein-DNA interactions and the assumed nucleosomal shape suggest potential mechanisms for chromosome rearrangements upon histone modification.

Chromosomes↗
PubMed2002

Promoter activation by enhancer-dependent and -independent loading of activator and coactivator complexes.

Activation of the pDbeta1 promoter at the TCRbeta locus requires a functional distal enhancer, Ebeta. Here, we have analyzed the mechanism of promoter activation in thymocytes from mice containing or lacking Ebeta. We found that pDbeta1 shows a complex profile of transcription factor and chromatin remodeling complex occupancy even at Ebeta(-) alleles. The presence of Ebeta, however, results in a few specific changes in factor occupancy at the promoter. These differences correlate with localized alterations in histone modifications and in the recruitment of the basal transcriptional machinery. In addition, Ebeta is also bound by CBP and Pol II, suggesting a mechanism for delivery of a holoenzyme complex to the pDbeta1 promoter. These results illustrate a specialized, long-range function of an enhancer in the hierarchical events that regulate assembly of a cell type-specific promoter.

3T3 Cells↗
PubMed2002

Pathogenesis of amebiasis.

It is an exciting time in the study of Entamoeba histolytica. Over the past two years, the natural history and burden of disease in humans has been redefined, mucosal immune responses associated with protection identified, and the developmental regulation of encystation outlined. The number of genes sequenced has increased from a few hundred to a few thousand, and study of the genome structure is revealing unusual repetitive elements and plasticity. DNA microarrays promise the first ability to examine global patterns of mRNA abundance. The mechanism of transcriptional control via histone modifications and sequence-specific DNA-binding proteins are to be delineated. Advances in cell biology are providing new insights into invasion through the intestinal epithelium.

Animals↗
PubMed2004

The early embryonic expression of TFII-I during mouse preimplantation development.

We studied the developmentally regulated expression of mouse TFII-I, a founding member of a family of transcription factors characterized by the presence of multiple helix-loop-helix repeat domains. TFII-I and BEN, a second member of this family, are involved in histone modification and SUMOylation. The genes, GTF2I and GTF2IRD1, encoding these proteins in human are located at chromosomal band 7q11.23, within the Williams syndrome critical region. Our immunohistochemical analysis revealed extensive expression of TFII-I at early stages of embryogenesis. Like BEN, TFII-I is detected in the cytoplasm and nuclei of postfertilization through first cleavage stage embryos. However, in E4.5 blastocysts, at the time of implantation, TFII-I is localized in the nucleus and cytoplasm of the inner cell mass (ICM) and trophectoderm. BEN, at this stage, is expressed only in the cytoplasm of trophoblast cells, but not in the ICM [Gene Expr. Patterns, 2003; 3, 577-587]. Using RT-PCR, we detected Gtf2i and Gtf2ird1 mRNA transcripts in unfertilized oocytes, which indicates the maternal expression of these genes. Thus, the early embryonic expression of TFII-I implicates this family of transcription factors in preimplantation development.

Animals↗
PubMed2025

Genetic and Epigenetic Approaches to Opioid Use Disorder.

BACKGROUND: Opioid use disorder (OUD) is a major global-scale social issue affecting public health. The high potential for addiction and dependence makes opioid use a significant concern, contributing to substance-related disorders. Both genetic and environmental factors contribute to the predisposition to OUD, with the opioidergic, dopaminergic, and GABAergic systems playing primary roles in itsonset. METHODS: This narrative review documents the association between genes and their variants related to these three systems, along with current evidence on epigenetic interventions in OUD. Relevant studies investigating candidate-gene associations and molecular mechanisms were synthesized to highlight genetic variants and epigenetic processes linked to OUD. RESULTS: Genetic associations play a prominent role in OUD, with several single-nucleotide variants identified in affected populations. Key genes implicated include OPRM1, OPRD1, OPRK1, PDYN, OPRL1, and POMC from the opioidergic system; DRD1, DRD2, DRD3, DRD4, ANKK1, and COMT from the dopaminergic system; and GABRA2, GABRB3, GABRG2, GAD1, and GAD2 from the GABAergic system. Evidence also indicates that chronic opioid use is associated with epigenetic changes through posttranslational histone modifications and DNA methylation. However, limitations in existing studies include small sample sizes, limited replication, and potential stratification biases. CONCLUSIONS: Although many candidate-gene associations have been proposed for OUD, robust evidence remains limited. Large, ancestrally diverse genome-wide association studies (GWAS) and systematic replication studies are urgently needed. A deeper understanding of the genetic, epigenetic, and neurobiological bases of addiction will be essential for the development of precisely targeted medications to improve prevention and treatment outcomes for OUD.

Humans↗
PubMed1997

Chromatin remodeling regulated by steroid and nuclear receptors.

Coactivators and corepressors regulate transcription by controlling interactions between sequence-specific transcription factors, the basal transcriptional machinery and the chromatin environment. This review consider the access of nuclear and steroid receptors to chromatin, their use of corepressors and coactivators to modify chromatin structure and the implications for transcriptional control. The assembly of specific nucleoprotein architectures and targeted histone modification emerge as central controlling elements for gene expression.

Animals↗
PubMed2006

Clustered DNA motifs mark X chromosomes for repression by a dosage compensation complex.

