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Benoit G Bruneau - One of the best experts on this subject based on the ideXlab platform.

  • an endocardial pathway involving TBX5 gata4 and nos3 required for atrial septum formation
    Proceedings of the National Academy of Sciences of the United States of America, 2010
    Co-Authors: Mathieu Nadeau, Benoit G Bruneau, Romain O Georges, Brigitte Laforest, Chantal Lefebvre, Gregor Andelfinger, Pierre Paradis, Abir Yamak, Janie Beauregard, Mona Nemer
    Abstract:

    In humans, septal defects are among the most prevalent congenital heart diseases, but their cellular and molecular origins are not fully understood. We report that Transcription Factor TBX5 is present in a subpopulation of endocardial cells and that its deletion therein results in fully penetrant, dose-dependent atrial septal defects in mice. Increased apoptosis of endocardial cells lacking TBX5, as well as neighboring TBX5-positive myocardial cells of the atrial septum through activation of endocardial NOS (Nos3), is the underlying mechanism of disease. Compound TBX5 and Nos3 haploinsufficiency in mice worsens the cardiac phenotype. The data identify a pathway for endocardial cell survival and unravel a cell-autonomous role for TBX5 therein. The finding that Nos3, a gene regulated by many congenital heart disease risk Factors including stress and diabetes, interacts genetically with TBX5 provides a molecular framework to understand gene-environment interaction in the setting of human birth defects.

  • Shox2 mediates TBX5 activity by regulating Bmp4 in the pacemaker region of the developing heart
    2010
    Co-Authors: Ra Puskaric, Benoit G Bruneau, Stefanie Schmitteckert, Ro D. Mori, Anne Glaser, Katja U. Schneider, Rüdiger J. Blaschke, Herbert Steinbeisser
    Abstract:

    Heart formation requires a highly balanced network of Transcriptional activation of genes. The homeodomain Transcription Factor, Shox2, is essential for the formation of the sinoatrial valves and for the development of the pacemaking system. The elucidation of molecular mechanisms underlying the development of pacemaker tissue has gained clinical interest as defects in its patterning can be related to atrial arrhythmias. We have analyzed putative targets of Shox2 and identified the Bmp4 gene as a direct target. Shox2 interacts directly with the Bmp4 promoter in chromatin immunoprecipitation assays and activates Transcription in luciferasereporter assays. In addition, ectopic expression of Shox2 in Xenopus embryos stimulates Transcription of the Bmp4 gene, and silencing of Shox2 in cardiomyocytes leads to a reduction in the expression of Bmp4. In TBX5 del/1 mice, a model for Holt-Oram syndrome, and Shox2 2/2 mice, we show that the T-box Transcription Factor TBX5 is a regulator of Shox2 expression in the inflow tract and that Bmp4 is regulated by Shox2 in this compartment of the embryonic heart. In addition, we could show that TBX5 acts cooperatively with Nkx2.5 to regulate the expression of Shox2 and Bmp4. This work establishes a link between TBX5, Shox2 and Bmp4 in the pacemaker region of the developing heart and thus contributes to the unraveling of the intricate interplay between the heart-specific Transcriptional machinery and developmental signaling pathways

  • abstract 1249 atrial septal defects caused by endocardial specific deficiency of Transcription Factor TBX5
    Circulation, 2007
    Co-Authors: Mona Nemer, Benoit G Bruneau, Mathieu Nadeau, Romain O Georges, Brigitte Laforest, Chantal Lefebvre, Gregor Andelfinger, Pierre Paradis
    Abstract:

    In human, mutations in Transcription Factor TBX5 cause the Holt Oram syndrome (HOS) characterized by forelimb and a large spectrum of cardiac malformations ranging from simple arrhythmia to complex...

