CTCF counter-regulates cardiomyocyte development and maturation programs in the embryonic heart

被引：49

作者：

Gomez-Velazquez, Melisa ^{[1
]}

Badia-Careaga, Claudio ^{[1
]}

Victoria Lechuga-Vieco, Ana ^{[1
]}

Nieto-Arellano, Rocio ^{[1
]}

Tena, Juan J. ^{[2
]}

Rollan, Isabel ^{[1
]}

Alvarez, Alba ^{[1
]}

Torroja, Carlos ^{[1
]}

Caceres, Eva F. ^{[1
,7
]}

Roy, Anna ^{[3
,4
]}

Galjart, Niels ^{[5
]}

Delgado-Olguin, Paul ^{[3
,4
,6
]}

Sanchez-Cabo, Fatima ^{[1
]}

Antonio Enriquez, Jose ^{[1
]}

Luis Gomez-Skarmeta, Jose ^{[2
]}

Manzanares, Miguel ^{[1
]}

机构：

[1] CNIC, Madrid, Spain

[2] Univ Pablo de Olavide Junta de Andalucia, CSIC, CABD, Seville, Spain

[3] Hosp Sick Children, Translat Med, Toronto, ON, Canada

[4] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada

[5] Erasmus MC, Dept Cell Biol & Genet, Rotterdam, Netherlands

[6] Heart & Stroke Richard Lewar Ctr Excellence, Toronto, ON, Canada

[7] Uppsala Univ, Dept Cell & Mol Biol, Sci Life Lab, Uppsala, Sweden

来源：

PLOS GENETICS | 2017年 / 13卷 / 08期

基金：

加拿大自然科学与工程研究理事会; 加拿大健康研究院;

关键词：

GENE-EXPRESSION; TRANSCRIPTION FACTORS; NEURAL DEVELOPMENT; DNA INTERACTIONS; HUMAN GENOME; HUMAN-CELLS; MITOCHONDRIAL; ORGANIZATION; MAP; DIFFERENTIATION;

D O I：

10.1371/journal.pgen.1006985

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Cardiac progenitors are specified early in development and progressively differentiate and mature into fully functional cardiomyocytes. This process is controlled by an extensively studied transcriptional program. However, the regulatory events coordinating the progression of such program from development to maturation are largely unknown. Here, we show that the genome organizer CTCF is essential for cardiogenesis and that it mediates genomic interactions to coordinate cardiomyocyte differentiation and maturation in the developing heart. Inactivation of Ctcf in cardiac progenitor cells and their derivatives in vivo during development caused severe cardiac defects and death at embryonic day 12.5. Genome wide expression analysis in Ctcf mutant hearts revealed that genes controlling mitochondrial function and protein production, required for cardiomyocyte maturation, were upregulated. However, mitochondria from mutant cardiomyocytes do not mature properly. In contrast, multiple development regulatory genes near predicted heart enhancers, including genes in the IrxA cluster, were downregulated in Ctcf mutants, suggesting that CTCF promotes cardiomyocyte differentiation by facilitating enhancer-promoter interactions. Accordingly, loss of CTCF disrupts gene expression and chromatin interactions as shown by chromatin conformation capture followed by deep sequencing. Furthermore, CRISPR-mediated deletion of an intergenic CTCF site within the IrxA cluster alters gene expression in the developing heart. Thus, CTCF mediates local regulatory interactions to coordinate transcriptional programs controlling transitions in morphology and function during heart development.

引用

页数：25

共 58 条

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