“ROLE OF miR-155 IN THE REGULATION OF LYMPHOCYTE

IMMUNE FUNCTION”

INDIAN VETERINARY RESEARCH INSTITUTEIZATNAGAR-243122

MASTERMAESTRO

Introduction

Biogenesis and mechanism of action

Evolutionary conservation

Targets and Tissue distribution

Regulation

Therapeutic aspects

Future prospects

Conclusion

NON-CODING RNA: FORMERLY KNOWN AS “JUNK”

http://catalyst.harvard.edu

miRNA

CHARACTERISTICS OF miRNA

Small non-coding double stranded RNA.

Approximately 19-22 nucleotide long.

Repress activity of complementary mRNAs.

Regulate 30% of mammalian gene products.

miRNAs show phenomena of multiplicity and cooperativity.

Have been described in invertebrates and vertebrates: worms, fungi, plants, and mammals.

Many are conserved between vertebrates and invertebrates.

Xiao and Rajewsky, 2009 and http://catalyst.harvard.edu

miRNA GENES

~60% of miRNAs are expressed independently.

~15% of miRNAs are expressed in clusters.

~25% of miRNAs are in introns.

WHAT IS miR-155 ?

MiR-155 is a microRNA that in humans is encoded by the MIR155 host gene or MIR155HG.

Formerly called as BIC (B-cell Integration Cluster).

It was later found that the MIR155HG was composed of three exons within human chromosome 21 (Hsa21 band q21.3).

The MIR155HG RNA transcript does not contain a long open reading frame (ORF).

Mol. Cell. Biol. 17 (3): 1490–502

BIOGENESIS

Advances.nutrition.org

Micro RNA silencing via many mechanism-

1)Inhibition of intiation

2)Post inhibiton initiation

3)m-RNA degradation- (a) Decapping

(b) Deadenylation

Mechanism of action of miRNA

Evolutionary Conservation

Sequence of pre-mir-155 and miR-155-5p was conserved between human, mouse, and chicken.

miR-155-5p express more conserved sequences in 22 different organisms including mammals, amphibians, birds, reptiles, sea squirts, and sea lampreys.

Less sequence data is available regarding miR-155-3p.

Teng G, Papavasiliou Faraoni I, Antonetti FR, Cardone J, Bonmassar E (2009)

WHERE IS MY TARGET

HERE IS SOMETHING MORE?

TARGAETS

CONTD....

PREDICTION OF COMMON CONSERVED SEED REGION

SITES THAT ARE CONSERVED , MORE RESPOND

SITES FALLING IN ORFs FEW RESPOND

SITES IN FAVORABLE PREDICTED CONTEXT MORE RESPOND (Grimson et al., 2007)

mRNAS WITH MORE SITES, MORE RESPONSE (Grimson et al., 2007)

miRNAs WITH STRONGER SEED PAIRING ,MORE EFFECTIVE (Garcia et al., 2011)

miRNAs WITH FEWER TARGET m-RNAs MORE EFFECTIVE (Garcia et al., 2011)

CONTD....

TISSUE DISTRIBUTION

miR-155 pri-miRNA was abundantly expressed in the spleen

and thymus.

miR-155 detectable in the liver, lung, and kidney.

miR-155 expression is specific for hematopoietic cells including

B-cells,T-cells, monocytes and granulocytes.

Expression levels of miR-155-3p were 20-200 fold less when

compared to miR-155-5p levels.

REGULATION

Recent miRNA deletion studies have revealed a

central role in the regulation of the immune response.

The deletion of miRNA-155 impaired T and B cell

differentiation in germinal centers.

Greatly decreased antibody and cytokine production.

REGULATION OF LYMPHOCYTE

An Overview of Regulation by miR-155

REGULATION OF T-LYMPHOCYTE

CONCEPT TO REGULATE IMMUNE FUNCTIONS

UP REGULATION

DOWN REGULATION

POSITIVE NEGATIVE

Goal

HOMEOSTASIS

STABLIZATION

HOW miR-155 REGULATE T- LYMPHOCYTE IMMUNE FUNCTION

Regulation of differentiation into the memory or effector

phenotypes of T cells .

Control of T-cell differentiation: to favour Th1 responses partially

by modulating cytokine production .

Control of proliferation and homeostasis of Treg cells by stabilizing

the signal of FOXP3 through the targeting of SOCS1.

