2,361 research outputs found

    Dynamic chromatin: concerted nucleosome remodelling and acetylation

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    The flexibility of chromatin that enables translation of environmental cues into changes in genome utilisation, relies on a battery of enzymes able to modulate chromatin structure in a highly targeted and regulated manner. The most dynamic structural changes are brought about by two kinds of enzymes with different functional principles. Changes in the acetylation status of histones modulate the folding of the nucleosomal fibre. The histone-DNA interactions that define the nucleosome itself can be disrupted by ATP-dependent remodelling factors. This review focuses on recent developments that illustrate various strategies for integrating these disparate activities into complex regulatory schemes. Synergies may be brought about by consecutive or parallel action during the stepwise process of chromatin opening or closing. Tight co-ordination may be achieved by direct interaction of (de-)acetylation enzymes and remodelling ATPases or even permanent residence within the same multi-enzyme complex. The fact that remodelling ATPases can be acetylated by histone acetyltransferases themselves suggests exciting possibilities for the coordinate modulation of chromatin structure and remodelling enzymes

    Temporal Expression Profiling Identifies Pathways Mediating Effect of Causal Variant on Phenotype

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    Even with identification of multiple causal genetic variants for common human diseases, understanding the molecular processes mediating the causal variants' effect on the disease remains a challenge. This understanding is crucial for the development of therapeutic strategies to prevent and treat disease. While static profiling of gene expression is primarily used to get insights into the biological bases of diseases, it makes differentiating the causative from the correlative effects difficult, as the dynamics of the underlying biological processes are not monitored. Using yeast as a model, we studied genome-wide gene expression dynamics in the presence of a causal variant as the sole genetic determinant, and performed allele-specific functional validation to delineate the causal effects of the genetic variant on the phenotype. Here, we characterized the precise genetic effects of a functional MKT1 allelic variant in sporulation efficiency variation. A mathematical model describing meiotic landmark events and conditional activation of MKT1 expression during sporulation specified an early meiotic role of this variant. By analyzing the early meiotic genome-wide transcriptional response, we demonstrate an MKT1-dependent role of novel modulators, namely, RTG1/3, regulators of mitochondrial retrograde signaling, and DAL82, regulator of nitrogen starvation, in additively effecting sporulation efficiency. In the presence of functional MKT1 allele, better respiration during early sporulation was observed, which was dependent on the mitochondrial retrograde regulator, RTG3. Furthermore, our approach showed that MKT1 contributes to sporulation independent of Puf3, an RNA-binding protein that steady-state transcription profiling studies have suggested to mediate MKT1-pleiotropic effects during mitotic growth. These results uncover interesting regulatory links between meiosis and mitochondrial retrograde signaling. In this study, we highlight the advantage of analyzing allele-specific transcriptional dynamics of mediating genes. Applications in higher eukaryotes can be valuable for inferring causal molecular pathways underlying complex dynamic processes, such as development, physiology and disease progression

    Chromosome–nuclear envelope tethering – a process that orchestrates homologue pairing during plant meiosis?

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    During prophase I of meiosis, homologous chromosomes pair, synapse and exchange their genetic material through reciprocal homologous recombination, a phenomenon essential for faithful chromosome segregation. Partial sequence identity between non-homologous and heterologous chromosomes can also lead to recombination (ectopic recombination), a highly deleterious process that rapidly compromises genome integrity. To avoid ectopic exchange, homology recognition must be extended from the narrow position of a crossover-competent double-strand break to the entire chromosome. Here, we review advances on chromosome behaviour during meiotic prophase I in higher plants, by integrating centromere- and telomere dynamics driven by cytoskeletal motor proteins, into the processes of homologue pairing, synapsis and recombination. Centromere–centromere associations and the gathering of telomeres at the onset of meiosis at opposite nuclear poles create a spatially organised and restricted nuclear state in which homologous DNA interactions are favoured but ectopic interactions also occur. The release and dispersion of centromeres from the nuclear periphery increases the motility of chromosome arms, allowing meiosis-specific movements that disrupt ectopic interactions. Subsequent expansion of interstitial synapsis from numerous homologous interactions further corrects ectopic interactions. Movement and organisation of chromosomes, thus, evolved to facilitate the pairing process, and can be modulated by distinct stages of chromatin associations at the nuclear envelope and their collective release

    DNA Sequence-Mediated, Evolutionarily Rapid Redistribution of Meiotic Recombination Hotspots: Commentary on Genetics 182: 459–469 and Genetics 187: 385–396

