THAP11通過調(diào)控纈氨酸代謝維持造血干細(xì)胞功能的作用研究

THAP11通過調(diào)控纈氨酸代謝維持造血干細(xì)胞功能的作用研究摘要：

THAP11是一種參與DNA結(jié)合和基因表達(dá)調(diào)控的轉(zhuǎn)錄因子，在造血系統(tǒng)中發(fā)揮重要作用。本研究通過轉(zhuǎn)基因小鼠模型和體外細(xì)胞培養(yǎng)實(shí)驗(yàn)，發(fā)現(xiàn)THAP11對于維持造血干細(xì)胞（HSC）的功能具有至關(guān)重要的作用。我們發(fā)現(xiàn)，THAP11的缺失會導(dǎo)致HSC數(shù)量和功能降低，并且，HSC粒線體內(nèi)的糖酵解代謝和TCA循環(huán)都發(fā)生了變化，其中，我們發(fā)現(xiàn)纈氨酸在THAP11調(diào)控的HSC代謝過程中發(fā)揮了重要的作用。具體而言，THAP11可調(diào)控纈氨酸合成、降解和代謝的相關(guān)基因表達(dá)，使得HSC能夠在應(yīng)激和損傷中快速、有效地應(yīng)對和恢復(fù)功能。因此，我們認(rèn)為，THAP11是維持HSC功能的關(guān)鍵因子之一，進(jìn)一步闡明THAP11調(diào)控HSC代謝和功能的分子機(jī)制對于深入理解造血過程具有重要的指導(dǎo)意義。

關(guān)鍵詞：THAP11；纈氨酸代謝；造血干細(xì)胞；糖酵解代謝；TCA循環(huán)

THAP11regulateshistidinemetabolismtomaintainhematopoieticstemcellfunction:astudy

Abstract:

THAP11isatranscriptionfactorthatplaysanimportantroleinDNAbindingandgeneexpressionregulationinthehematopoieticsystem.Inthisstudy,wefoundthatTHAP11iscriticalformaintainingthefunctionofhematopoieticstemcells(HSC)throughtransgenicmousemodelsandinvitrocellcultureexperiments.WefoundthatthelossofTHAP11ledtoadecreaseinHSCnumberandfunction,andthattheglycolyticmetabolismandTCAcycleinHSCmitochondriawerealtered.Specifically,wefoundthathistidineplaysanimportantroleintheTHAP11-regulatedmetabolicprocessinHSC.THAP11regulatestheexpressionofgenesrelatedtohistidinesynthesis,degradation,andmetabolism,allowingHSCtorespondandrecoverquicklyandeffectivelyfromstressanddamage.Therefore,webelievethatTHAP11isoneofthekeyfactorsthatmaintainHSCfunction,andfurtherelucidatingthemolecularmechanismsofTHAP11regulationofHSCmetabolismandfunctionisofgreatguidingsignificanceforabetterunderstandingofhematopoiesis.

Keywords:THAP11;histidinemetabolism;hematopoieticstemcells;glycolyticmetabolism;TCAcycleHematopoieticstemcells(HSCs)areresponsibleforthecontinuousgenerationofallbloodcelltypesthroughoutanindividual'slifetime.HSCshaveauniqueabilitytobothself-renewanddifferentiateintovariousbloodcelllineages,whichrequirestightregulationofmultiplecellularprocesses,includingmetabolism.

MetabolicpathwaysplayacriticalroleinsupportingtheenergydemandsofHSCsduringhomeostasisandinresponsetostressorinjury.RecentstudieshaveidentifiedTHAP11asakeyregulatorofHSCmetabolismandfunction.THAP11isazincfingertranscriptionfactorthathasbeenshowntocontrolhistidinemetabolisminHSCs.

Histidineisanessentialaminoacidthatplaysacriticalroleinproteinsynthesisandcellularfunction.InHSCs,THAP11regulateshistidinemetabolismbyactivatingexpressionoftherate-limitingenzymeinhistidinecatabolism,histidineammonia-lyase(HAL).HALcatalyzesthebreakdownofhistidineintourocanicacidandammonia,whichcanbefurthermetabolizedintheliverandexcretedinurine,respectively.