Gene expression in metazoans is regulated not only at the level of individual genes but also in a coordinated manner across large chromosomal domains (for example centromeres, telomeres and imprinted gene clusters) and along entire chromosomes (for example X-chromosome dosage compensation). The primary DNA sequence usually specifies the regulation of individual genes, but the nature of cis-acting information that controls genes over large regions has been elusive: higher-order DNA structure, specific histone modifications, subnuclear compartmentalization and primary DNA sequence are possibilities. One paradigm of chromosome-wide gene regulation is Caenorhabditis elegans dosage compensation in which a large dosage compensation complex (DCC) is targeted to both X chromosomes of hermaphrodites to repress transcript levels by half. This essential process equalizes X-linked gene expression between the sexes (XO males and XX hermaphrodites). Here we report the discovery and dissection of cis-acting sites that mark nematode X chromosomes as targets for gene repression by the DCC. These rex (recruitment element on X) sites are widely dispersed along X and reside in promoters, exons and intergenic regions. rex sites share at least two distinct motifs that act in combination to recruit the DCC. Mutating these motifs severely reduces or abolishes DCC binding in vivo, demonstrating the importance of primary DNA sequence in chromosome-wide regulation. Unexpectedly, the motifs are not enriched on X, but altering motif numbers within rex sites demonstrates that motif co-occurrence in unusually high densities is essential for optimal DCC recruitment. Thus, X-specific repression is established through sequences not specific to X. The distribution of common motifs provides the foundation for repression along an entire chromosome.

Animals↗
PubMed2003

Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals.

Cells of a multicellular organism are genetically homogeneous but structurally and functionally heterogeneous owing to the differential expression of genes. Many of these differences in gene expression arise during development and are subsequently retained through mitosis. Stable alterations of this kind are said to be 'epigenetic', because they are heritable in the short term but do not involve mutations of the DNA itself. Research over the past few years has focused on two molecular mechanisms that mediate epigenetic phenomena: DNA methylation and histone modifications. Here, we review advances in the understanding of the mechanism and role of DNA methylation in biological processes. Epigenetic effects by means of DNA methylation have an important role in development but can also arise stochastically as animals age. Identification of proteins that mediate these effects has provided insight into this complex process and diseases that occur when it is perturbed. External influences on epigenetic processes are seen in the effects of diet on long-term diseases such as cancer. Thus, epigenetic mechanisms seem to allow an organism to respond to the environment through changes in gene expression. The extent to which environmental effects can provoke epigenetic responses represents an exciting area of future research.

Aging↗
PubMed2004

Interaction between differentially methylated regions partitions the imprinted genes Igf2 and H19 into parent-specific chromatin loops.

Imprinted genes are expressed from only one of the parental alleles and are marked epigenetically by DNA methylation and histone modifications. The paternally expressed gene insulin-like growth-factor 2 (Igf2) is separated by approximately 100 kb from the maternally expressed noncoding gene H19 on mouse distal chromosome 7. Differentially methylated regions in Igf2 and H19 contain chromatin boundaries, silencers and activators and regulate the reciprocal expression of the two genes in a methylation-sensitive manner by allowing them exclusive access to a shared set of enhancers. Various chromatin models have been proposed that separate Igf2 and H19 into active and silent domains. Here we used a GAL4 knock-in approach as well as the chromosome conformation capture technique to show that the differentially methylated regions in the imprinted genes Igf2 and H19 interact in mice. These interactions are epigenetically regulated and partition maternal and paternal chromatin into distinct loops. This generates a simple epigenetic switch for Igf2 through which it moves between an active and a silent chromatin domain.

Animals↗
PubMed2006

Epigenetic remodeling in colorectal cancer results in coordinate gene suppression across an entire chromosome band.

We report a new mechanism in carcinogenesis involving coordinate long-range epigenetic gene silencing. Epigenetic silencing in cancer has always been envisaged as a local event silencing discrete genes. However, in this study of silencing in colorectal cancer, we found common repression of the entire 4-Mb band of chromosome 2q.14.2, associated with global methylation of histone H3 Lys9. DNA hypermethylation within the repressed genomic neighborhood was localized to three separate enriched CpG island 'suburbs', with the largest hypermethylated suburb spanning 1 Mb. These data change our understanding of epigenetic gene silencing in cancer cells: namely, epigenetic silencing can span large regions of the chromosome, and both DNA-methylated and neighboring unmethylated genes can be coordinately suppressed by global changes in histone modification. We propose that loss of gene expression can occur through long-range epigenetic silencing, with similar implications as loss of heterozygosity in cancer.

Chromatin↗
PubMed2005

Reversal of the cellular phenotype in the premature aging disease Hutchinson-Gilford progeria syndrome.

Hutchinson-Gilford progeria syndrome (HGPS) is a childhood premature aging disease caused by a spontaneous point mutation in lamin A (encoded by LMNA), one of the major architectural elements of the mammalian cell nucleus. The HGPS mutation activates an aberrant cryptic splice site in LMNA pre-mRNA, leading to synthesis of a truncated lamin A protein and concomitant reduction in wild-type lamin A. Fibroblasts from individuals with HGPS have severe morphological abnormalities in nuclear envelope structure. Here we show that the cellular disease phenotype is reversible in cells from individuals with HGPS. Introduction of wild-type lamin A protein does not rescue the cellular disease symptoms. The mutant LMNA mRNA and lamin A protein can be efficiently eliminated by correction of the aberrant splicing event using a modified oligonucleotide targeted to the activated cryptic splice site. Upon splicing correction, HGPS fibroblasts assume normal nuclear morphology, the aberrant nuclear distribution and cellular levels of lamina-associated proteins are rescued, defects in heterochromatin-specific histone modifications are corrected and proper expression of several misregulated genes is reestablished. Our results establish proof of principle for the correction of the premature aging phenotype in individuals with HGPS.

Alternative Splicing↗