PLACENTAL MICRORNA EXPRESSION · 30 PLACENTA-SPECIFIC MICRORNAS ! C19MC – 19q13.41 miRNA cluster...
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PLACENTAL MICRORNA EXPRESSION
Daniel A. Enquobahrie, MD, PhD Associate Professor
Department of Epidemiology March 24, 2016
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OUTLINE
Ò Background
Ò Placental miRNA expression
Ò Circulating placenta-specific miRNAs
Ò Opportunities and challenges
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Background - MicroRNAs
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NON-CODING RNAS
Ò Human genome É ~50-70% transcribed É ~1-2% protein coding É ~98% Noncoding
Ò List growing
Ò Groups É Housekeeping: tRNAs, rRNA, Telomerase RNA, etc É Regulatory: miRNA, long ncRNA, Antisense-RNA,etc
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HISTORY
Ò Discovery: lin-4 (1993), C. elegans
Ò Plants, RNAi research
Ò http://www.mirbase.org/ É 28,645 entries: Release 21 (June 2014)
Ò ~2,500 miRNAs (human)
Ò Explosion of research over the past decade
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BIOLOGY
Ò Small (~22 nucleotides), conserved
Ò Production regulation: mostly unknown, tissue or developmental stage specific (1/3)
Ò Location É Introns, exon UT, intergenic É Single or cluster
Ò Post transcription regulation, though recent reports of transcription regulation
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BIOLOGY
Cardiovascular Research (2008) 79, 562-570
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BIOLOGY
Physiol Genomics (2008), 33:139-147
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POST TRANSCRIPTION REGULATION
Ò Gene expression regulation (1/3 genes) Ð Target 3’ UT seed regions of mRNA Ð Multiple sites on each mRNA Vs same site on
many mRNA
Ò Mechanisms Ð Inhibit translation of mRNA (non-perfect match) Ð Promote mRNA degradation (perfect/near
perfect match) Ð miRNA mediated mRNA decay
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MEASUREMENT/PROFILING
J Cell Mol Med (2014), 18:371-390
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DATABASES
Ò miRBase
Ò miRWalk
Ò miRTarBase
Ò Targetscan
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NOMENCLATURE – CLASSIFICATION
12 Am J Epidemiol (2014), 180, 140-152
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TARGET IDENTIFICATION
Ò Computational approaches É Complementarities
Ð “seed region” of 2-8 nucleotides at 5’ end
É Thermodynamic stability of complex É Degree of conservation of orthologues target sites
in the 3’ UT across species
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MOTIVATION
É Understanding pathophysiology
É Generating hypotheses (e.g. Gene & Env)
É Biomarkers: prediction, prognosis, monitoring
É Therapeutic targets
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Placental MiRNA Expression
Preeclampsia
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CENTER FOR PERINATAL STUDIES
Ò Multiple cohort and case-control studies É Cohort (>6,500): Omega study, Pregnancy Migraine Study É Case-control: Ferritin, Abruptio etc.
Ò Recruitment É Early pregnancy (7-8 weeks, first prenatal visit) É Eligibility/exclusion É Participation (>80%), Follow up (>96%), Data (92%)
Ò Data collection
É Interview-adminstered QA, FFQ, É Blood (16wks, on average), urine, placenta, cord blood É Medical records
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MICROARRAY EXPERIMENT Ò RNA extraction: Guanidinium TPC extraction
method
Ò RNA QC: UV spectrophotometry and gel electrophoresis
Ò Platform: custom microarray @ Ocean Ridge Biosciences
Ò Confirmatory QRT-PCR
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ANALYSIS Ò Data normalized and log2 transformed
Ò Fold change, 1-way ANOVA, Clustering
Ò Targetscan (www.targetscan.com)
Ò Path analysis: KEGG and IPA
Ò Confirmatory qRT-PCR: Correlations
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STUDY POPULATION CHARACTERISTICS
PE Cases (N=20)
Controls (N=20)
Age* 32.8 30.4
Gestational age* 36.0 38.8
Caesarian delivery 55.0 40.0
Whites 60.0 70.0
Nullipara 65 60
*mean (otherwise %)
Enquobahrie et al, Am J Obstet Gynecol 2011 19
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EXPRESSION MEASUREMENT
Ò 1,295 probes (human=854)
Ò miRNAs with ≥ 90% information (n=611)
Ò Differentially expressed miRNAs (n=8) (AFC>1.5, p-value <0.05)
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Enquobahrie et al, Am J Obstet Gynecol 2011
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DIFFERENTIALLY EXPRESSED MICRORNAS
21 Enquobahrie et al, Am J Obstet Gynecol 2011
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PREVIOUSLY REPORTED Ò miR-210
É Hypoxia, endothelial cell response, VEGF activities
Ò miR-1 É Smooth muscle calcium signaling
Ò miR-1247 (14q32.31 chromosomal cluster) É Conserved region with imprinted domain É Cluster (~40 miRNAs), embryonic/placental growth É Methylation region ~200kb upstream
22 Enquobahrie et al, Am J Obstet Gynecol 2011
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NOVEL Ò miR-584
É Binds to conserved 3’ region on lactoferrin receptor É Immune activation, platelet aggregation
Ò miR-34c-5p É Family of miR-34b and miR-34c É Mediators of p53 dependent suppression of
endometrial proliferation (cell cycle) É Endometriosis and preeclampsia (?)
