Publications by authors named "Martin Leeb"

Naïve pluripotency is sustained by a self-reinforcing gene regulatory network (GRN) comprising core and naïve pluripotency-specific transcription factors (TFs). Upon exiting naïve pluripotency, embryonic stem cells (ESCs) transition through a formative post-implantation-like pluripotent state, where they acquire competence for lineage choice. However, the mechanisms underlying disengagement from the naïve GRN and initiation of the formative GRN are unclear.

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Article Synopsis
  • Enhancers interact with transcription factors, chromatin regulators, and non-coding RNA to influence gene expression, particularly during cell differentiation.
  • The study examines 3D genome structures of mouse embryonic stem cells transitioning from pluripotency to neuroectodermal differentiation, revealing significant reorganization of chromosome interactions.
  • This reorganization leads to the creation of multiway hubs that connect enhancers and promoters from distant chromosomal regions, implicating these structural changes in the regulation of gene expression and the establishment of new cell identities.
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Huntington's disease (HD) is a neurodegenerative disorder caused by CAG-repeat expansions in the huntingtin (HTT) gene. The resulting mutant HTT (mHTT) protein induces toxicity and cell death via multiple mechanisms and no effective therapy is available. Here, we employ a genome-wide screening in pluripotent mouse embryonic stem cells (ESCs) to identify suppressors of mHTT toxicity.

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While extended loop extrusion across the entire Igh locus controls V -DJ recombination, local regulatory sequences, such as the PAIR elements, may also activate V gene recombination in pro-B-cells. Here, we show that PAIR-associated V 8 genes contain a conserved putative regulatory element (V8E) in their downstream sequences. To investigate the function of PAIR4 and its V8.

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Cell fate transitions depend on balanced rewiring of transcription and translation programs to mediate ordered developmental progression. Components of the nonsense-mediated mRNA decay (NMD) pathway have been implicated in regulating embryonic stem cell (ESC) differentiation, but the exact mechanism is unclear. Here we show that NMD controls expression levels of the translation initiation factor and its premature termination codon-encoding isoform ( ).

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The C-terminal domain (CTD) of the largest subunit of RNA polymerase II (Pol II) is a regulatory hub for transcription and RNA processing. Here, we identify PHD-finger protein 3 (PHF3) as a regulator of transcription and mRNA stability that docks onto Pol II CTD through its SPOC domain. We characterize SPOC as a CTD reader domain that preferentially binds two phosphorylated Serine-2 marks in adjacent CTD repeats.

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In mammalian genomes, differentially methylated regions (DMRs) and histone marks including trimethylation of histone 3 lysine 27 (H3K27me3) at imprinted genes are asymmetrically inherited to control parentally-biased gene expression. However, neither parent-of-origin-specific transcription nor imprints have been comprehensively mapped at the blastocyst stage of preimplantation development. Here, we address this by integrating transcriptomic and epigenomic approaches in mouse preimplantation embryos.

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In the mammalian embryo, epiblast cells must exit the naïve state and acquire formative pluripotency. This cell state transition is recapitulated by mouse embryonic stem cells (ESCs), which undergo pluripotency progression in defined conditions in vitro. However, our understanding of the molecular cascades and gene networks involved in the exit from naïve pluripotency remains fragmentary.

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Article Synopsis
  • Many genes are regulated by multiple enhancers, which can work together to activate transcription, but the specifics of how they collaborate are unclear.
  • Researchers studied five enhancer elements involved in activating the Fgf5 gene during the transition out of naive pluripotency in mice, finding that four intergenic elements form a super-enhancer and contribute at different times.
  • One intronic enhancer boosts overall Fgf5 expression levels at all time points, indicating that even weak individual enhancers can collectively have a powerful effect, correlating with increased RNA polymerase II accumulation at the enhancer.
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  • Researchers developed a new protocol that combines fluorescence imaging and Hi-C assays to study genome organization in individual cells.
  • This method allows for the simultaneous capture of chromosome contacts and fluorescence images, providing comprehensive data on genome structures with high resolution.
  • The entire process of preparing single-cell Hi-C libraries takes about 5 days for experienced researchers, requiring basic knowledge of microscopy and bioinformatics for data analysis.
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  • The folding of genomic DNA is essential for nuclear functions, and researchers have developed a new technique to visualize and study individual mammalian genomes in 3D.
  • This method allows scientists to observe genome folding at a scale smaller than 100kb, revealing that individual structures vary between cells while certain genomic features have consistent organization across cells.
  • By examining gene regulation mechanisms, this research demonstrates how single-cell genomic structure can provide insights into biological processes.
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One of the two X chromosomes in female mammals is inactivated by the noncoding Xist RNA. In mice, X chromosome inactivation (XCI) is regulated by the antisense RNA Tsix, which represses Xist on the active X chromosome. In the absence of Tsix, PRC2-mediated histone H3 lysine 27 trimethylation (H3K27me3) is established over the Xist promoter.