  • connexin 40 a target of Transcription Factor TBX5 patterns wrist digits and sternum
    Molecular and Cellular Biology, 2005
    Co-Authors: David L. Paul, Anne Pizard, Patrick G Burgon, Benoit G Bruneau, Christine E Seidman, J G Seidman
    Abstract:

    Haploinsufficiency of T-box Transcription Factor 5 (TBX5) causes human Holt-Oram syndrome (HOS), a developmental disorder characterized by skeletal and heart malformations. Mice carrying a TBX5 null allele (TBX5+/Δ) have malformations in digits, wrists, and sternum joints, regions where TBX5 is expressed. We demonstrate that mice deficient in connexin 40 (Cx40), a TBX5-regulated gap junction component, shared axial and appendicular skeletal malformations with TBX5+/Δ mice. Although no role in skeleton patterning has been described for gap junctions, we demonstrate here that Cx40 is involved in formation of specific joints, as well as bone shape. Even a 50% reduction in either TBX5 or Cx40 produces bone abnormalities, demonstrating their crucial control over skeletal development. Further, we demonstrate that TBX5 exerts in part its key regulatory role in bone growth and maturation by controlling via Cx40 the expression of Sox9 (a Transcription Factor essential for chondrogenesis and skeleton growth). Our study strongly suggests that Cx40 deficiency accounts for many skeletal malformations in HOS and that TBX5 regulation of Cx40 plays a critical role in the exquisite developmental patterning of the forelimbs and sternum.

  • TBX5 is essential for forelimb bud initiation following patterning of the limb field in the mouse embryo
    Development, 2003
    Co-Authors: Pooja Agarwal, John N Wylie, Juan Galceran, Oksana Arkhitko, Chuxia Deng, Rudolf Grosschedl, Benoit G Bruneau
    Abstract:

    Transcriptional cascades responsible for initiating the formation of vertebrate embryonic structures such as limbs are not well established. Limb formation occurs as a result of interplay between fibroblast growth Factor (FGF) and Wnt signaling. What initiates these signaling cascades and thus limb bud outgrowth at defined locations along the anteroposterior axis of the embryo is not known. The T-box Transcription Factor TBX5 is important for normal heart and limb formation, but its role in early limb development is not well defined. We report that mouse embryos lacking TBX5 do not form forelimb buds, although the patterning of the lateral plate mesoderm into the limb field is intact. TBX5 is not essential for an early establishment of forelimb versus hindlimb identity. In the absence of TBX5, the FGF and Wnt regulatory loops required for limb bud outgrowth are not established, including initiation of Fgf10 expression. TBX5 directly activates the Fgf10 gene via a conserved binding site, providing a simple and direct mechanism for limb bud initiation. Lef1/Tcf1-dependent Wnt signaling is not essential for initiation of TBX5 or Fgf10 Transcription, but is required in concert with TBX5 for maintenance of normal levels of Fgf10 expression. We conclude that TBX5 is not essential for the early establishment of the limb field in the lateral plate mesoderm but is a primary and direct initiator of forelimb bud formation. These data suggest common pathways for the differentiation and growth of embryonic structures downstream of T-box genes.

Irfan S Kathiriya - One of the best experts on this subject based on the ideXlab platform.

  • modeling human TBX5 haploinsufficiency predicts regulatory networks for congenital heart disease
    Developmental Cell, 2020
    Co-Authors: Irfan S Kathiriya, Kavitha S Rao, Giovanni Iacono, Patrick W Devine, Andrew Blair, Swetansu K Hota
    Abstract:

    Summary Haploinsufficiency of Transcriptional regulators causes human congenital heart disease (CHD); however, the underlying CHD gene regulatory network (GRN) imbalances are unknown. Here, we define Transcriptional consequences of reduced dosage of the CHD Transcription Factor, TBX5, in individual cells during cardiomyocyte differentiation from human induced pluripotent stem cells (iPSCs). We discovered highly sensitive dysregulation of TBX5-dependent pathways—including lineage decisions and genes associated with heart development, cardiomyocyte function, and CHD genetics—in discrete subpopulations of cardiomyocytes. Spatial transcriptomic mapping revealed chamber-restricted expression for many TBX5-sensitive transcripts. GRN analysis indicated that cardiac network stability, including vulnerable CHD-linked nodes, is sensitive to TBX5 dosage. A GRN-predicted genetic interaction between TBX5 and Mef2c, manifesting as ventricular septation defects, was validated in mice. These results demonstrate exquisite and diverse sensitivity to TBX5 dosage in heterogeneous subsets of iPSC-derived cardiomyocytes and predicts candidate GRNs for human CHDs, with implications for quantitative Transcriptional regulation in disease.

