Genetics of biological processes EPh 2018 Miretti Plos
Genetics of biological processes EPh - 2018 Miretti Plos 2008
Possible responses Apoptosis Diffenerentiation Self-renewal Who am I? Where am I? Cell proliferation Mutation Transformation Polarization, cell migration
Cell fates Differentiation REGENERATIVE THERAPY POTENCY http: //www. sciencedirect. com/science/article/pii/S 0168952510002222
Early phase of embryonic development In 16 day develops to multipotent Fertilization Implantation Multipotent cells http: //stemcells. nih. gov/info/scireport/pages/appendixa. aspx
Merrel-Stanger, Nat. Rev. Mol. Cell. Biol. - 2016
Canonical vs. stochastic models of differentiation Significance of regenerative medicine !? ! http: //www. nature. com/nrm/journal/v 10/n 10/fig_tab/nrm 2766_F 2. html
Decreasing potencies during differentiation Totipotens Pluripotens Multipotens Unipotens
Stem cells - Regenerative medicine John B Gurdon és Shinya Yamanaka 2012
Developmental potencies – Epigenetic conditions Level of differentiation Totipotent Zygote Pluripotent ICM, embryo, i. PS Multipotent Stem cells of adult Unipotent Differenated cells Epigenetical conition Total methylation of DNA Active X chrs; Differentiation - genes repr. Promoter hypometihylation X inactivation; Germ-line specific genes - repr. Promoter hypomethylation
Transcription factor mediated „reprogramming”
Steps of „reprogramming” to pluripotent level
Who am I? Origin = lineage Endogen factors • Asymmetric cleavage • Receptors, transcription factors – uneven distribution Where am I? Position= positional identity Exocrine factors • Morphogenes = Signal molecules • Cell-cell interactions • Cell-matrix interactions
Preferred directions in embryonic development Anterior- posterior (head-tail axis) (Wnt, HOX) Dorso-ventral ( SHH) Proximal- distal (SHH) Right-left symmetry
Governing molecules I. Morphogenes: – Direction of development is influenced by concentration gradients – Oocyte or embryo origin – Transcription factors Molekules: Hedgehog protein family TGFβ family (BMP) WNT family (Drosophila Wingless mutation) FGF
Signal pathways Other members: FGF – Ras – MAPK pathway RA (retinoic acid)
Hedgehog protein family Sonic hedgehog – Expressed in the notochord and then in the ventral part of the neural tube – Influences on: CNS, skeletal muscl. and limbs TGFβ family BMP SHH BMP: Bone morphogenetic protein Edward B. Lewis
Concentration of morphogen itself serves as information Example: Differentiation of mesoderm Morphogen: Activin (TGF family)
Activation of signal pathways
Governing molecules II. Homeobox / homeotic genes: – Hox genes (homeobox sequence) – 60 AA, helix-turn-helix structure proteins – Positional information – longitudinal axis – Max. 13 box – Spatial colinearity
Human HOX genes
Expression of Hox in development Diseases: • developmental abnormality (e. g. synpolydactylia, brachydactylia, Hand‑foot‑genital syndrome ) HOXA 13 and HOXD 13 • MLL (therapeutic target) http: //www. cell. com/abstract/S 0092 -8674%2811%2901273 -6? switch=standard
Interaction of SHH and Hox expression Epithel-mesenchymal connections Sadler, 9 th ed.
