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Developmental signals control chromosome segregation fidelity during early lineage specification and neurogenesis by modulating replicative stress

ABSTRACT: Developmental signals control chromosome segregation fidelity during early lineage specification and neurogenesis by modulating replicative stress

PROVIDER: PRJNA1131787 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR29705351_1.fastq.gz	Fastqsanger.gz
	SRR29705351_2.fastq.gz	Fastqsanger.gz
	SRR29705352_1.fastq.gz	Fastqsanger.gz
	SRR29705352_2.fastq.gz	Fastqsanger.gz
	SRR29705353_1.fastq.gz	Fastqsanger.gz

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Developmental signals control chromosome segregation fidelity during pluripotency and neurogenesis by modulating replicative stress

Project description:Human development relies on the correct replication, maintenance and segregation of our genetic blueprints. How these processes are monitored across embryonic lineages, and why genomic mosaicism varies during development remain unknown. Using pluripotent stem cells, we identify that several patterning signals –including WNT, BMP and FGF– converge into the modulation of DNA replication stress and damage during S-phase, which in turn controls chromosome segregation fidelity in mitosis. We show that the WNT and BMP signals protect from excessive origin firing, DNA damage and chromosome missegregation derived from stalled forks in pluripotency. Cell signalling control of chromosome segregation declines during lineage specification into the three germ layers, but re-emerges in neural progenitors. In particular, we find that the neurogenic factor FGF2 induces DNA replication stress-mediated chromosome missegregation during the onset of neurogenesis, which could provide a rationale for the elevated chromosomal mosaicism of the developing brain. Our results highlight roles for morphogens and cellular identity in genome maintenance that contribute to somatic mosaicism during mammalian development.

2024-07-31 | PXD054388 | Pride

Developmental signals control chromosome segregation fidelity during early lineage specification and neurogenesis by modulating replicative stress

Project description:Human development and homeostasis rely on the correct replication, maintenance and segregation of our genetic blueprints. How these intracellular processes are monitored across different human cellular lineages, and why the spatio-temporal distribution of mosaicism varies during development remain unknown. Using human and mouse pluripotent stem cells, we identify that several lineage specification signals –including WNT, BMP and FGF– converge into the modulation of DNA replication stress and damage during S-phase, which in turn controls spindle dynamics and chromosome segregation fidelity in mitosis. We show that patterning signals associated with anteriorisation during mammalian gastrulation increase chromosome missegregation, while the posteriorising signals WNT and BMP protect pluripotent stem cells from excessive origin firing, DNA damage and chromosome missegregation derived from stalled forks. Through epistasis experiments, we find that WNT, BMP and FGF have distinct roles during DNA replication, and demonstrate that WNT/GSK3 signalling sits at the helm of this regulatory cascade. Cell signalling control of chromosome segregation declines after pluripotency exit and specification into the three human germ layers, but re-emerges in differentiating neural progenitors. Through ex vivo and in vivo analyses, we also show that FGF and WNT signalling display opposite roles in chromosome segregation fidelity in mouse neural progenitors during the onset of neurogenesis (E14.5), but not during their expansion (E12.5). In particular, we find that the neurogenic factor FGF2 induces DNA replication stress-mediated chromosome missegregation, which could provide a rationale for the elevated chromosomal mosaicism of the developing brain. Our results highlight a role for patterning signals and cellular identity in genome maintenance that contributes to somatic mosaicism during mouse and human early lineage specification and neurogenesis.

2024-07-08 | GSE271478 | GEO

A signalling rheostat controls chromosome segregation fidelity during early lineage specification and neurogenesis by modulating replicative stress

Project description:Developmental signals link genome maintenance to stem cell identity

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Cell non-autonomous regulation of chromosome segregation

Project description:Chromosome segregation has been assumed to be a cell-autonomous process. We tested this assumption by comparing chromosome segregation fidelity in epithelial cells in various contexts and discovered that these cells have increased chromosome missegregation outside of their native tissue. Using organoid culture systems, we show that tissue architecture, specifically integrin function, is required for accurate chromosome segregation in epithelia. We find that tissue architecture enhances the correction of merotelic microtubule-kinetochore attachments, and this is critically important for maintaining chromosome stability in the polyploid liver. Our data lead to the surprising conclusion that chromosome segregation in epithelia is a cell non-autonomous process. We propose that disruption of tissue architecture could underlie the chromosome instability that characterizes and drives epithelial cancers. Moreover, our findings highlight the importance of context for fundamental cellular processes and caution against the exclusive reliance on cell culture systems for deciphering and manipulating mammalian biology.