  • modeling human TBX5 haploinsufficiency predicts regulatory networks for congenital heart disease
    bioRxiv, 2020
    Co-Authors: Irfan S Kathiriya, Kavitha S Rao, Giovanni Iacono, Patrick W Devine, Andrew Blair, Swetansu K Hota
    Abstract:

    Abstract Haploinsufficiency of Transcriptional regulators causes human congenital heart disease (CHD). However, underlying CHD gene regulatory network (GRN) imbalances are unknown. Here, we define Transcriptional consequences of reduced dosage of the CHD-linked Transcription Factor, TBX5, in individual cells during cardiomyocyte differentiation from human induced pluripotent stem cells (iPSCs). We discovered highly sensitive dysregulation of TBX5-dependent pathways— including lineage decisions and genes associated with cardiomyocyte function and CHD genetics—in discrete subpopulations of cardiomyocytes. GRN analysis identified vulnerable nodes enriched for CHD genes, indicating that cardiac network stability is sensitive to TBX5 dosage. A GRN-predicted genetic interaction between TBX5 and Mef2c was validated in mouse, manifesting as ventricular septation defects. These results demonstrate exquisite sensitivity to TBX5 dosage by diverse Transcriptional responses in heterogeneous subsets of iPSC-derived cardiomyocytes. This predicts candidate GRNs for human CHDs, with implications for quantitative Transcriptional regulation in disease.

  • a TBX5 dosage sensitive gene regulatory network for human congenital heart disease
    bioRxiv, 2019
    Co-Authors: Irfan S Kathiriya, Kavitha S Rao, Giovanni Iacono, Patrick W Devine, Swetansu K Hota, Michael H Lai, Bayardo I Garay
    Abstract:

    Haploinsufficiency of Transcriptional regulators causes human congenital heart disease (CHD) 1. This observation predicts gene regulatory network (GRN) imbalances 2, but the nature of dosage-vulnerable GRNs and their contribution to human cardiogenesis and CHDs are unknown. Here, we define Transcriptional consequences of reduced dosage of the CHD Transcription Factor TBX5 during human cardiac differentiation from induced pluripotent stem (iPS) cells. Single cell RNAseq revealed that Transcriptional responses to reduced TBX5 levels are not homogeneous, and instead, discrete sub-populations of cardiomyocytes exhibit dysregulation of distinct TBX5 dose-sensitive genes related to cellular phenotypes and CHD-associated genetics. Cellular trajectory inference revealed TBX5 dosage-dependent differentiation paths, with implications for cardiac developmental identity. GRN analysis of the single cell RNAseq data identified vulnerable nodes enriched for CHD genes, implicating a critical sensitivity to TBX5 dosage in cardiac network stability. A novel GRN-predicted genetic interaction between TBX5 and MEF2C was validated in mouse, revealing a highly dosage-sensitive pathway for CHD. Our results reveal unforeseen complexity and exquisite sensitivity to TBX5 dosage in discrete sub-populations of iPSC-derived cardiomyocytes, providing mechanistic insights into human CHDs and quantitative Transcriptional regulation in disease.

Mona Nemer - One of the best experts on this subject based on the ideXlab platform.

