Benoit Bruneau, PhD

The main focus of our lab is to understand how a heart becomes a heart: what cell lineage decisions take place to direct cardiac differentiation, and what morphogenetic and patterning processes occur to assemble all of the heart's components into a functional organ. We are primarily interested in regulation of these processes by transcriptional regulatory mechanisms that include DNA-binding transcription factors, chromatin remodeling complexes, and histone modifications. We have used this knowledge to understand disease mechanisms, but also to devise strategies for cardiac regeneration.

Why study heart development? We believe that primary defects in patterning in early heart development are at the root of congenital heart defects, which affect approximately 1% of live-born children, and we want to understand how these defects occur, to perhaps be able to uncover new and improved diagnostic or even therapeutic options. Also, by understanding how cardiac lineage specification occurs, we can better design stem cell-based interventions of cardiac repair, based on the knowledge of what drives an uncommitted cell towards a specific cardiac fate. We have recently focused our efforts on cardiac chromatin remodeling and modification factors, enzymes that unwind DNA or modify histones to turn genes on or off. We are particularly interested in how these factors control cardiac cell lineage decisions. These chromatin remodeling factors may also be key to pushing a stem cell into becoming a heart cell, perhaps opening up new avenues for cardiac regenerative medicine.
Publications
  1. Transcription factor protein interactomes reveal genetic determinants in heart disease.
  2. Brahma safeguards canalization of cardiac mesoderm differentiation.
  3. Co-emergence of cardiac and gut tissues promotes cardiomyocyte maturation within human iPSC-derived organoids.
  4. Dissecting CTCF site function in a tense HoxD locus.
  5. Mechanisms of Congenital Heart Disease Caused by NAA15 Haploinsufficiency.
  6. Modeling Human TBX5 Haploinsufficiency Predicts Regulatory Networks for Congenital Heart Disease.
  7. WAPL maintains a cohesin loading cycle to preserve cell-type-specific distal gene regulation.
  8. Molecular basis of CTCF binding polarity in genome folding.
  9. The developing heart: from The Wizard of Oz to congenital heart disease.
  10. Regulation of single-cell genome organization into TADs and chromatin nanodomains.
  11. Author Correction: Transcriptional profiling and therapeutic targeting of oxidative stress in neuroinflammation.
  12. Author Correction: Defining the relative and combined contribution of CTCF and CTCFL to genomic regulation.
  13. Salt-inducible kinase 1 maintains HDAC7 stability to promote pathologic cardiac remodeling.
  14. Cardiac natriuretic peptides.
  15. Defining the relative and combined contribution of CTCF and CTCFL to genomic regulation.
  16. Transcriptional profiling and therapeutic targeting of oxidative stress in neuroinflammation.
  17. Minimal in vivo requirements for developmentally regulated cardiac long intergenic non-coding RNAs.
  18. CTCF confers local nucleosome resiliency after DNA replication and during mitosis.
  19. Chromatin and epigenetics in development: a Special Issue.
  20. RNA Interactions Are Essential for CTCF-Mediated Genome Organization.
  21. Genome of the Komodo dragon reveals adaptations in the cardiovascular and chemosensory systems of monitor lizards.
  22. Dynamic BAF chromatin remodeling complex subunit inclusion promotes temporally distinct gene expression programs in cardiogenesis.
  23. A De Novo Shape Motif Discovery Algorithm Reveals Preferences of Transcription Factors for DNA Shape Beyond Sequence Motifs.
  24. Identifying cis Elements for Spatiotemporal Control of Mammalian DNA Replication.
  25. Heart enhancers with deeply conserved regulatory activity are established early in zebrafish development.
  26. Chromatin Domains Go on Repeat in Disease.
  27. A novel reporter allele for monitoring Dll4 expression within the embryonic and adult mouse.
  28. Cardiac-enriched BAF chromatin-remodeling complex subunit Baf60c regulates gene expression programs essential for heart development and function.
  29. Targeted Degradation of CTCF Decouples Local Insulation of Chromosome Domains from Genomic Compartmentalization.
  30. Cooperative activation of cardiac transcription through myocardin bridging of paired MEF2 sites.
  31. Single-Cell Resolution of Temporal Gene Expression during Heart Development.
  32. ATP-dependent chromatin remodeling during mammalian development.
  33. Loss of Iroquois homeobox transcription factors 3 and 5 in osteoblasts disrupts cranial mineralization.
  34. Expandable Cardiovascular Progenitor Cells Reprogrammed from Fibroblasts.
  35. KMT2D regulates specific programs in heart development via histone H3 lysine 4 di-methylation.
  36. Complex Interdependence Regulates Heterotypic Transcription Factor Distribution and Coordinates Cardiogenesis.
  37. Accelerated Evolution of Enhancer Hotspots in the Mammal Ancestor.
  38. Polycomb Regulates Mesoderm Cell Fate-Specification in Embryonic Stem Cells through Activation and Repression Mechanisms.
