pH dynamics determining DNA binding specificity of FOX transcription factors
pH 动态决定 FOX 转录因子的 DNA 结合特异性
基本信息
- 批准号:10389680
- 负责人:
- 金额:$ 4.39万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-03-01 至 2024-02-29
- 项目状态:已结题
- 来源:
- 关键词:AdhesionsAffinityApoptosisBarberingBehaviorBindingBiochemicalCell divisionCell physiologyCellsChIP-seqCollaborationsComplexConsensus SequenceDNADNA BindingDNA Binding DomainDNA SequenceDataDiseaseDysplasiaEvolutionFOXM1 geneFamilyFamily memberFluorescence AnisotropyGene ExpressionGenesGenetic TranscriptionHistidineHuman PathologyHydrogen BondingIn VitroInterferonsKineticsLigandsMaintenanceMajor GrooveMalignant NeoplasmsMolecularMusNeoplasm MetastasisNucleic Acid BindingNucleic AcidsNucleotidesOncogenesOutcomeOutcome StudyPathologyPlayPost-Translational Protein ProcessingPromoter RegionsProtein DynamicsProtein FamilyProteinsRecombinantsRegenerative MedicineRegulationReportingRoleSpecificityStructureTestingTherapeuticTitrationsTranscriptional RegulationWorkbasecancer cellcell behaviorcell motilityclinically relevantdaughter cellembryonic stem cellgenome-widehuman diseasein silicomembermolecular dynamicsnovelnovel therapeutic interventionpreferencepromoterprotein functionprotein structureprotonationresponsesensorsimulationstem cell differentiationstem cell self renewalstem cellstranscription factortumor progressiontumorigenesis
项目摘要
Project Summary/Abstract
Members of the mammalian FOX family of transcription factors regulate a broad range of cellular processes
including cell division, differentiation, and apoptosis. Despite sharing a highly conserved DNA-binding sequence,
each FOX family member binds a distinct set of target genes to regulate myriad cell behaviors. The current
understanding of DNA-binding selectivity of different FOX family transcription factors is that regulation is
conferred by co-factor association, post-translational modifications, and cell specific expression. This proposal
aims to resolve a new idea that intracellular pH (pHi) dynamics is an additional mechanism regulating target
gene selectivity of FOX family transcription factors. Although all FOX proteins contain an invariant histidine
residue in the DNA-binding domain that directly forms hydrogen bonds with nucleotides and histidine residues
can titrate with pHi dynamics, whether pHi regulates nucleotide binding specificity of FOX proteins has not been
reported. Building on preliminary data demonstrating pH-dependent binding of FoxM1 to a common consensus
sequence, this proposal tests the overall hypothesize that the invariant histidine in FOX DNA-binding
domains is a pH sensor for pHi-regulated binding selectivity to target genes. The objective of Aim 1 is to
determine pH-regulated DNA binding selectivity of FOX family proteins. Predictions on pH-regulated DNA-
binding specificity of a number of FOX family members will be tested in silico using molecular dynamic
simulations that will inform in vitro biochemical approaches to determine binding affinities using fluorescence
anisotropy. Additionally, genome-wide pH-dependent binding preferences will be determined using systematic
evolution of ligand by exponential enrichment (SELEX). The objective of Aim 2 is to determine the role of pHi
dynamics in regulating FoxM1 target genes in cells, focusing on naïve mouse embryonic stem cells and cancer
cells because they to have behaviors regulated by pHi dynamics. Global FoxM1 promoter binding preferences
in response to pHi dynamics will be identified in embryonic stem cells and cancer cells by using ChiP-seq that
will inform mechanistic analysis by determining pHi regulated gene expression using RT-qPCR. In addition to
revealing a new paradigm for transcriptional regulation of FOX proteins the principles being tested have
significance for the activity of other transcription factors that contain histidines in the DNA binding domain,
including members of IRF, GATA and ETV families. Moreover, because pHi-regulated transcription factor activity
and gene expression remain understudied, outcomes will add mechanistic understanding of how pHi dynamics
regulates cell behaviors. Finally, because FOX transcriptional activity and pHi dynamics are dysregulated in
many diseases, these findings will have clinical relevance toward new therapeutic approaches, particularly to
limit cancer progression and also for controlling regenerative medicine.
项目总结/文摘
项目成果
期刊论文数量(0)
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Kyle Kisor其他文献
Kyle Kisor的其他文献
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{{ truncateString('Kyle Kisor', 18)}}的其他基金
pH dynamics determining DNA binding specificity of FOX transcription factors
pH 动态决定 FOX 转录因子的 DNA 结合特异性
- 批准号:
10576266 - 财政年份:2022
- 资助金额:
$ 4.39万 - 项目类别:
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