Epigenetic regulation of cardiogenesis
•
3 j'aime•443 vues
Présentation de Michel Pucéat réalisée durant le cours du réseau international des instituts Pasteur de "Médecine Génomique: du diagnostic à la thérapie " (17-21 octobre 2016)
Recommandé
Recommandé
Contenu connexe
Tendances
Tendances (20)
En vedette
En vedette (20)
Similaire à Epigenetic regulation of cardiogenesis
Similaire à Epigenetic regulation of cardiogenesis (20)
Plus de Pasteur_Tunis
Plus de Pasteur_Tunis (20)
Dernier
Dernier (20)
Epigenetic regulation of cardiogenesis
- 1. INSERM UMR 910 Faculté de Médecine La Timone , Marseille , France Michel Pucéat Cours Réseau International des Instituts Pasteur 19 october 2016 Epigenetic regulation of cardiogenesis
- 2. Nuclear structure Darkly stained and condensed Transcriptionally silent and silences adjacent genes Present at centromeres and telomeres Repressive structure can be propagated Euchromatic gene placed in heterochromatin is repressed Lodish et al., Molecular Cell Biology, 6th ed. Fig 6-33
- 3. Chromatin fibers + charged N termini (bind DNA on neigboring nucleosomes) highly acetylated core histones (especially H3 and H4) 30 nm chromatin fiber 11 nm (beads) • HIGH level of histone H1 • Reduced level of histone H1 • NO gene transcription • Gene transcription possible
- 7. Modified from Matharu et al Plos Gen 2015 Chromatin is organized in three dimensions CTCFCTCF LAD euchromatin
- 8. Unicellular ancestor of metazoan Metazoan Complex gene repertoire involved in multicellular functions Evolution is not corelated with new genes Shift in genomic regulatory capabilities Genetics does not fully account for cell lineage determination during embryogenesis Enhancer diversity , Distal Enhancer-promoter loops: major evolutionnery innovation Histones H3/H4 Modifications CONSERVED Transcription factors Science 2006 311, 96 Davidson and Erwin Nature rev gen 2012, 13,233 Lenhart etal Genome Biol 14, R15, 2013, Fairclough et al Nature 2013 424, 147 Levine et al Cell 2011 144, 324 Buldger and Goudine Cell 2016, 165 1124 Sebe-Pedros et al
- 9. De Witt, De Laat, 2012 Technologies to be used to decrypt epigenetic regulation of gene transcription
- 10. BMP2 FGF TGFβ Wnt/βCat ⊥ Epiblast Definitive Endoderm Posterior Anterior Goosecoid Foxa2 Brachyury Primitive Streak Brachyury Flk1, FoxH1 Sox17 Hex Cardiac Mesoderm Wnt non Canonical ICM ESC in vitro Primitive Endoderm Visceral Endoderm Mesp1 BMP Cerberus Activin A BMP2 FGF Wnt-βCat Sox17 Hex Sox17 Hex Notch ⊥ Wnt-βCat ⊥ Ectoderm E5 E6 E6.5 E7.5 E13.5E7.75 E8.25E4 E4.25 FGF Notch Wnt/βCat ⊥ E10.5 SM-MHC SMA Atrial Cardiomyocyte Atrioventricular Nodal Cell Endothelial Cell Right Ventricular Cardiomyocyte Sinostrial Nodal Cell Smooth Muscle Cell Vascular Smooth Muscle Cell HCN4 Atrial and Left Ventricular Cardiomyocyte Smooth Muscle Cell Aorta smooth muscle cells Autonomous nervous system Epicardium Coronary vessels Fibroblasts BMP2 FGF Endocardium Tbx18 Wt1 FHL SHL Nkx2.5 FGF8/10 Hand2 Isl1 Mef2c Tbx1 Tbx20 Nkx2.5 Hand1 Tbx5 Extraembryonic Ectoderm BMP BMP2 Cardiac Neural Crest Sox17 Hex Sox17 Hex cTNT The cardiac developmental pathways GATA5,Cx37 valves
- 11. 1st Heart Field (Cardiac Crescent) 2nd Heart Field (SHF) Modified from Vincent and Buckingham, 2010 Main steps of Heart morphogenesis in the mouse embryos PA
- 13. Weber et al Birth Defects Res A Clin Mol Teratol. 2015.