  39. Brg1 modulates enhancer activation in mesoderm lineage commitment.
  40. Human disease modeling reveals integrated transcriptional and epigenetic mechanisms of NOTCH1 haploinsufficiency.
  41. Evolution of lysine acetylation in the RNA polymerase II C-terminal domain.
  42. Investigating the transcriptional control of cardiovascular development.
  43. Looking inwards: opening a window onto human development.
  44. Ezh2-mediated repression of a transcriptional pathway upstream of Mmp9 maintains integrity of the developing vasculature.
  45. Early patterning and specification of cardiac progenitors in gastrulating mesoderm.
  46. Finding a niche for cardiac precursors.
  47. HDAC-regulated myomiRs control BAF60 variant exchange and direct the functional phenotype of fibro-adipogenic progenitors in dystrophic muscles.
  48. Function-based identification of mammalian enhancers using site-specific integration.
  49. Congenital heart disease: entering a new era of human genetics.
  50. Acetylation of RNA polymerase II regulates growth-factor-induced gene transcription in mammalian cells.
  51. An interview with Benoit Bruneau.
  52. Chromatin modulators as facilitating factors in cellular reprogramming.
  53. Direct reprogramming of human fibroblasts toward a cardiomyocyte-like state.
  54. ENU-induced mutation in the DNA-binding domain of KLF3 reveals important roles for KLF3 in cardiovascular development and function in mice.
  55. ETS factors regulate Vegf-dependent arterial specification.
  56. Stem cells and regeneration: a special issue.
  57. The western painted turtle genome, a model for the evolution of extreme physiological adaptations in a slowly evolving lineage.
  58. Signaling and transcriptional networks in heart development and regeneration.
  59. Regulation of retinal interneuron subtype identity by the Iroquois homeobox gene Irx6.
  60. Cooperative and antagonistic roles for Irx3 and Irx5 in cardiac morphogenesis and postnatal physiology.
  61. Dynamic and coordinated epigenetic regulation of developmental transitions in the cardiac lineage.
  62. Iroquois homeodomain transcription factors in heart development and function.
  63. Epigenetic repression of cardiac progenitor gene expression by Ezh2 is required for postnatal cardiac homeostasis.
  64. Epigenetics and cardiovascular development.
  65. Iroquois homeobox gene 3 establishes fast conduction in the cardiac His-Purkinje network.
  66. Atrial natriuretic factor in the developing heart: a signpost for cardiac morphogenesis.
  67. Ezh2 regulates anteroposterior axis specification and proximodistal axis elongation in the developing limb.
  68. Tinman/Nkx2-5 acts via miR-1 and upstream of Cdc42 to regulate heart function across species.
  69. A Slit/miR-218/Robo regulatory loop is required during heart tube formation in zebrafish.
  70. Chromatin remodelling complex dosage modulates transcription factor function in heart development.
  71. CTCF promotes muscle differentiation by modulating the activity of myogenic regulatory factors.
  72. An endocardial pathway involving Tbx5, Gata4, and Nos3 required for atrial septum formation.
  73. Shox2 mediates Tbx5 activity by regulating Bmp4 in the pacemaker region of the developing heart.
  74. Chromatin remodeling in heart development.
  75. Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors.
  76. Epigenetic regulation of the cardiovascular system: introduction to a review series.
  77. Lessons for cardiac regeneration and repair through development.
  78. Extensive enteric nervous system abnormalities in mice transgenic for artificial chromosomes containing Parkinson disease-associated alpha-synuclein gene mutations precede central nervous system changes.
  79. The ubiquitin ligase Nedd4-1 is required for heart development and is a suppressor of thrombospondin-1.
  80. Reptilian heart development and the molecular basis of cardiac chamber evolution.
  81. NKX2-5 regulates the expression of beta-catenin and GATA4 in ventricular myocytes.
  82. Directed transdifferentiation of mouse mesoderm to heart tissue by defined factors.
  83. Alternative induced pluripotent stem cell characterization criteria for in vitro applications.
  84. Influence of cysteamine on in vitro maturation, in vitro and in vivo fertilization of equine oocytes.
  85. miR-126 regulates angiogenic signaling and vascular integrity.
