Congenital heart disease is the leading cause of infant morbidity in the Western world, but only in the past ten years has its aetiology been understood. Recent studies have uncovered the genetic ...basis for some common forms of the disease and provide new insight into how the heart develops and how dysregulation of heart development leads to disease.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The molecular mechanisms underlying folding of mammalian chromosomes remain poorly understood. The transcription factor CTCF is a candidate regulator of chromosomal structure. Using the ...auxin-inducible degron system in mouse embryonic stem cells, we show that CTCF is absolutely and dose-dependently required for looping between CTCF target sites and insulation of topologically associating domains (TADs). Restoring CTCF reinstates proper architecture on altered chromosomes, indicating a powerful instructive function for CTCF in chromatin folding. CTCF remains essential for TAD organization in non-dividing cells. Surprisingly, active and inactive genome compartments remain properly segregated upon CTCF depletion, revealing that compartmentalization of mammalian chromosomes emerges independently of proper insulation of TADs. Furthermore, our data support that CTCF mediates transcriptional insulator function through enhancer blocking but not as a direct barrier to heterochromatin spreading. Beyond defining the functions of CTCF in chromosome folding, these results provide new fundamental insights into the rules governing mammalian genome organization.
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•Acute depletion of endogenous CTCF in ESCs with an auxin-inducible degron•CTCF instructs chromatin loops and TAD insulation genome wide•Disrupting TAD insulation does not impact higher-order genomic compartmentalization•CTCF depletion impacts transcriptional activity but not spread of H3K27me3 domains
Dissecting out the roles of CTCF on genome looping, organization into TADs, and overall chromatin compartmentalization reveals fine layers of regulation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Precise gene expression ensures proper stem and progenitor cell differentiation, lineage commitment and organogenesis during mammalian development. ATP-dependent chromatin-remodeling complexes ...utilize the energy from ATP hydrolysis to reorganize chromatin and, hence, regulate gene expression. These complexes contain diverse subunits that together provide a multitude of functions, from early embryogenesis through cell differentiation and development into various adult tissues. Here, we review the functions of chromatin remodelers and their different subunits during mammalian development. We discuss the mechanisms by which chromatin remodelers function and highlight their specificities during mammalian cell differentiation and organogenesis.
The heart is an essential organ with a fascinating developmental biology. It is also one of the organs that is most often affected in human disease, either during development or in postnatal life. ...Over the last few decades, insights into the development of the heart have led to fundamental new concepts in gene regulation, but also to genetic and mechanistic insights into congenital heart defects. In more recent years, the lessons learned from studying heart development have been applied to interrogating regeneration of the diseased heart, exemplifying the importance of understanding the mechanistic underpinnings that lead to the development of an organ.
The mammalian heart is the first functional organ, the first indicator of life. Its normal formation and function are essential for fetal life. Defects in heart formation lead to congenital heart ...defects, underscoring the finesse with which the heart is assembled. Understanding the regulatory networks controlling heart development have led to significant insights into its lineage origins and morphogenesis and illuminated important aspects of mammalian embryology, while providing insights into human congenital heart disease. The mammalian heart has very little regenerative potential, and thus, any damage to the heart is life threatening and permanent. Knowledge of the developing heart is important for effective strategies of cardiac regeneration, providing new hope for future treatments for heart disease. Although we still have an incomplete picture of the mechanisms controlling development of the mammalian heart, our current knowledge has important implications for embryology and better understanding of human heart disease.
Heart disease is the leading cause of mortality and morbidity in the western world. The heart has little regenerative capacity after damage, leading to much interest in understanding the factors ...required to produce new cardiac myocytes. Despite a robust understanding of the molecular networks regulating cardiac differentiation, no single transcription factor or combination of factors has been shown to activate the cardiac gene program de novo in mammalian cells or tissues. Here we define the minimal requirements for transdifferentiation of mouse mesoderm to cardiac myocytes. We show that two cardiac transcription factors, Gata4 and Tbx5, and a cardiac-specific subunit of BAF chromatin-remodelling complexes, Baf60c (also called Smarcd3), can direct ectopic differentiation of mouse mesoderm into beating cardiomyocytes, including the normally non-cardiogenic posterior mesoderm and the extraembryonic mesoderm of the amnion. Gata4 with Baf60c initiated ectopic cardiac gene expression. Addition of Tbx5 allowed differentiation into contracting cardiomyocytes and repression of non-cardiac mesodermal genes. Baf60c was essential for the ectopic cardiogenic activity of Gata4 and Tbx5, partly by permitting binding of Gata4 to cardiac genes, indicating a novel instructive role for BAF complexes in tissue-specific regulation. The combined function of these factors establishes a robust mechanism for controlling cellular differentiation, and may allow reprogramming of new cardiomyocytes for regenerative purposes.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The mechanisms by which transcription factor haploinsufficiency alters the epigenetic and transcriptional landscape in human cells to cause disease are unknown. Here, we utilized human induced ...pluripotent stem cell (iPSC)-derived endothelial cells (ECs) to show that heterozygous nonsense mutations in NOTCH1 that cause aortic valve calcification disrupt the epigenetic architecture, resulting in derepression of latent pro-osteogenic and -inflammatory gene networks. Hemodynamic shear stress, which protects valves from calcification in vivo, activated anti-osteogenic and anti-inflammatory networks in NOTCH1+/+, but not NOTCH1+/−, iPSC-derived ECs. NOTCH1 haploinsufficiency altered H3K27ac at NOTCH1-bound enhancers, dysregulating downstream transcription of more than 1,000 genes involved in osteogenesis, inflammation, and oxidative stress. Computational predictions of the disrupted NOTCH1-dependent gene network revealed regulatory nodes that, when modulated, restored the network toward the NOTCH1+/+ state. Our results highlight how alterations in transcription factor dosage affect gene networks leading to human disease and reveal nodes for potential therapeutic intervention.
