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SYSTEMS GENETICS VIEW of ENNDOMETRIOSIS PART 1

SYSTEMS GENETICS VIEW of ENNDOMETRIOSIS PART 1. Vladislav S BARANOV Ott’s Institute of Obstetrics & Gynecology & Reproductology Saint- Petersburg, RUSSIA. Endometriosis(EM) Uterine Leiomyoma (UL). GENE-NET of ENDOMETRIOSIS. Baranov et al.,2014. Метилирование ДНК.

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SYSTEMS GENETICS VIEW of ENNDOMETRIOSIS PART 1

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  1. SYSTEMS GENETICS VIEW of ENNDOMETRIOSIS PART 1 Vladislav S BARANOV Ott’s Institute of Obstetrics & Gynecology & Reproductology Saint- Petersburg, RUSSIA

  2. Endometriosis(EM) Uterine Leiomyoma (UL)

  3. GENE-NET of ENDOMETRIOSIS Baranov et al.,2014

  4. Метилирование ДНК EPIGENETIC of ENDOMETRIOSIS Gene methylation Hypermethylatied (suppressed) CYP2C19, HOX-A, PR-8, СDKN2B, CDKN2A, Hypomethylated (active)Erβ, SF1, CYR61,P53 Regulatory miRNAs 14 sites for miR142 regulation WHCS1, TNFα,TGFβ,ERα,ERβ, PRβ miR125b,miR153 regulators of inflammation a & immune response miR220-miR221 –NO-synthase (NOS2) miR210 - STAT3 protein mojety regulation miR148a –WNT- β-catenin signalling Pathway miR-196b ( repressed) pro apoptotic (BCL2), antiproliferative ( c-myc) (Montgomery et al.2014)

  5. Metabolic pathway STAT3with micro RNA210 actively expressed in endometriosis miR-21, miR-203, miR-205 Basic regulators miR-210, miR148a IIdentiification of STAT-3 proteins, SMAD transcription factors& MEK/ERK metabolic pathway as a central tegulator of Endometriosis Okamoto et.al.2014

  6. MOLECULAR MECHNISMS of ENDOMETRIOSIS Most obvious candidate genes: proliferation(GALT, HBA, CDKN2BAS,NFE213), embryogenesis(HOX-10, HOX-11, WNT4I), hormone receptors (CYP2C19,PRα,AR,SRFP4), cytokines(TNFα), immune response иммунного ответа (IL4R), сосудистого роста (VEGF2) Epigenetically deregulated genes caused by hypermethylation or miRNA imbakancesHOX10, PR-8,CYP2C19, CDKN2A,CDKN1B,CYR6,P53) (TGFβ,TNFα, ERα, ERβ,NOS2, СOX2), high activity of mettalloproteses genesзMMP1,ММР9, NFE213 unfavorable (harmfull) combination of environmentak genes GSTM1,GSTT1,NAT2 According to GWAS analysis (Rahimyoglu et al. 2014 ) 11 506 EM patients + 32 678 control) The genes : WNT4,VEZT, CDKN2b,AS1,ID4, CREB,NFE213 also HOXA, HOA10, FN1, CYP2C19 .

  7. Whole genome profiling & MALDI-TOFF spectrometria in endometriosis development(meta-analysis) Functionallly deregulated 107 genes: from 13 metabolic pathways i( 47 –increased 30 reduced) (Kadayashi et al.2014).

  8. ENDOMETRIUM EPITHELIUM tf-TWIST1suppression of CDH1 gene (cadherines ) mRNA OCT4 NANOG ENDOMETRIOSISAS a RESULT of STEM CELLS PROLIFERATION METAOLASIA MESENCHYMAL CELLS Proliferation MYC gene STEM CELLS OCT4, NANOG mRNA- migration of endometriosis cells Proestling et al.,2015 PRINCIPAL: epithelial cells transformation into mesenchyma stromal l stem cells which give rise to the cells of endometriosis lesions ENDOMETRIOID CELLS