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Lesion Segregation

Project description:Liver Cancer Evolution - Lesion segregation

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Retina-derived signals control pace of neurogenesis in visual brain areas but not circuit configuration

Project description:Retina-derived signals control pace of neurogenesis in visual brain areas but not circuit configuration

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Mouse neurogenesis

Project description:Mouse neurogenesis

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Retina-derived signals control pace of neurogenesis in visual brain areas but not circuit configuration

Project description:Brain development is orchestrated by both innate and experience-dependent mechanisms, but their relative contributions are often difficult to resolve. Here we asked if and how central visual areas are altered in a vertebrate brain depleted of any and all signals from retinal ganglion cells throughout development. We transcriptionally profiled neurons in pretectum, thalamus and other retinorecipient areas of larval zebrafish and searched for changes in lakritz mutants that lack all retinal connections. Although individual genes are dysregulated, the complete set of 77 neuronal types develops in apparently normal proportions, at normal locations, and along normal differentiation trajectories. Strikingly, the cell-cycle exits of proliferating progenitors in these areas are delayed, and a greater fraction of early postmitotic precursors remain uncommitted or are diverted to a glial fate. Optogenetic stimulation targeting groups of neurons normally involved in processing visual information evokes behaviors indistinguishable from wildtype. In conclusion, we show that signals emitted by retinal axons influence the pace of neurogenesis in visual areas, but do not detectably affect the specification or wiring of downstream neurons.

2023-10-02 | GSE238240 | GEO

Interaction between TBP and condensing drives the organization and faithful segregation of mitotic chromosomes

Project description:Genome/chromosome organization is highly ordered and controls nuclear events. Here, we show that the TATA box-binding protein (TBP) interacts with the Cnd2 kleisin subunit of condensin to mediate interphase and mitotic chromosome organization in fission yeast. TBP recruits condensin onto RNA polymerase III-transcribed (Pol III) genes and highly transcribed Pol II genes; condensin in turn associates these genes with centromeres. Inhibition of the Cnd2-TBP interaction disrupts condensin localization across the genome and the proper assembly of mitotic chromosomes, leading to severe defects in chromosome segregation and eventually causing cellular lethality. We propose that the Cnd2-TBP interaction coordinates transcription with chromosomal architecture by linking dispersed gene loci with centromeres. This chromosome arrangement can contribute to the efficient transmission of physical force at the kinetochore to chromosomal arms, thereby supporting the fidelity of chromosome segregation. Genome-wide distributions of condensin and Pol III factors in fission yeast.

2015-08-12 | E-GEOD-60273 | biostudies-arrayexpress

Coordination of histone chaperones for parental histone segregation and epigenetic inheritance

Project description:Chromatin-based epigenetic memory relies on the accurate distribution of parental histone tetramers to newly replicated DNA strands, serving as templates for chromatin structure duplication. Mcm2, a subunit of the replicative helicase, and the Dpb3/4, subunits of polymerase epsilon, govern parental histone deposition to the lagging and leading strands, respectively. However, their contribution to epigenetic inheritance remains controversial. Here we show in fission yeast that a Mcm2 histone chaperone mutation severely disrupts heterochromatin inheritance, while Dpb3/4 mutations cause only moderate defects. Surprisingly, simultaneous Mcm2 and Dpb3/4 mutations stabilizes heterochromatin inheritance. eSPAN analyses confirm the conservation of Mcm2 and Dpb3/4 functions in parental histone segregation, with their collective absence reducing segregation bias. Furthermore, the FACT histone chaperone also regulates parental histone transfer independently of strands and collaborates with Mcm2 and Dpb3/4 to maintain parental histone density, ensuring faithful heterochromatin inheritance. These results underscore the importance of precise parental histone segregation to the lagging strand for epigenetic inheritance and unveil unique properties of parental histone chaperones during DNA replication.

2024-04-17 | GSE237770 | GEO

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