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•Shear stress protects human endothelial cells by suppressing osteogenesis and inflammation•NOTCH1 (N1) mediates the normal anti-calcific response induced by shear stress•N1 haploinsufficiency leads to differential H3K27ac at N1-bound enhancers•Intervention at key regulatory nodes can alleviate N1-dependent network dysregulation
Heterozygous mutations in NOTCH1 that cause aortic valve calcification disrupt the transcriptional and epigenetic response to hemodynamic shear stress, resulting in derepression of latent pro-osteogenic and -inflammatory gene networks.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
In this issue of
, Amândio and colleagues (pp. 1490-1509) dissect the function of a cluster of several CTCF binding sites in the HoxD cluster by iterative deletions in mice. They found additive ...functions for some, and intriguingly found that some sites function as insulators, while others function as anchors for enhancer-promoter interactions. These functions vary depending on developmental context. The work provides new insights into the roles played by CTCF in regulating developmental patterns and 3D chromatin organization.
The function of the CCCTC-binding factor (CTCF) in the organization of the genome has become an important area of investigation, but the mechanisms by which CTCF dynamically contributes to genome ...organization are not clear. We previously discovered that CTCF binds to large numbers of endogenous RNAs, promoting its self-association. In this regard, we now report two independent features that disrupt CTCF association with chromatin: inhibition of transcription and disruption of CTCF-RNA interactions through mutations of 2 of its 11 zinc fingers that are not required for CTCF binding to its cognate DNA site: zinc finger 1 (ZF1) or zinc finger 10 (ZF10). These mutations alter gene expression profiles as CTCF mutants lose their ability to form chromatin loops and thus the ability to insulate chromatin domains and to mediate CTCF long-range genomic interactions. Our results point to the importance of CTCF-mediated RNA interactions as a structural component of genome organization.
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•Transcriptional inhibition disrupts CTCF binding to chromatin•RNA-binding regions (RBRs) in CTCF are found within ZF1 and ZF10•Gene expression and chromatin binding are disrupted by RBR mutants•Chromatin loops are markedly decreased in ZF1Δ and ZF10Δ mutant rescues
RNA binding promotes CTCF-dependent chromatin loops. Saldaña-Meyer et al. show that mutation of the RNA-binding regions in CTCF (ZF1 and ZF10) disrupts gene expression, chromatin binding, and the formation of chromatin loops.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The cardiovascular system is broadly composed of the heart, which pumps blood, and the blood vessels, which carry blood to and from tissues of the body. Heart malformations are the most serious ...common birth defect, affecting at least 2% of newborns and leading to significant morbidity and mortality. Severe heart malformations cause heart failure in fetuses, infants, and children, whereas milder heart defects may not trigger significant heart dysfunction until early or midadulthood. Severe vasculogenesis or angiogenesis defects in embryos are incompatible with life, and anomalous arterial patterning may cause vascular aberrancies that often require surgical treatment. It is therefore important to understand the underlying mechanisms that control cardiovascular development. Understanding developmental mechanisms will also help us design better strategies to regenerate cardiovascular tissues for therapeutic purposes. An important mechanism regulating genes involves the modification of chromatin, the higher-order structure in which DNA is packaged. Recent studies have greatly expanded our understanding of the regulation of cardiovascular development at the chromatin level, including the remodeling of chromatin and the modification of histones. Chromatin-level regulation integrates multiple inputs and coordinates broad gene expression programs. Thus, understanding chromatin-level regulation will allow for a better appreciation of gene regulation as a whole and may set a fundamental basis for cardiovascular disease. This review focuses on how chromatin-remodeling and histone-modifying factors regulate gene expression to control cardiovascular development.
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