Ultrasound 3 D detection of face development Week 4 Week 10 Teratogenic effects http: //www. sheknows. com/parenting/articles/830813/seehow-your-babys-face-develops-in-the-womb
Development of prominencies (frontal, maxillar, mandibular) and the influencing factors FGF 10 FGFR” SHH MSX 1 LHX 8 SHOX 2 OSR 2 Cholesterin MSX 1 LHX 8 TGFBR 2 SHH HAND 2 Smoking Dioxine 1 growing of upper frontal prominence 2 retraction of toung 3 -4 fusion of the two maxillar prominences FGF 10 JAG NOTCH TBX 22 PAX 9 PITX 1 OSR 2 GABA Bensodiazepin TGBb 3 LEF 1 SMAD TWIST SNAIL Pi 3 Kináz RHO IRF 6 Viruses
Development of teeth
Sequence of events in expression of signal molecules Epithelium cells Cap Mesenchymal cells Terminal differentiation of odontoblasts and ameloblasts Mineralization of teeth Defficiency of Pax 9 and Msx results familiar tooth agenezis Early bell
Developmental disorders of teeth Disorder Disease Gene Locus Inheritance Other Emanel defects Amelogenesis imperfecta AMELX amelogenin Xp 22. 3 p 22. 1 XD 5% ENAM enamelin 4 q 13 AD MMP 20 enamelysin 11. q 22. 3 AR KLK 4 kallikrein 4 19 q 13. 41 AR Taurodontizmus DLX 3 Homeobox, BMP signal regulatory 17 q 21. 3 Hypophosphatasia ALPL Alkalic phosphatase 1 p 36. 1 p 34 AR 14 mutations Pigmented form
Therapeutic targets of cellular plasticity Merrel-Stanger, Nat. Rev. Mol. Cell. Biol. - 2016
Autonomous mitogen signal Insensitive to antiproliferatíive signals Resistent to apoptosis Characteristics of tumor cells (Hanahan és Weinberg 2000) Angiogenezis induction Invasion and metastases Immortal
Sitting too much boosts cancer risk Read more: http: //digitaljournal. com/article/313893#ixzz 2 Pto. Dvla. Z
Frequency of tumorous diseases The most important determinant of tumor formation is the age risk Risk groups: Childhood Young adult (< 30 yrs) Adult Oral tumors: 3 -6%
Tumorigenesis – Genetical evolution (multiple hit theory) Adenomatosis polyposis coli (APC) – its inherited mutation increases dramatically the risk of adenocarcinomas 17 p 18 q 12 q 5 q 34
• Oncogenes – dominant mutations – somatic • Tumor suppressor genes – mutations are recessive on cellular level, but result frequently dominantly inherited predispositions • Mutator genes – DNA reparation – germline and somatic mutations – result dominant predisposition or AR tumorigenesis syndrome
Oncogenes turn to be active by: • point mutation • gene amplification • chromosome translocation • genome epimutation (hypomethylation, loss of imprinting – LOI)
Mutations characteristic to proto – oncogenes Point mutation Amplification DNA rearrangement Chromosome ab. Insertion mutagenesis. + Epigenetic effects: hypomethylation
Point mutation - RAS H-RAS, K-RAS and N-RAS point mutation e. g. thyroid tumors
N-MYC gene amplification in neuroblastoma The normal n-myc locus (2 p 2) and the HSR (homogeneously stained region) http: //www. readcube. com/articles/10. 1038/nrc 2231
Chromosome aberration – Reciprocal translocation Philadelphia chromosome (Ph 1) ABL (Abelson cluster region) gene – coding thyrozine kinase enzyme BCR (breakpoint cluster region) • New fusion protein – coded by bcr/abl • Promoter of abl is lost • High synthetic activity • The non controlled proliferation of cells – TUMORS ( Leukemias: ALL, CML) • Therapy: Gleevec (imitanib mesylate)
Burkitt’s Lymphoma specific translocations • Translocation between chromosomes: – 8 & 2 , 8 & 14 , 8 & 22 • Chromosome 8 C-MYC oncogen • Chr. 2, 14, 22 IG-H Immunglobulin enhancer region • Oncogen activation
Tumor suppressors – Loss- of- function mutations – Deletions • Smaller – limited to one gene (p 16 CDK inhibítor) • Involves a full chromosome arm – 3 p (FHIT, RASSF 1, LIMD 1) – non papillary kidney cc. – 1 p – breast tumors – Frequently AD – Molecules: • • p 53, Rb BRCA 1 and 2 APC and DCC PTEN and PPA 2 LKB 1 p 16 WT 1 and WTX
Knudsons „two hit” hypothesis
Haploinsufficiency Mutation of one of the two tumorsuppressor allels the remaining normal allel results a limited function only.
Inherited syndromes
Tumorigenesis Colorectal carcinoma Prostata adenoma The loss-of-function mutations are present in majority © John Wiley & Sons, Inc.
Other factors influencing tumorigenesis I. – Viruses – Chemical substances (carcinogens) • Azbest, vinyl-chloride and benzen • Aryl carbohydrates of cigarette smoke • Aflatoxin – Irradiation: • UV • X-ray • Radon, cosmic and gamma irradiations – Immun-defficiencies – Nutrition
Circular viral DNA recombination into host DNA
Nutrients (vegetables) can influence – decrease – the risk of tumorigenesis
Epigenetic factors, hypermethylated tumorsuppressor or mutator genes
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