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Haploid genetics has facilitated new insights into mammalian pathways and disease mechanisms. Most animal cells are diploid, and mammalian haploid cell cultures have remained elusive for a long time. Recent methodological progress has enabled the routine derivation of haploid stem cell lines from mammalian haploid embryos.

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Self-renewal circuitry in embryonic stem cells (ESCs) is increasingly defined. How the robust pluripotency program is dissolved to enable fate transition is less appreciated. Here we develop a forward genetic approach using haploid ESCs.

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Sequencing projects have revealed the information of many animal genomes and thereby enabled the exploration of genome evolution. Insights into how genomes have been repeatedly modified provide a basis for understanding evolutionary innovation and the ever increasing complexity of animal developmental programs. Animal genomes are diploid in most cases, suggesting that redundant information in two copies of the genome increases evolutionary fitness.

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Background: Histone deacetylase inhibitors (HDACi) cause histone hyperacetylation and H3K4 hypermethylation in various cell types. They find clinical application as anti-epileptics and chemotherapeutic agents, but the pathways through which they operate remain unclear. Surprisingly, changes in gene expression caused by HDACi are often limited in extent and can be positive or negative.

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Haploid embryonic stem cells (ESCs) have recently been derived from parthenogenetic mouse embryos and offer new possibilities for genetic screens. The ability of haploid ESCs to give rise to a wide range of differentiated cell types in the embryo and in vitro has been demonstrated. However, it has remained unclear whether haploid ESCs can contribute to the germline.

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The distinct cell types of the body are established from the fertilized egg in development and assembled into functional tissues. Functional characteristics and gene expression patterns are then faithfully maintained in somatic cell lineages over a lifetime. On the molecular level, transcription factors initiate lineage-specific gene expression programmmes and epigenetic regulation contributes to stabilization of expression patterns.

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Most animals are diploid, but haploid-only and male-haploid (such as honeybee and ant) species have been described. The diploid genomes of complex organisms limit genetic approaches in biomedical model species such as mice. To overcome this problem, experimental induction of haploidy has been used in fish.

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How polycomb group proteins repress gene expression in vivo is not known. While histone-modifying activities of the polycomb repressive complexes (PRCs) have been studied extensively, in vitro data have suggested a direct activity of the PRC1 complex in compacting chromatin. Here, we investigate higher-order chromatin compaction of polycomb targets in vivo.

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Mammals compensate X chromosome gene dosage between the sexes by silencing of one of the two female X chromosomes. X inactivation is initiated in the early embryo and requires the non-coding Xist RNA, which encompasses the inactive X chromosome (Xi) and triggers its silencing. In differentiated cells, several factors including the histone variant macroH2A and the scaffold attachment factor SAF-A are recruited to the Xi and maintain its repression.

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Polycomb complexes establish chromatin modifications for maintaining gene repression and are essential for embryonic development in mice. Here we use pluripotent embryonic stem (ES) cells to demonstrate an unexpected redundancy between Polycomb-repressive complex 1 (PRC1) and PRC2 during the formation of differentiated cells. ES cells lacking the function of either PRC1 or PRC2 can differentiate into cells of the three germ layers, whereas simultaneous loss of PRC1 and PRC2 abrogates differentiation.

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The noncoding Xist RNA triggers silencing of one of the two female X chromosomes during X inactivation in mammals. Gene silencing by Xist is restricted to a special developmental context in early embryos and specific hematopoietic precursors. Here, we show that Xist can initiate silencing in a lymphoma model.

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Non-coding RNAs regulate dosage compensation in mammals by controlling transcriptional silencing of one of the two X chromosomes in females. The two major transcripts involved in this process are Xist and its antisense counterpart Tsix. Expression of Xist and Tsix from the X inactivation center is mutually exclusive.

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