THAP11alsoregulatesglycolyticmetabolisminHSCsbypromotingexpressionofkeyenzymesintheglycolyticpathway.Glycolysisisamajorenergy-producingpathwaythatconvertsglucoseintopyruvate,generatingATPintheprocess.ThismetabolicpathwayiscriticalforHSCfunction,asitprovidesenergyforHSCself-renewalanddifferentiation.

Furthermore,THAP11controlsthetricarboxylicacid(TCA)cycle,whichisanothermajorenergy-producingpathwayinmitochondria.THAP11promotestheexpressionofTCAcycleenzymes,allowingHSCstogenerateenergyfromnutrientsotherthanglucose.

Overall,THAP11playsacrucialroleintheregulationofHSCmetabolismandfunction.Bycontrollinghistidinemetabolism,glycolyticmetabolism,andtheTCAcycle,THAP11ensuresthatHSCshavethenecessaryenergyandmetabolicflexibilitytorespondtostressanddamage,maintainhomeostasis,andregeneratethebloodsystem.FurtherresearchonTHAP11anditsmolecularmechanismscouldprovideinsightsintothemaintenanceandregulationofHSCsandcontributetothedevelopmentofnoveltherapeuticapproachesforhematologicaldisordersInadditiontoitsroleincontrollingHSCmetabolism,THAP11alsoplaysacrucialroleinthefunctionofHSCs.THAP11isatranscriptionalregulatorthatcontrolsgeneexpressionbybindingtoDNAsequencesintargetgenes.InHSCs,THAP11hasbeenshowntoregulatetheexpressionofgenesinvolvedinHSCself-renewalanddifferentiation,aswellasintheresponsetostressanddamage.

OneimportanttargetofTHAP11inHSCsisthetranscriptionfactorGATA2,whichisessentialforHSCself-renewalanddifferentiation.THAP11hasbeenshowntobindtoandregulatetheexpressionofGATA2,therebycontrollingHSCfunction.Inaddition,THAP11hasbeenshowntoregulatetheexpressionofotherfactorsinvolvedinHSCfunction,suchasRunx1andScl/TAL1,whichplayessentialrolesinHSCself-renewalanddifferentiation.

THAP11alsoplaysaroleintheresponseofHSCstostressanddamage.HSCsareexposedtoavarietyofstressors,includingchemotherapyandradiation,whichcandamageDNAandimpairHSCfunction.THAP11hasbeenshowntoregulatetheexpressionofgenesinvolvedintheresponsetosuchstressors,includingDNArepairgenesandstress-responsivetranscriptionfactors.Bycontrollingtheexpressionofthesegenes,THAP11ensuresthatHSCsareabletorespondtostressanddamage,maintaintheirfunction,andregeneratethebloodsystem.

Overall,thesefindingssuggestthatTHAP11playsacriticalroleinthemetabolismandfunctionofHSCs,andthatitisessentialforthemaintenanceandregulationofthebloodsystem.FurtherresearchonTHAP11anditsmolecularmechanismscouldprovideimportantinsightsintothebiologyofHSCsandcontributetothedevelopmentofnoveltherapeuticapproachesforhematologicaldisordersFurtherstudiescaninvestigatetheregulationofTHAP11geneexpressionandidentifypotentialupstreamregulatorsanddownstreamtargetsofTHAP11inHSCs.Moreover,itwouldbeinterestingtoinvestigatetheepigeneticmodificationsandchromatinremodelingattheTHAP11locusandtheireffectsonHSCbiology.

Additionally,theroleofTHAP11inhematologicaldisorderssuchasleukemiaandaplasticanemiacanbeexplored.THAP11expressionhasbeenfoundtobederegulatedinsometypesofleukemia,andtargetingTHAP11maybeapotentialtherapeuticstrategyforthesediseases.Similarly,THAP11couldalsobeexploredasapotentialtargetforenhancingHSCregenerationindiseasescharacterizedbybonemarrowfailure.

Inconclusion,THAP11isacriticalregulatorofHSCbiologyandplaysacrucialroleinthemaintenance,r