  • an endocardial pathway involving TBX5 gata4 and nos3 required for atrial septum formation
    Proceedings of the National Academy of Sciences of the United States of America, 2010
    Co-Authors: Mathieu Nadeau, Benoit G Bruneau, Romain O Georges, Brigitte Laforest, Chantal Lefebvre, Gregor Andelfinger, Pierre Paradis, Abir Yamak, Janie Beauregard, Mona Nemer
    Abstract:

    In humans, septal defects are among the most prevalent congenital heart diseases, but their cellular and molecular origins are not fully understood. We report that Transcription Factor TBX5 is present in a subpopulation of endocardial cells and that its deletion therein results in fully penetrant, dose-dependent atrial septal defects in mice. Increased apoptosis of endocardial cells lacking TBX5, as well as neighboring TBX5-positive myocardial cells of the atrial septum through activation of endocardial NOS (Nos3), is the underlying mechanism of disease. Compound TBX5 and Nos3 haploinsufficiency in mice worsens the cardiac phenotype. The data identify a pathway for endocardial cell survival and unravel a cell-autonomous role for TBX5 therein. The finding that Nos3, a gene regulated by many congenital heart disease risk Factors including stress and diabetes, interacts genetically with TBX5 provides a molecular framework to understand gene-environment interaction in the setting of human birth defects.

  • abstract 1249 atrial septal defects caused by endocardial specific deficiency of Transcription Factor TBX5
    Circulation, 2007
    Co-Authors: Mona Nemer, Benoit G Bruneau, Mathieu Nadeau, Romain O Georges, Brigitte Laforest, Chantal Lefebvre, Gregor Andelfinger, Pierre Paradis
    Abstract:

    In human, mutations in Transcription Factor TBX5 cause the Holt Oram syndrome (HOS) characterized by forelimb and a large spectrum of cardiac malformations ranging from simple arrhythmia to complex...

  • a murine model of holt oram syndrome defines roles of the t box Transcription Factor TBX5 in cardiogenesis and disease
    Cell, 2001
    Co-Authors: Benoit G Bruneau, Georges Nemer, Joachim P Schmitt, Frederic Charron, Lynda Robitaille, Sophie Caron, David A Conner, Manfred Gessler, Mona Nemer
    Abstract:

    Heterozygous TBX5(del/+) mice were generated to study the mechanisms by which TBX5 haploinsufficiency causes cardiac and forelimb abnormalities seen in Holt-Oram syndrome. TBX5 deficiency in homozygous mice (TBX5(del/del)) decreased expression of multiple genes and caused severe hypoplasia of posterior domains in the developing heart. Surprisingly, TBX5 haploinsufficiency also markedly decreased atrial natriuretic Factor (ANF) and connexin 40 (cx40) Transcription, implicating these as TBX5 target genes and providing a mechanism by which 50% reduction of T-box Transcription Factors cause disease. Direct and cooperative transactivation of the ANF and cx40 promoters by TBX5 and the homeodomain Transcription Factor Nkx2-5 was also demonstrated. These studies provide one potential explanation for Holt-Oram syndrome conduction system defects, suggest mechanisms for intrafamilial phenotypic variability, and account for related cardiac malformations caused by other Transcription Factor mutations.

Swetansu K Hota - One of the best experts on this subject based on the ideXlab platform.

  • modeling human TBX5 haploinsufficiency predicts regulatory networks for congenital heart disease
    Developmental Cell, 2020
    Co-Authors: Irfan S Kathiriya, Kavitha S Rao, Giovanni Iacono, Patrick W Devine, Andrew Blair, Swetansu K Hota
    Abstract:

    Summary Haploinsufficiency of Transcriptional regulators causes human congenital heart disease (CHD); however, the underlying CHD gene regulatory network (GRN) imbalances are unknown. Here, we define Transcriptional consequences of reduced dosage of the CHD Transcription Factor, TBX5, in individual cells during cardiomyocyte differentiation from human induced pluripotent stem cells (iPSCs). We discovered highly sensitive dysregulation of TBX5-dependent pathways—including lineage decisions and genes associated with heart development, cardiomyocyte function, and CHD genetics—in discrete subpopulations of cardiomyocytes. Spatial transcriptomic mapping revealed chamber-restricted expression for many TBX5-sensitive transcripts. GRN analysis indicated that cardiac network stability, including vulnerable CHD-linked nodes, is sensitive to TBX5 dosage. A GRN-predicted genetic interaction between TBX5 and Mef2c, manifesting as ventricular septation defects, was validated in mice. These results demonstrate exquisite and diverse sensitivity to TBX5 dosage in heterogeneous subsets of iPSC-derived cardiomyocytes and predicts candidate GRNs for human CHDs, with implications for quantitative Transcriptional regulation in disease.