  9. . Conrad Waddington (1905-1975) 2. Canalized development –different genetic , biochemical or immunologic factors can launch pathologic processes which inevitably finalize in the same disease –equifinality Epigenetics– the science dealing with stable variations in genome functions without changes in the primary DNA structure bне (Waddington, 1942). Epigenotype– functionaly active part of genome 1. Epigenetic landscape feasible ways of embryonic cells differentiation or pathologic development respective of variableinternal & external factors GENOME + EHIGENOME= FENOME

  10. HYPOTHESIS of TWO STAGES MODEL of ENDOMETRIOSIS Primary Endometriosis Cells DEREGULTION of mRNA , methylation abnormalities, Early gene activation Activation of proliferation Бblock of antisuppressor Ruined metabolic pathways Нарушения метаболических путей STAGE 1the origin of primary endometriotic cellsК ЛЕТОК(ПЭК) 1 2 4 3 1.dedifferentiation 2.Metaplasia 3 Vestgial embryonic cells, 4.Stem cells • PATHOFISIOLOGY of EM • Deficiency of natural killers • Activation of estrogens • Repression of progesterone Toxines, тinfestions MSC Stage 2 Cliinicalmanifetation 1-4 EMст. I - IV 5. Adenomyosis 6 Hyperplasia of endometrium • Invasiveness of peritoneum implantation of PEC, Endometriotic lesions (EL) • Vascularizationof EL invasive growth III V II I 1V Баранов , 2013, 2014

  11. PART 2SYSTEMS GENETICS VIEW of UTERINE LEIOMYOMA

  12. CANDIDATE GENTES of UTERINE LEIOMYOMA GROWTH FACTORS -19 GENES IGF2 , MEST, NEGF2 IGFBP6, CYR61/ IGFBP10, NOV, CRIM1, CTGF ,EGF, EGFR, FADD, LIM, MMP11, TGFB1, TGFB3, TTF1, VEGF,VDR STEROID HORMONES & RECEPTORS CYP1А1, CYP1B1, COMT, GSTM1,UGTA1A1, SULT1A1,ERα , ERβ , PR, ALDH3A1, CYP3A4, CYP17, CYP19, GSTA1, GSTP1, GSTT1 ГЕННАЯ СЕТЬ ММ UTERUS FIBROIDS GENOME STABILITY -8 genes XRCC1, XRCC4, ТР53, HMGA2 , RAD51B, HMGA1, CULT1, ORC5L CELL ADHISION 8-genes DTP, SELE, EFEMP1, S100A4, S100A6, SRPX, DCL1, PECAM1 Osinovskaya et al. 2014.

  13. STAGING OF LEIOMYOMA Stem cells markers OCT-4, NANOG, DNMT3B, GDF3 NORMA МСSC mesechima lineagel committed stem cells Initiation of tumorogenesis Location in junction zone- of the uterus - boundary of endometrium & myometrium Advanced UL Bulun, 2013

  14. STEM CELL ORIGIN OF UTERINE LEIOMYOMA Tal, Segars, 2013

  15. FEASIBLE MOLECULAR MECHANISMS of UL 1. Chromotripsis- sponteneous chromosome breakages ( chimeric genes , apoptos, aging,metaplasia – 40%2. Typical translocations with gene activation HMGA2,RAD51B (oncogeic stress) 40-50% 3. MED12 mutation >70 %; 4. biallelic lnactivation FH -1,5% (metabolic stress) Mehine et al.,2013

  16. EPIGENETIC LANDSCAPE of UTERINE LEIOMYOMA PRIMARY UL CELLs ORIGIN s side population Mesenchymal Progenitor Stem Cells STRESS HORMONAL IMBALANCE MYOMETRIAL Stem Cells CLINICAL MANIFETATTION DIFFERENT CLINICAL UNITS OF UTERIINE LEIOMYOMA , Number of fibroids, growth rates, position in the uterus, malignant transformation

