Viruses, and Epigenetics Yaron Tomer, MD Division of - - PowerPoint PPT Presentation

▶
viruses and epigenetics
SMART_READER_LITE
LIVE PREVIEW

Viruses, and Epigenetics Yaron Tomer, MD Division of - - PowerPoint PPT Presentation

Jul 22, 2023 263 likes •512 views

Triggering Thyroid Autoimmunity: Genes, Viruses, and Epigenetics Yaron Tomer, MD Division of Endocrinology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York Nothing to Disclose PRESENTATION FROM THE 83rd ANNUAL

slide-1
SLIDE 1

Triggering Thyroid Autoimmunity: Genes, Viruses, and Epigenetics

Yaron Tomer, MD

Division of Endocrinology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York

Nothing to Disclose

PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Yaron Tomer)

slide-2
SLIDE 2

Genes Viruses Interactions

PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Yaron Tomer)

slide-3
SLIDE 3

Genes Viruses Interactions

PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Yaron Tomer)

slide-4
SLIDE 4

HLA-DRb1-Arg74 CTLA-4 PTPN22 Tg ARID5B

GD HT

TSHR CD40 CD25 12q (BTG1)

Reviewed in:

  • Tomer. Thyroid 2010; 20: 715-725

Huber, et al. Endocr Rev 2008; 29: 697-725 Brand, Gough, Curr Genomics 2011; 12: 526-541

PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Yaron Tomer)

slide-5
SLIDE 5

Tg, TSHR

B-cell

Translational Implications

+

PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Yaron Tomer)

slide-6
SLIDE 6

Genes Viruses Interactions

PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Yaron Tomer)

slide-7
SLIDE 7

Country Year Patients Controls P-value Study

  • No. %TAb’s
  • No. %TAb’s

France 1993 72 12.5 60 1.7 0.02

Tran

Japan 1994 109 9.2

  • Watanabe

Spain 1995 96 5.2 96 8.3 NS

Boadas

Italy 1995 75 10.7

  • Carella

UK 1997 111 4.5 99 11.1 NS

Metcalfe

Italy 1999 86 9.3 1147 17.1 NS

Loviselli

France 2000 97 13.4 97 3.1 0.02 Ganne-Carrie Italy 2004 630 21 389 12 0.0001 Antonelli

Hepatitis C and Thyroiditis

Reviewed in: Mandac, Chaudhry, Sherman, and Tomer. Hepatology; 2006; 43: 661-672

PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Yaron Tomer)

slide-8
SLIDE 8

How can HCV infection trigger thyroiditis?

Can HCV infect human thyroid cells Non-specific effects of the virus

PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Yaron Tomer)

slide-9
SLIDE 9

Detection of HCV-RNA in the thyroid by in-situ hybridization

Bartolome et al J Med Virol 2008; 80: 1588-1594

PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Yaron Tomer)

slide-10
SLIDE 10

Control – PS cells Control – PS supernatant Control – NS cells Control – NS supernatant NS sup: uninfected NS supernatant: infected NS cells: uninfected NS cells: infected PS sup: uninfected PS cells: uninfected PS cells: infected PS sup: infected 295 bp 295 bp

ML-1 Huh7.5

Blackard et al. Thyroid 2013; 23: 863-870

PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Yaron Tomer)

slide-11
SLIDE 11

HCV Infection in the Presence or Absence of anti-CD81

0.00 0.25 0.50 0.75 1.00 0.00 0.25 0.50 0.75 1.00

Huh 7.5 ML-1

Blackard et al. Thyroid 2013; 23: 863-870

PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Yaron Tomer)

slide-12
SLIDE 12

Exposure of cryptic Ag’s Alteration of self Ag’s Inflammatory response Secretion of cytokines (IL-8)

Mechanisms of induction of Thyroiditis by HCV: Bystander Activation

PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Yaron Tomer)

slide-13
SLIDE 13

Genes Viruses Interactions

PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Yaron Tomer)

slide-14
SLIDE 14

Non-coding effects on gene expression/function that are mitotically stable (i.e. long lasting)

  • DNA methylation
  • Histone modifications
  • microRNA activation

Epigenetics: Definition

PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Yaron Tomer)

slide-15
SLIDE 15

Non-coding effects on gene expression/function that are mitotically stable (i.e. long lasting)

  • DNA methylation
  • Histone modifications
  • microRNA activation

Epigenetics: Definition Which environmental factor triggers epigenetic changes in thyroid cells?

PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Yaron Tomer)

slide-16
SLIDE 16

Interferon  and AITD

  • IFN is a key cytokine secreted during infections
  • IFN therapy has been associated with autoimmunity –

AITD, type 1 DM, SLE

  • Transgenic mice expressing IFN in thyroid develop thyroiditis

IFN is a Key Cytokine Triggering AITD

  • Akeno. J Immunol 2011; 186: 4693-4706
  • Tomer. J Autoimmun 2010; 34: J322-J326

Stewart . Science 1993; 260: 1942-1946

  • Eisenbarth. Clin Immunol 2004; 111: 225-233
  • Diana. Nat Med 2013; 19: 65-73

PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Yaron Tomer)

slide-17
SLIDE 17

IFNa

Human Thyroid Cells

Epigenetic Effects of IFNa

Global histone modifications H3K4me1 H3K4me3 Genetic Variants Associated with AITD

PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Yaron Tomer)

slide-18
SLIDE 18

Tg Promoter

rs180195

IFNa + IFNa -

AAA(A/G)GAAA

Exon 1

TSS ATG

TATA CAAT 40

cAMP-RE

1623

A Tg Promoter SNP That is Associated with AITD Shows Enrichment in H3K4me1

Stefan et al. JBC 2011; 286; 31168-31179

PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Yaron Tomer)

slide-19
SLIDE 19

183 120 173 TG (-1623 G) HLA-B promoter TSHR promoter

Tg Promoter -1623 G Allele Binds IRF-1

Stefan et al. JBC 2011; 286; 31168-31179

PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Yaron Tomer)

slide-20
SLIDE 20

TG proximal promoter

H3K4me3 H3K4me1

TG -1623 G

H3Ac Active Chromatin Active Transcriptional Element Active Chromatin Enhancer Element

Binding of IRF-1 to the -1623 G-Allele Induces Epigenetic Changes Driving TG Transcription

Stefan et al. JBC 2011; 286: 31168-31179

PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Yaron Tomer)

slide-21
SLIDE 21

Luciferase Activity

5 10 15 20 25 30

p=0.007 p=0.008

pGL4.10-TG (A) pGL4.10-TG (G) pGL4.10-TG (del)

Construct

Tg Promoter -1623 G Allele Increases Promoter Activity

Stefan et al. JBC 2011; 286: 31168-31179

PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Yaron Tomer)

slide-22
SLIDE 22

Fold change

IFNα conc. (U/ml)

1000 5000 10,000

TG

IFNα conc. (U/ml)

Fold change

IRF-1

0.5 1 1.5 2 2.5 3 1000 5000 10,000

** * *

0.5 1 1.5 2 2.5

* * *

Interferon  Induces Tg Expression in Thyroid Cells

How can upregulation of Tg trigger AITD?

PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Yaron Tomer)

slide-23
SLIDE 23

MECHANISM

Infection

Tg

ER Stress

PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Yaron Tomer)

slide-24
SLIDE 24

Mihaela Stefan Erlinda Concepcion Angela Lombardi Francesca Menconi Cheuk Wun Li Nagako Akeno Eric Jacobson Alia Hasham Molecular Modeling Roman Osman Taiji Oashi

Collaborators

Proteomics Rong Wang Bioinformatics Weijia Zhang Lucy Skrabanek Statistical Genetics David Greenberg Susan Hodge Cristina Monti Next gen Sequencing, Genotyping Mehdi Keddache Small molecule screening Dan Felsenfeld

PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Yaron Tomer)