MOLECULAR BASIS REGULATION

PLoS ONE (2012) Yao R, Ma YL, Liang W, Li HH, Ma ZJ, Yu X, Liao YH

CONTD…

IL-2

FOXP3

miR-155

c-Maf

IL-4 production

Th2 Phenotype

IFN-Y and IL—2 release

ROLE OF Mir-155 IN REGULATION OF B- LYMPHOCYTE

miR-155

Molecules ISSN 1420-3049 www.mdpi.com/journal/molecules 2014

HOW miR-155 REGULATE B- LYMPHOCYTE IMMUNE FUNCTION

Control of B-cell differentiation and GC reaction: activation and function of B cell in germinal centres and for T-cell dependent antibody responses by negatively modulating somatic hypermutation and class-switch recombination through the targeting of AID and PU.1 .

Required for normal production of isotype-switched, high affinity IgG1 antibodies in B-cells

Molecules ISSN 1420-3049 www.mdpi.com/journal/molecules 2014

MOLECULAR BASIS REGULATION

Mark A. Lindsay, Trends in Immunology Vol.29 No.7347 cell

ROLE OF Mir-155 IN LYMPHOCYTE IMMUNE FUNCTION

An overview

OVERVIEW OF REGULATION BY DIFFERENT PATHWAY AND OUTCOME

Immunology Review: Nabila Seddiki,Vedran Brezar,Nicolas Ruffin,Yves Levy and Sanjay Swaminathan

THERAPEUTIC ASPECTS

THERAPEUTIC APPROACH

CANCER

Lung cancer, Breast cancer, B-cell lymphomas

CONTD…

HYPERTENSION AND CARDIOVASCULAR DISEASES

Mir-155

REGULATION OF

AGTR1 GENE

DOWNREGULATION

OF AGTR1 PROTEIN

HYPERTENSION

DOWN-MODULATES INFLAMMATORY

CYTOKINE PRODUCTION

DECREASES AS PROGRESSION

FUTURE PROSPECTS

MiR-155 serves as important targets in cancer therapy.

Nanoparticle-based therapy in an in- vivo microRNA-155.

Suggesting a promising therapeutic option for lymphoma/leukemia.

We show that systemic delivery of antisense peptide nucleic acids encapsulated in unique polymer nanoparticles inhibits miR-155 and slows the growth of these “addicted” pre-B-cell tumors in vivo.

miRNAs in disease diagnosis and therapy as biomarkers miR-155.

CONCLUSION

miR-155 IS A HIGHLY EXPRESSED AND IMPORTANT miRNA WITH FUNCTIONAL RELEVANCE IN THE BIOLOGY OF LYMPHOCYTES

DYSREGULATION OF miR-155 HAS BEEN SHOWN TO HAVE RELEVANCE IN A NUMBER OF HUMAN TUMOURS, AUTOIMMUNE DISEASES AND RESPONSES TO VIRAL INFECTIONS BY T CELLS AND B CELLS

miR-155 IN LYMPHOCYTES IN VARIOUS DISEASE STATES, MAY LEAD TO THE IDENTIFICATION OF NEW PROTEIN TARGETS THAT LEAD TO NOVEL THERAPIES FOR THESE CONDITIONS

miR-155, IN CONCERT WITH OTHER MIRNAS, REGULATE GENE FUNCTION IN LYMPHOCYTES AND ALSO THEIR PRECISE ROLE IN DISEASE PATHOGENESIS

POINEER WORKER

Victor Ambros Gary Bruce Ruvkun

David Baulcombe

Craig C. Mello Andrew Z. Fire

REFERENCES

Requirement of bic/microRNA-155 for normal immune function Rodriguez A, Vigorito E, Clare S et al. Science 2007.

New regulators of immune cell development and function- Nat Immunol Baltimore D, Boldin MP, O’Connell RM, Rao DS, Taganov KD. MicroRNAs: 2008.

SOCS,inflammation,andautoimmunity -AkihikoYoshimura, MayuSuzuki , RyotaSakaguchi ,ToshikatsuHanada and HideoYasukawa.

Challenges and Opportunities of MicroRNAs in Lymphomas -Giacoma De Tullio , Vincenza De Fazio , Nicola Sgherza , Carla Minoia , Simona Serratì ,Francesca Merchionne , Giacomo Loseto , Angela Iacobazzi , Antonello Rana ,Patrizia Petrillo , Nicola Silvestris , Pasquale Iacopino ,and Attilio Guarini :MOLECULE 2014

A role for miR-155 in enabling tumor-infiltrating innate immune cells to mount effective antitumor responses in mice -Zonari E, Pucci F, Saini M, Mazzieri R, Politi LS, Gentner B, Naldini L.. Blood 2013.

Role of miR-155 in the regulation of lymphocyte immune function and disease-Nabila Seddiki, Vedran Brezar,Nicolas Ruffin, Yves Levy, and Sanjay Swaminathan