  17. PART 3 ENDOMETRIOSIS & UTERINE LEIO MYOMA AS SYNTROPIC DISORDERS

  18. Comparative analysis of EM & LM

  19. ENDOMETRIOSIS GENE-NETS UTERINE LEIOMYOMA PROLIFERATION & EMBRYOGEBESIS XRCC1, XRCC4, ТР53, HMGA2 , RAD51B, HMGA1, CULT1, ORC5L MED-12,HMGA2 • PROLIFERATION & EMBRYOGENESSIS • GALT , INHBA • HOX-10, HOX-11GALT , • WNT4I, CDKN2BAS EM MSC LM • TUMOR SUPPRESSORS & • ONCOGENES • TP-53, ,CDKN2A, CDKN2B, NFE213 ,ARFEM + LM GROWTH FACTORS IGF2 , MEST, NEGF2 IGFBP6, CYR61 IGFBP10, NOV, CRIM, CTGF , TGFB1, TGFB3, TTF1, VEGF,VDR, ENDOMETRIOSIS LIOMYOMA • HORMONES & RECEPTORS • ESR1 • PGE-2 PR-α ; • PR-β • PROGINS • AR • SRFP4 EGFR, FADD, LIM FH, • CYTOKINES & RECEPTORS • TNF , IL-4, IL-4R IL-8, IL-6, IL-11,SCF, TGFβ, RANTES • NRIP EM+LM LM + EM CYP1B1, COMT, SULT1A1,ERα , ERβ , PR, ALDH3A1, CYP3A4, CYP17, CELL MATRIX & CELL ADHESION DTP, SELE, EFEMP1, S100A4, S100A6, SRPX, DCL1, PECAM1 COL1A1. Cyr61,CTGF,TGF-β,E2F1 ,c-MYC,GM-CSF,TSP1,IL-11 MMP11 • CELL MATRIX • FN1, MMP2, COL1A1 EM EM + LM LM DETOXIFICATION & METABOLISM CYP1A1. GSTP1, AHR , NAT2 GSTM1 ,mEPXHP62 (DOK) GSTT1 EM miRNA mIR-148a miR-23B, miR-542-3p miR-17-5p hsa-miR-142 miR-125b, miR-155, miR-220, miR-221 Mir21 mir148_a mir 196 mir210 miRNA let7, miR-21, miR-93, miR-106b, miR-200 mir-181A mir23b mir15b Mir26a ANGIOGENESIS VEGF, FGF,HIF. CTGF,TSP-1, c-kit, LM + EM eNOS LM EM Fig.1 Leiomyoma fibroides Endometriotic lesions

  20. ENDOMETRIOSIS & UTERINE LEIOMYOMA as SYNTROPIC DISEASES Synntropic diseases tend to occur in patients or their relatives more often than what is expected by chance (Pfaunder ,Seht, 1921]. At the age of molecular medicine syntropy is usually treated as a natural genetic phenomenon of nonrandom combination of two or more genetically related pathological configurations affecting the same or several individuals and their relatives [Puzyrev et al.2010]

  21. EM & UL as syntropic diseases • identity or obvious similarity of progenitor stem cells • feasible common site of their origin. within or close to junction zone of the uterus • rather similar sequence of molecular events accompanying tumorigenicity • deregulation of hormonal & immunological reactions due to global abnormal methylation/ demethylation of relevant genes, abnormal profiles of regulatory micro-RNA

  22. Hypoxia Hormonal shifts Oxidative stress Overstrain UL Chromotripsis UL FH UL Med12 UL HMGA Uterine leiomyoma Juctional zoe «COIN»: Myometrium/endometrium junctional zone Toxins Inflammations Hormonal shifts Oxidative stress E M I stage EM III stage Adenomyosis EM II stage Endometrial hyperplasia EM IV stage Endometriosis HYPOTHESIS :junctional zone of the uterus as a common place of origin of EM and UL Progenitor/ Stem Cells

  23. CONCLUSION • Endometriosis (EM) & Uterine Leiomyoma (UL) – complex syntropic disorders affecting almost half of all women In their reproductive age . • EM & UL start from stem cells with mesenchymal llineage in endometrium and myometrium • Boundary separating endometrial and myometrial tissues within the uterus wall so called “Junction zone” is the most feasible source of the progenitor / stem cells with mesenchymal commitment , giving rise to EM or UL

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