  • modeling human TBX5 haploinsufficiency predicts regulatory networks for congenital heart disease
    bioRxiv, 2020
    Co-Authors: Irfan S Kathiriya, Kavitha S Rao, Giovanni Iacono, Patrick W Devine, Andrew Blair, Swetansu K Hota
    Abstract:

    Abstract Haploinsufficiency of Transcriptional regulators causes human congenital heart disease (CHD). However, underlying CHD gene regulatory network (GRN) imbalances are unknown. Here, we define Transcriptional consequences of reduced dosage of the CHD-linked Transcription Factor, TBX5, in individual cells during cardiomyocyte differentiation from human induced pluripotent stem cells (iPSCs). We discovered highly sensitive dysregulation of TBX5-dependent pathways— including lineage decisions and genes associated with cardiomyocyte function and CHD genetics—in discrete subpopulations of cardiomyocytes. GRN analysis identified vulnerable nodes enriched for CHD genes, indicating that cardiac network stability is sensitive to TBX5 dosage. A GRN-predicted genetic interaction between TBX5 and Mef2c was validated in mouse, manifesting as ventricular septation defects. These results demonstrate exquisite sensitivity to TBX5 dosage by diverse Transcriptional responses in heterogeneous subsets of iPSC-derived cardiomyocytes. This predicts candidate GRNs for human CHDs, with implications for quantitative Transcriptional regulation in disease.

  • a TBX5 dosage sensitive gene regulatory network for human congenital heart disease
    bioRxiv, 2019
    Co-Authors: Irfan S Kathiriya, Kavitha S Rao, Giovanni Iacono, Patrick W Devine, Swetansu K Hota, Michael H Lai, Bayardo I Garay
    Abstract:

    Haploinsufficiency of Transcriptional regulators causes human congenital heart disease (CHD) 1. This observation predicts gene regulatory network (GRN) imbalances 2, but the nature of dosage-vulnerable GRNs and their contribution to human cardiogenesis and CHDs are unknown. Here, we define Transcriptional consequences of reduced dosage of the CHD Transcription Factor TBX5 during human cardiac differentiation from induced pluripotent stem (iPS) cells. Single cell RNAseq revealed that Transcriptional responses to reduced TBX5 levels are not homogeneous, and instead, discrete sub-populations of cardiomyocytes exhibit dysregulation of distinct TBX5 dose-sensitive genes related to cellular phenotypes and CHD-associated genetics. Cellular trajectory inference revealed TBX5 dosage-dependent differentiation paths, with implications for cardiac developmental identity. GRN analysis of the single cell RNAseq data identified vulnerable nodes enriched for CHD genes, implicating a critical sensitivity to TBX5 dosage in cardiac network stability. A novel GRN-predicted genetic interaction between TBX5 and MEF2C was validated in mouse, revealing a highly dosage-sensitive pathway for CHD. Our results reveal unforeseen complexity and exquisite sensitivity to TBX5 dosage in discrete sub-populations of iPSC-derived cardiomyocytes, providing mechanistic insights into human CHDs and quantitative Transcriptional regulation in disease.

Kavitha S Rao - One of the best experts on this subject based on the ideXlab platform.

