Investigating the role of nuclear mechanics in the regulation of chromatin structure and embryonic cell fate
研究核力学在染色质结构和胚胎细胞命运调节中的作用
基本信息
- 批准号:10723483
- 负责人:
- 金额:$ 12.47万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-08-10 至 2025-07-31
- 项目状态:未结题
- 来源:
- 关键词:AdhesionsAffectAutomobile DrivingBindingBiological AssayCell Differentiation processCell NucleusCellsChromatinChromatin ModelingChromatin StructureClustered Regularly Interspaced Short Palindromic RepeatsCritical PathwaysCryoelectron MicroscopyCytoplasmCytoskeletonDetectionDevelopmentEducationElectron MicroscopyEmbryoEmbryonic DevelopmentFertilizationGene ExpressionGenerationsGenetic TranscriptionGenomicsGerm LayersGoalsHeterochromatinImageImmunofluorescence ImmunologicInfertilityInner Cell MassLabelLamin Type ALearningLightLinkMaintenanceMammalian CellMammalsMechanicsMembrane ProteinsMentorsMethodsMolecularMusNuclearNuclear EnvelopeNuclear MatrixNucleosomesPathway interactionsPlacentaPostdoctoral FellowPregnancyProcessProteinsProtocols documentationRegulationRegulatory PathwayResearchResistanceResolutionRoleRunningScientistSignal PathwaySignal TransductionSpecialistSpecific qualifier valueSupporting CellTechniquesTestingTrainingVisualizationWorkblastocystblastomere structurecell fate specificationcell typeearly pregnancyembryo cellembryo tissueexperimental studyimplantationin vivoinsightmechanical forcemechanical propertiesmechanical signalnovelnovel strategiespluripotencypost-doctoral trainingpreimplantationprogramssensortomographytranscriptome sequencingtransmission process
项目摘要
SUMMARY
The inner cell mass (ICM) and trophectoderm (TE) are the first two cell types specified during mammalian
development. TE cells support implantation and give rise to the placenta, whereas ICM cells forms the embryo
and some extraembryonic tissues. Their differentiation is therefore critical for successful pregnancy. The
mechanically-regulated Hippo signaling pathway is differentially activated in ICM and TE cells, driving gene
expression programs that define these cell states. These programs also depend on cell type-specific chromatin
landscapes. How mechanical forces regulate chromatin structure and embryonic cell fates during pre-
implantation is however not fully understood. I hypothesize that mechanical forces transmitted though the
cytoskeleton, regulate TE transcriptional programs by modulating both Hippo signaling and chromatin structure.
In this proposal, I will test this hypothesis by defining how nuclear tension regulates Hippo signaling and
chromatin organization during early embryonic differentiations. My ultimate goal is to define the mechanistic links
connecting mechanical and regulatory pathways to cell and chromatin states. This work will enhance our
understanding of cell fate specification, both in relationship to early embryogenesis and implantation, and more
broadly. My postdoctoral work in the Giraldez lab showed that Lamin A/C is transcriptionally up-regulated in TE,
compared to ICM, and that it regulates TE identify; LMNA/C depletion leads to an ICM-like transcriptional state
reminiscent of Hippo pathway activation. In Aim 1 (K99), I will investigate regulation of Hippo by Lamin A/C and
determine the role of mechanical sensing by cytoskeletal networks in the regulation of this signaling. In Aim 2
(K99/R00), to determine how mechanical forces regulate chromatin, I will apply advanced electron microscopy
approaches to visualize nucleosome resolution chromatin structure in vivo. During the training period in the
Giraldez lab, I will apply a novel labeling strategy, combined with cryo EM to characterize lamina-heterochromatin
interactions. During the R00 period and beyond, I will apply these approaches to determine how compaction of
the embryo and the generation of mechanical forces on the nucleus impact chromatin structure and ICM/TE
fates. In Aim 3 (R00), I will use chimeric embryos and other developmental assays to examine how changes in
the mechanical properties of the nucleus affects differentiation potential. I will also quantify nuclear stiffness and
chromatin structure in developing mouse embryos. This work paves the way for a deeper understanding of the
role of mechanical forces in regulating gene expression and cell identity. This proposal brings together training
and concepts that I have acquired throughout my education and new approaches (RNA-seq and cryo-EM) that
I will learn in my mentor’s (Giraldez) lab, from other scientists and specialists at Yale, and at the lab of my co-
mentors, Elizabeth Villa and Berna Sozen. This proposal will complete my postdoctoral training and prepare me
for my ultimate goal of running a competitive independent research program.
总结
项目成果
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