  86. Tbx5-dependent pathway regulating diastolic function in congenital heart disease.
  87. The developmental genetics of congenital heart disease.
  88. 4D cardiac MRI in the mouse.
  89. The heart's Da Vinci code: a Renaissance at Keystone.
  90. Baf60c is a nuclear Notch signaling component required for the establishment of left-right asymmetry.
  91. Irxl1, a divergent Iroquois homeobox family transcription factor gene.
  92. Tbx5-dependent rheostatic control of cardiac gene expression and morphogenesis.
  93. Chromatin modification and remodeling in heart development.
  94. [Irx5: a transcription factor that regulates the cardiac repolarization gradient].
  95. Cooperative and antagonistic interactions between Sall4 and Tbx5 pattern the mouse limb and heart.
  96. The homeodomain transcription factor Irx5 establishes the mouse cardiac ventricular repolarization gradient.
  97. A Gja1 missense mutation in a mouse model of oculodentodigital dysplasia.
  98. The Iroquois homeobox gene, Irx5, is required for retinal cone bipolar cell development.
  99. Genome-wide analysis of mouse transcripts using exon microarrays and factor graphs.
  100. Developmental biology: tiny brakes for a growing heart.
  101. Connexin 40, a target of transcription factor Tbx5, patterns wrist, digits, and sternum.
  102. Abnormal cardiac inflow patterns during postnatal development in a mouse model of Holt-Oram syndrome.
  103. Tbx20 dose-dependently regulates transcription factor networks required for mouse heart and motoneuron development.
  104. Serum response factor, an enriched cardiac mesoderm obligatory factor, is a downstream gene target for Tbx genes.
  105. The functional landscape of mouse gene expression.
  106. Baf60c is essential for function of BAF chromatin remodelling complexes in heart development.
  107. Lats2/Kpm is required for embryonic development, proliferation control and genomic integrity.
  108. The T-Box transcription factor Tbx5 is required for the patterning and maturation of the murine cardiac conduction system.
  109. Tbx1 has a dual role in the morphogenesis of the cardiac outflow tract.
  110. TBX5 mutations and congenital heart disease: Holt-Oram syndrome revealed.
  111. The Iroquois homeobox gene Irx2 is not essential for normal development of the heart and midbrain-hindbrain boundary in mice.
  112. Cardiac T-box factor Tbx20 directly interacts with Nkx2-5, GATA4, and GATA5 in regulation of gene expression in the developing heart.
  113. Tbx5 is required for forelimb bud formation and continued outgrowth.
  114. The developing heart and congenital heart defects: a make or break situation.
  115. Tbx5 is essential for forelimb bud initiation following patterning of the limb field in the mouse embryo.
  116. Transcriptional regulation of vertebrate cardiac morphogenesis.
  117. A murine model of Holt-Oram syndrome defines roles of the T-box transcription factor Tbx5 in cardiogenesis and disease.
  118. Cardiomyopathy in Irx4-deficient mice is preceded by abnormal ventricular gene expression.
  119. Cardiac expression of the ventricle-specific homeobox gene Irx4 is modulated by Nkx2-5 and dHand.
  120. Chamber-specific cardiac expression of Tbx5 and heart defects in Holt-Oram syndrome.
  121. Characterization of natriuretic peptide production by adult heart atria.
  122. Regulation of chamber-specific gene expression in the developing heart by Irx4.
  123. BNP gene expression is specifically modulated by stretch and ET-1 in a new model of isolated rat atria.
  124. Tissue-specific regulation of renal and cardiac atrial natriuretic factor gene expression in deoxycorticosterone acetate-salt rats.
  125. Mutations in human TBX3 alter limb, apocrine and genital development in ulnar-mammary syndrome.
  126. Evidence for load-dependent and load-independent determinants of cardiac natriuretic peptide production.
  127. Alpha 1-adrenergic stimulation of isolated rat atria results in discoordinate increases in natriuretic peptide secretion and gene expression and enhances Egr-1 and c-Myc expression.
  128. Mechanical and neuroendocrine regulation of the endocrine heart.
  129. Dissociation of cardiac hypertrophy, myosin heavy chain isoform expression, and natriuretic peptide production in DOCA-salt rats.
  130. Atrial natriuretic factor significantly contributes to the mineralocorticoid escape phenomenon. Evidence for a guanylate cyclase-mediated pathway.
  131. Selective changes in natriuretic peptide and early response gene expression in isolated rat atria following stimulation by stretch or endothelin-1.