- 14. Modified histone marks and cardiac congenital defects Liu et al epigenomics 2015
- 15. Cell lineages ? Physiological Pathological (cohesinopathies, laminopathies) ? Gen Biological questions and clinical relevance Genome- Wide Association Studies Not a single TRANSCRIPTION FACTOR is specific of a cell lineage
- 16. Oct-4 targets the cohesin complex and change 3D chromatin structure to specify cardiogenesis: from basic science to a rare disease
- 17. OCT4 a reprogramming transcription factor more than a stem cell marker • A gatekeeper for ICM/ES cell pluripotency and a reprogramming factor • A key player in early cardiogenesis • An inducer of MesP1, and in turn of EMT of epiblast cells into mesodermal cells E7.5 OCT4 SOX2 NANOG Pluripotency network SALL4
- 18. A siRNA approach to down regulate Oct-4 in the blastocyst Pseudopregnant mouse 96h cultured blastocyst
- 19. Cardiac defects in embryos developed from Oct-4 downregulated blastocysts Zeinedinne et al Dev Cell 2006
- 20. Embryonic stem cells: a powerful cell model to carry out mechanistic studies in early embryonic development
- 21. Mouse Human Oct-4, a dual function conserved in Human cells
- 22. OCT4 increase in expression gives rise to mesendodermal cells
- 23. Oct-4 improves cardiac differentiation of HUES cells within embryoid bodies
- 24. Sox2/17 enhancer /promoter Chromatin Anti-Oct4 Oct4 An increased level of Oct-4 leads to a loss in its interaction with Sox2 enhancer/promoter and a gain in its interaction with Sox17 enhancer/promoter Stefanovic et al J Cell Biol 2009
- 26. How Oct-4 switches from Sox2 to Sox17 regulatory regions ?
- 27. The search for Oct4 targets: ChIP on chip analysis
- 28. OCT4 binds SALL4 promoter Abboud, Moore-morris et al Nature Com 2015
- 29. SALL4 mediates the switch of OCT4 from Sox2 to Sox17 enhancers Abboud, Moore-morris et al Nature Com 2015
- 30. SALL4 is required for the cardiogenic function of OCT4 Abboud, Moore-morris et al Nature Com 2015
- 31. The Epigenetic code Resolution of bivalent chromatin domains during ES cell differentiation. Schuettengruber B , and Cavalli G Development 2009;136:3531-3542
- 32. OCT4 induced changes in epigenetic marks on Soxs promoters Abboud, Moore-morris et al Nature Com 2015
- 33. SALL4-targeted Polycombs in OCT4 switch from Sox2 to Sox17 enhancers se Sequential ChIP Abboud, Moore-morris et al Nature Com 2015
- 34. SALL4-targeted Polycombs in OCT4 switch from Sox2 to Sox17 enhancers Abboud, Moore-morris et al Nature Com 2015
- 35. Cohesin and CTCF organise higher order chromatin structure in the genome Dorsett, 2011 Cohesin
- 36. OCT4 targets the cohesin complex Abboud, Moore-morris et al Nature Com 2015
- 37. Chromosome conformation capture (3C) reveals Sox2/Sox17 enhancers interactions Abboud, Moore-morris et al Nature Com 2015
- 38. Chromosome conformation capture (3C) reveals Sox2/Sox17 enhancers interactions Abboud, Moore-morris et al Nature Com 2015
- 39. Abboud, Moore-morris et al Nature Com 2015
- 40. Cohesin is required for Oct-4 mediated cardiogenic function Abboud, Moore-morris et al Nature Com 2015
- 41. Abboud, Moore-morris et al Nature Com 2015
- 42. Mutations in the cohesin complex and partner proteins lead to a cohesinopathy
- 43. Chatfield et al Am J Gen 2012
- 44. E17.5 E17.5
- 45. Haploinsufficiency of Nipbl exacerbates the phenotype of Nk2.5 haploinsufficient mice and leads to cardiac dilatation
- 46. Nutrition and epigenetics: What is the link ? Vitamin D : a proof of concept ?
- 47. Fetahu et al Frontiers in physiology 2014 Vitamin D deficiency is becoming a public health problem ( malnutrition, obesity, in North Europe countries with short days… (WHO) )
- 48. Vit D-R : In Cis-modulatory modules enriched in TF binding sites (superenhancers) Enriched in H3K4me1, K4me2, H3K27ac ( enhancers marks) Co-occupied by cohesin or cohesin:CTCF
- 49. VitD starvation in female mice lead to cardiac hypertrophy in the offsprings
- 50. Acquisition and Maintenance of locus –specific 3D configuration of chromatin is key for normal cardiac cell lineage determination and possibly for adult cardiac homeostasis Haploinsuficiency of cohesin complex genes leads to developmental diseases and accelerated ageing in Cornelia de Lange patients Fetal life may prime for healthy ageing or cardiovascular pathologies Haploinsuficiency in other players in the 3D structure of chromatin such as mediators also leads do developmental disease with cardiac malformations ( FL Lujan syndrome) Take Home messages Environmental factors including nutrition affects epigenetic regulation of gene transcription and are a source of developmental diseases
- 51. THANK YOU ! Former students: Nesrine Abboud Sonia Stefanovic Dana Zeinedinne Corinne Grey Thomas Moore-Morris Imen Jebeniani Batoul Fahrat Fanny Boulet Eva Seipelt Julien Boissadier Sylvia Evans, UCSD, La Jolla, CA Valerie Cormier Daire Necker Hospital Paris Henry Yang Bioinformatics, Biopolis , Singapore