  • modeling human TBX5 haploinsufficiency predicts regulatory networks for congenital heart disease
    Developmental Cell, 2020
    Co-Authors: Irfan S Kathiriya, Kavitha S Rao, Giovanni Iacono, Patrick W Devine, Andrew Blair, Swetansu K Hota
    Abstract:

    Summary Haploinsufficiency of Transcriptional regulators causes human congenital heart disease (CHD); however, the underlying CHD gene regulatory network (GRN) imbalances are unknown. Here, we define Transcriptional consequences of reduced dosage of the CHD Transcription Factor, TBX5, in individual cells during cardiomyocyte differentiation from human induced pluripotent stem cells (iPSCs). We discovered highly sensitive dysregulation of TBX5-dependent pathways—including lineage decisions and genes associated with heart development, cardiomyocyte function, and CHD genetics—in discrete subpopulations of cardiomyocytes. Spatial transcriptomic mapping revealed chamber-restricted expression for many TBX5-sensitive transcripts. GRN analysis indicated that cardiac network stability, including vulnerable CHD-linked nodes, is sensitive to TBX5 dosage. A GRN-predicted genetic interaction between TBX5 and Mef2c, manifesting as ventricular septation defects, was validated in mice. These results demonstrate exquisite and diverse sensitivity to TBX5 dosage in heterogeneous subsets of iPSC-derived cardiomyocytes and predicts candidate GRNs for human CHDs, with implications for quantitative Transcriptional regulation in disease.

  • modeling human TBX5 haploinsufficiency predicts regulatory networks for congenital heart disease
    bioRxiv, 2020
    Co-Authors: Irfan S Kathiriya, Kavitha S Rao, Giovanni Iacono, Patrick W Devine, Andrew Blair, Swetansu K Hota
    Abstract:

    Abstract Haploinsufficiency of Transcriptional regulators causes human congenital heart disease (CHD). However, underlying CHD gene regulatory network (GRN) imbalances are unknown. Here, we define Transcriptional consequences of reduced dosage of the CHD-linked Transcription Factor, TBX5, in individual cells during cardiomyocyte differentiation from human induced pluripotent stem cells (iPSCs). We discovered highly sensitive dysregulation of TBX5-dependent pathways— including lineage decisions and genes associated with cardiomyocyte function and CHD genetics—in discrete subpopulations of cardiomyocytes. GRN analysis identified vulnerable nodes enriched for CHD genes, indicating that cardiac network stability is sensitive to TBX5 dosage. A GRN-predicted genetic interaction between TBX5 and Mef2c was validated in mouse, manifesting as ventricular septation defects. These results demonstrate exquisite sensitivity to TBX5 dosage by diverse Transcriptional responses in heterogeneous subsets of iPSC-derived cardiomyocytes. This predicts candidate GRNs for human CHDs, with implications for quantitative Transcriptional regulation in disease.

  • a TBX5 dosage sensitive gene regulatory network for human congenital heart disease
    bioRxiv, 2019
    Co-Authors: Irfan S Kathiriya, Kavitha S Rao, Giovanni Iacono, Patrick W Devine, Swetansu K Hota, Michael H Lai, Bayardo I Garay
    Abstract:

    Haploinsufficiency of Transcriptional regulators causes human congenital heart disease (CHD) 1. This observation predicts gene regulatory network (GRN) imbalances 2, but the nature of dosage-vulnerable GRNs and their contribution to human cardiogenesis and CHDs are unknown. Here, we define Transcriptional consequences of reduced dosage of the CHD Transcription Factor TBX5 during human cardiac differentiation from induced pluripotent stem (iPS) cells. Single cell RNAseq revealed that Transcriptional responses to reduced TBX5 levels are not homogeneous, and instead, discrete sub-populations of cardiomyocytes exhibit dysregulation of distinct TBX5 dose-sensitive genes related to cellular phenotypes and CHD-associated genetics. Cellular trajectory inference revealed TBX5 dosage-dependent differentiation paths, with implications for cardiac developmental identity. GRN analysis of the single cell RNAseq data identified vulnerable nodes enriched for CHD genes, implicating a critical sensitivity to TBX5 dosage in cardiac network stability. A novel GRN-predicted genetic interaction between TBX5 and MEF2C was validated in mouse, revealing a highly dosage-sensitive pathway for CHD. Our results reveal unforeseen complexity and exquisite sensitivity to TBX5 dosage in discrete sub-populations of iPSC-derived cardiomyocytes, providing mechanistic insights into human CHDs and quantitative Transcriptional regulation in disease.