Role of Mirn 155 in thr regulation of lymhocyte
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Transcript of Role of Mirn 155 in thr regulation of lymhocyte
“ROLE OF miR-155 IN THE REGULATION OF LYMPHOCYTE
IMMUNE FUNCTION”
INDIAN VETERINARY RESEARCH INSTITUTEIZATNAGAR-243122
Introduction
Biogenesis and mechanism of action
Evolutionary conservation
Targets and Tissue distribution
Regulation
Therapeutic aspects
Future prospects
Conclusion
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
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)
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.
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.
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
OVERVIEW OF REGULATION BY DIFFERENT PATHWAY AND OUTCOME
Immunology Review: Nabila Seddiki,Vedran Brezar,Nicolas Ruffin,Yves Levy and Sanjay Swaminathan
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
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