PRDM16 in cardiac development

PRDM16 在心脏发育中的作用

基本信息

  • 批准号:
    10242912
  • 负责人:
  • 金额:
    $ 39.48万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-08-20 至 2024-04-30
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY Cardiac morphogenesis requires complex and well-orchestrated transcriptional programs. PRDI-BF1 and RIZ homology (PR) domain-containing 16 (PRDM16) is a member of the conserved PRDM family that function as transcriptional regulators and methyltransferases in diverse cell types. PRDM16 is expressed in both murine and human cardiomyocytes (CMs). Mutations in PRDM16 are associated with congenital heart disease (CHD), highlighting its importance for cardiac development. Furthermore, a previous study has reported that global Prdm16-deficient mice (gKO) die perinatally and display heart abnormalities. However, little is known as to the specific role of PRDM16 in CMs, or molecular mechanisms by which loss of PRDM16 results in CHD. Further, requirements for the DNA-binding function(s) and/or histone methyltransferase (HMT) activity of PRDM16 in CMs are yet to be determined. To examine the role of PRDM16 in CMs, we generated a Prdm16 CM-specific knockout (cKO) mouse model. Our preliminary data revealed that Prdm16 cKO mice die before postnatal day 7, suggesting that the primary cause of lethality in gKO mice is due to loss of PRDM16 in CMs. Prdm16 cKO mice exhibited dramatic left ventricular dilation, first observed at embryonic day (E)15.5. Taken together, the foregoing observations suggest that PRDM16 plays a critical role in developing CMs. To determine the target genes of Prdm16 in developing CMs, we performed RNA- and ChIP-sequencing analysis of ventricular tissue isolated from Prdm16 cKO and control hearts at E13.5. Results demonstrated significant alterations in gene expression, with 69.3% of dysregulated genes having PRDM16 binding peaks, suggesting that PRDM16 plays a critical role in the transcriptional program of developing CMs. Accordingly, our hypothesis is that PRDM16 plays an essential role in CMs by exhibiting unique functional activities that shape key events in transcriptional regulation of cardiac morphogenesis, and mutation to abolish its DNA-binding or HMT activity will impair specific aspects of PRDM16 function to lead to cardiac developmental defects. To study the specific roles of PRDM16 DNA-binding and HMT activity in developing CMs, we have generated two novel mouse models, in which the DNA-binding or HMT activity has been abolished, respectively, by mutating functionally critical amino acid(s). In the “DB” mutant, a critical “DNA-binding” Arginine (R1000) is mutated to Glutamine (Q), resulting in the loss of DNA-binding activity of PRDM16. In the “HMT” mutant, the Tyrosine (Y113) and Valine (V115) in the PR domain have been mutated to Phenylalanine (F) and Glycine (G), respectively, resulting in loss of HMT activity. Our specific aims are to (1) determine the role and mechanisms by which PRDM16 is required in cardiac development by histological, physiological, biochemical, and molecular analyses of Prdm16 cKO mice; and (2) determine specific roles of DNA-binding and/or HMT activities of PRDM16 in developing CMs by analyzing “DB” and “HMT” mutant mice, in which either the DNA-binding or HMT activity has been abolished.
项目总结

项目成果

期刊论文数量(0)
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Ju Chen其他文献

Ju Chen的其他文献

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{{ truncateString('Ju Chen', 18)}}的其他基金

ATF4 a Novel Regulator of Cardiac Development
ATF4 心脏发育的新型调节剂
  • 批准号:
    10657081
  • 财政年份:
    2023
  • 资助金额:
    $ 39.48万
  • 项目类别:
Novel function of a mitochondria phosphatase in cardiac development
线粒体磷酸酶在心脏发育中的新功能
  • 批准号:
    10436945
  • 财政年份:
    2021
  • 资助金额:
    $ 39.48万
  • 项目类别:
Protein Kinase Novel 2 (PKN2) in heart
心脏中的蛋白激酶 Novel 2 (PKN2)
  • 批准号:
    10322445
  • 财政年份:
    2021
  • 资助金额:
    $ 39.48万
  • 项目类别:
Nuclear envelope protein LEMD2 in heart
心脏中的核膜蛋白 LEMD2
  • 批准号:
    10278926
  • 财政年份:
    2021
  • 资助金额:
    $ 39.48万
  • 项目类别:
Protein Kinase Novel 2 (PKN2) in heart
心脏中的蛋白激酶 Novel 2 (PKN2)
  • 批准号:
    10548141
  • 财政年份:
    2021
  • 资助金额:
    $ 39.48万
  • 项目类别:
Nuclear envelope protein LEMD2 in heart
心脏中的核膜蛋白 LEMD2
  • 批准号:
    10662287
  • 财政年份:
    2021
  • 资助金额:
    $ 39.48万
  • 项目类别:
Nuclear envelope protein LEMD2 in heart
心脏中的核膜蛋白 LEMD2
  • 批准号:
    10463758
  • 财政年份:
    2021
  • 资助金额:
    $ 39.48万
  • 项目类别:
Novel function of a mitochondria phosphatase in cardiac development
线粒体磷酸酶在心脏发育中的新功能
  • 批准号:
    10687847
  • 财政年份:
    2021
  • 资助金额:
    $ 39.48万
  • 项目类别:
Novel function of a mitochondria phosphatase in cardiac development
线粒体磷酸酶在心脏发育中的新功能
  • 批准号:
    10181409
  • 财政年份:
    2021
  • 资助金额:
    $ 39.48万
  • 项目类别:
PRDM16 in cardiac development
PRDM16 在心脏发育中的作用
  • 批准号:
    10025986
  • 财政年份:
    2020
  • 资助金额:
    $ 39.48万
  • 项目类别:

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