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Circulation Research СHDAC3ػ

ʱ䣺2022-07-13 ȶȣ

 

ǰ
 

ȫֲѾ “”ѧҽѧԺDr. Deqiang LiоŶ20227Circulation Research־ϽΪ“Epicardial HDAC3 promotes myocardial growth through a novel microRNA pathway”Ѫоչ෢ĤHDAC3ͨmiR-322/miR-503̼Fgf9Igf2ļ ΪȱݵIJļṩµսԺͿ

 


 

 ಡCHD¹ģijȱԴȱݳʽĹIJйоȷļʶDZڵ²Եԭ ļϸİͨѶñĤĤϸܹͨ͸źŴŵļ֯ķ ͨṩ͸ӣFgf9Igf2ڵҪŦ

HDACѰȥø3һHDACijԱ Դ߻Ѱβлȥ ִͨﳡѧ߲ȫóHDAC3ɵ¼Դȱݺ̥ ļԵHDAC3ȱʧȴ෢ж̬ͱӰ ǻ𺦳ڵ๦ЧעHDAC3ڷǼϸҼĹЧܶļҪоּ̽Ѱ෢ HDAC3ĤеԼFgf9Igf2ıܵHDACsmiRsĵ

 


ͼ. The schematics of the working model
 

Ҫ

1еĤHdac3ıļҪ

2HDAC3ĤϸֽǨǺҪ

3miR-322miR-503Fgf9Igf2ת¼

4HDAC3ͨmiR-322miR-503ıFgf9Igf2ת¼


о
 

01
 

оȹĤHdac3óHdac3ekoо෢Hdac3ĤеDZóHdac3Ĥϵ׷E12.5-E16.5 epdcĤϸEMTǨļΪάϸ͹״ѪϸE14.5ekoǨļepdc עHdac3ȱepdcбDZڵEMTǨȱĤ̥״ ekoй״ѪϸSox17ϸ̭ עekoй״Ĥepdcͨ໥ļܻ о̥ĤHdac3ȱļ E13.5/E14.5 ekoܲűȱౡֶϸֳ/Ƿekoұڷ֤ E13.5 ekoСļpH3/Brduļϸİٷֱļ ֤ʵ෢ĤHdac3ȱʧұڷȫ


Figure 1. Epicardial deletion of Hdac3 resulted in hypoplasia of ventricular compact wall.

 


02
 

 Ϊ˽һֵ̽ekoұڷȫ͵DZڷӻ оʹCRISPR/Cas9 СĤϸMECsHdac3¡óHdac3óMECsȱMECsֶϸRNAͻ 1681µGOͨ· ǰ14ͨ·ϸµepdc͸Ӻ ȷFgf9Igf2Ŀķ֤Hdac3óFgf9Igf2mRNAѰˮƽϾekoFgf9Igf2ҲFgf9Igf2ı½Hdac3ȱʧй

 
Figure 2. Hdac3 deletion resulted in downregulation of Fgf9 and Igf2.

 

03
 

оͼȷFgf9Igf2̭Ƿļϸֳ̭йϸEV Hdac3óKOҺFgf9Igf2ϸ崦óͷE13.5ɢԭ̥ļϸEV KO崦óͷpH3ļϸٷֱȺļϸͲļϸֳźͨ·ERKữļKOFgf9Igf2޸ļϸֳȱݲʹp-FGFR1/p-IGFR1Чע Ĥϸ͸Fgf9Igf2ṩļϸֳҪ
 


Figure 3. Supplementation of Fgf9 or Igf2 rescues CM proliferation defects.

 


04
 

ΪȷHDAC3ͨøյFgf9Igf2ı оѡHDAC3ȥøƼRGFP966óͷMECs RGFP966óͷFgf9Igf2о־RescueʵHdac3óرֳɻָFgf9Igf2ı ȥøʧͻHdac3رﲢFgf9Igf2ı֤ʵHDAC3ȷʵͨøԵFgf9Igf2ı

Figure 4. HDAC3 induces the expression of Fgf9 and Igf2 dependent on its deacetylase activity.

 


05


FgfsIgfsıɱmiRs о߶ómiRͨģϵλɸѡmiR-322miR-503ģﴦóͷFgf9Igf2ıͨWestern blotһ֤miR-322 mimics/miR-503 mimicsóͷFgf9Igf2ʹmiR-322miR-503ģﴦóͷE13.5ļϸ pH3ļϸİٷֱ עmiR-322miR-503ļϸֳHDAC3ȥøԱRGFP966ʱ miR-322miR-503óͬϵE13.5 ekoҲӲ쵽miR-322miR-503ϵ֤ʵmiR-322miR-503ܹFgf9Igf2ļϸֳ
 

 

Figure 5.miR-322 and miR-503 repress the expression of Fgf9 and Igf2 and CM proliferation.


06
 

ΪȷHdac3óʱ miR-322miR-503ϵFgf9Igf2ĽӰ ʹmiRZipmiR-322miR-503ı õmiR-322miR-503ָóFgf9Igf2ıЧעHDAC3ͨmiR-322miR-503Fgf9Igf2ı

Figure 6. Knockdown of miR-322 or miR-503 restores the expression of Fgf9 and Igf2.

 

07
 

H3K27Acǻӵı ҲHDAC3ֱΰеHdac3ȱʧMECsH3K27AcENCODEʵ鷢 miR-322/miR-503ܱŴΪȷHdac3ȱʧǷӰmiR-322/miR-503ӵȾɫʿɼ оͨChIP-qPCRоH3K27Acóеϵ׺Hdac3ȱʧH3K27AcmiR-322/miR-503ӵϵ עHdac3ȱʧʹmiR-322/miR-503Ӹױת¼ӿΪȷȾɫʿɼԵǷӰmiR-322/miR-503ӵĻ ־miR-322/miR-503ӫøʵϸ óRGFP966óͷӫø עHDAC3miR-322/miR-503ӵĵͬȥø


Figure 7. HDAC3 represses miR-322/miR-503 promoter activity.

 

Ѫܼлģʵ8Żݣսʵң

 

UGж긻ĶʵѪܶģӹʵ ߾ʵĻ벡ͬʱй˾ļƽ̨ƽ̨ϸƽ̨רҵʵƽ̨ ΪṩѪܶģӵԤ⡢ϸЧѧоһվʽѪоЧϵͳ 漰Ѫǰоֶ֧ӴעUGںʶʵЧ UGڴĵ 
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