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    Hotspots regulate the position and frequency of Spo11 (Rec12)-initiated meiotic recombination, but paradoxically they are suicidal and are somehow resurrected elsewhere in the genome. After the DNA sequence-dependent activation of hotspots was discovered in fission yeast, nearly two decades elapsed before the key realizations that (A) DNA site-dependent regulation is broadly conserved and (B) individual eukaryotes have multiple different DNA sequence motifs that activate hotspots. From our perspective, such findings provide a conceptually straightforward solution to the hotspot paradox and can explain other, seemingly complex features of meiotic recombination. We describe how a small number of single-base-pair substitutions can generate hotspots de novo and dramatically alter their distribution in the genome. This model also shows how equilibrium rate kinetics could maintain the presence of hotspots over evolutionary timescales, without strong selective pressures invoked previously, and explains why hotspots localize preferentially to intergenic regions and introns. The model is robust enough to account for all hotspots of humans and chimpanzees repositioned since their divergence from the latest common ancestor

    Modeling meiotic chromosomes indicates a size dependent contribution of telomere clustering and chromosome rigidity to homologue juxtaposition.

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    Meiosis is the cell division that halves the genetic component of diploid cells to form gametes or spores. To achieve this, meiotic cells undergo a radical spatial reorganisation of chromosomes. This reorganisation is a prerequisite for the pairing of parental homologous chromosomes and the reductional division, which halves the number of chromosomes in daughter cells. Of particular note is the change from a centromere clustered layout (Rabl configuration) to a telomere clustered conformation (bouquet stage). The contribution of the bouquet structure to homologous chromosome pairing is uncertain. We have developed a new in silico model to represent the chromosomes of Saccharomyces cerevisiae in space, based on a worm-like chain model constrained by attachment to the nuclear envelope and clustering forces. We have asked how these constraints could influence chromosome layout, with particular regard to the juxtaposition of homologous chromosomes and potential nonallelic, ectopic, interactions. The data support the view that the bouquet may be sufficient to bring short chromosomes together, but the contribution to long chromosomes is less. We also find that persistence length is critical to how much influence the bouquet structure could have, both on pairing of homologues and avoiding contacts with heterologues. This work represents an important development in computer modeling of chromosomes, and suggests new explanations for why elucidating the functional significance of the bouquet by genetics has been so difficult

    A Switch from a Gradient to a Threshold Mode in the Regulation of a Transcriptional Cascade Promotes Robust Execution of Meiosis in Budding Yeast

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    Tight regulation of developmental pathways is of critical importance to all organisms, and is achieved by a transcriptional cascade ensuring the coordinated expression of sets of genes. We aimed to explore whether a strong signal is required to enter and complete a developmental pathway, by using meiosis in budding yeast as a model. We demonstrate that meiosis in budding yeast is insensitive to drastic changes in the levels of its consecutive positive regulators (Ime1, Ime2, and Ndt80). Entry into DNA replication is not correlated with the time of transcription of the early genes that regulate this event. Entry into nuclear division is directly regulated by the time of transcription of the middle genes, as premature transcription of their activator NDT80, leads to a premature entry into the first meiotic division, and loss of coordination between DNA replication and nuclear division. We demonstrate that Cdk1/Cln3 functions as a negative regulator of Ime2, and that ectopic expression of Cln3 delays entry into nuclear division as well as NDT80 transcription. Because Ime2 functions as a positive regulator for premeiotic DNA replication and NDT80 transcription, as well as a negative regulator of Cdk/Cln, we suggest that a double negative feedback loop between Ime2 and Cdk1/Cln3 promotes a bistable switch from the cell cycle to meiosis. Moreover, our results suggest a regulatory mode switch that ensures robust meiosis as the transcription of the early meiosis-specific genes responds in a graded mode to Ime1 levels, whereas that of the middle and late genes as well as initiation of DNA replication, are regulated in a threshold mode

    Live Hot, Die Young: Transmission Distortion in Recombination Hotspots

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    There is strong evidence that hotspots of meiotic recombination in humans are transient features of the genome. For example, hotspot locations are not shared between human and chimpanzee. Biased gene conversion in favor of alleles that locally disrupt hotspots is a possible explanation of the short lifespan of hotspots. We investigate the implications of such a bias on human hotspots and their evolution. Our results demonstrate that gene conversion bias is a sufficiently strong force to produce the observed lack of sharing of intense hotspots between species, although sharing may be much more common for weaker hotspots. We investigate models of how hotspots arise, and find that only models in which hotspot alleles do not initially experience drive are consistent with observations of rather hot hotspots in the human genome. Mutations acting against drive cannot successfully introduce such hotspots into the population, even if there is direct selection for higher recombination rates, such as to ensure correct segregation during meiosis. We explore the impact of hotspot alleles on patterns of haplotype variation, and show that such alleles mask their presence in population genetic data, making them difficult to detect
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