23 Enquobahrie et al, Am J Obstet Gynecol 2011
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GENE TARGETS Ò 76 genes targeted by 2 or more DE microRNAs
Ò Functions É Organ system development (CVS/RS) É Immune dysfunction É Cell cycle É Cell signaling
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Significant network (IPA)
Genetic disorder, immunological disease, cardiovascular system development and function (score=30) 25
Enquobahrie et al, Am J Obstet Gynecol 2011
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Network from the GE study
Am J Obstet Gynecol 2008;199:566 e1-11
Cell death, cellular growth and proliferation, inflammatory disease
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Ò Previously identified (miR-210, miR-1, and miRNA cluster at 14q32.31) and novel (miR-584 and miR-34c-5p) microRNAs differentially expressed
Ò Target genes participate in diverse patho-physiological processes with potential importance in preeclampsia (e.g. organ/system development, immunologic dysfunction)
SUMMARY
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Circulating Placenta-specific
MicroRNAs
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CIRCULATING MICRORNAS
Ò Passive leakage (injury, inflammation, necrosis) É Extracellular miRNAs regulate vascular endothelium
Ò Active secretion through cell-derived membrane vesicles (e.g. exosomes) É Adipocytes release exosomes that contain miRNAs
(e.g. miR-16, -27a, 146b, -222)
Ò Protein-miRNA complexes (e.g. HDL-AGO2) É Participate in intercellular communication
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PLACENTA-SPECIFIC MICRORNAS
Ò C19MC – 19q13.41 miRNA cluster É Primate specific, expressed from the paternal allele É Expression increases from first to third trimester É Member miRNAs (e.g. miR-517) regulate cell proliferation,
immune function and antiviral activity
Ò C14MC – 14q32 miRNA cluster É DLK-DI03 domain, maternally imprinted É Expression decreases from first to third trimester É Member miRNAs (e.g. miR-379/410) regulate metabolic
functions (glucose homeostasis and hepatic gene expression)
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PLACENTA-SPECIFIC MICRORNAS
Ò Have been identified in plasma or serum
Ò Both placental expression and circulating levels has been related to preeclampsia or intrauterine growth retardation
Ò Most of these studies were conducted in mid/late pregnancy or post-delivery
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EARLY PREGNANCY CIRCULATING MICRORNAS
Ò Participants of the Omega Study (Seattle, WA) and POUCH (Pregnancy Outcomes and Community Health) Study (Michigan)
Ò Early (Omega, 8-20 weeks) to Mid (POUCH, 15-27 weeks) pregnancy blood collection
Ò Microarray and candidate miRNA profiling in relation to subsequent risk of preterm birth (primary outcome) and pre-pregnancy body mass index
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CIRCULATING MICRORNAS AND BMI
Ò 27 miRNAs were differentially expressed in relation to pre-pregnancy BMI in both Omega and POUCH cohorts
Ò Functions in regulation of organismal injury and abnormalities, reproductive system diseases, connective tissue disorders, and cancer
Ò Identified miRNAs included placenta-specific miRNAs in C14MC cluster (e.g. -377)
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CIRCULATING MICRORNAS AND BMI
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Opportunities and Challenges
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OPPORTUNITIES
Ò Research É Stability, omnipresence, smaller size, smaller # (?) É Uncovering gene expression regulation (DNA→RNA→Protein)
É Role of unknown genomic regions Ð e.g. miR-15, miR-16 at 13q14.3 in CLL, chromosome 9 (MI)
É Gene environment interactions
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OPPORTUNITIES
Ò Therapeutics
É Small size practical for synthesis and delivery
É Effect (on regulation) can be seen quickly (in 3 wks)
É Antisense RNA, alternate to knock-outs
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CHALLENGES - MEASUREMENT
Ò Limited sample volumes, low recovery, interference (e.g. anti-coagulants, platelet activation)
Ò Pre-processing steps, pre-analytic and analytic variables
Ò Lack of standardized protocols for extraction, profiling, and analyses
Ò Lack of good, universal control (house keeping miRNA) for normalization
Ò Diurnal variation and effect of fasting/non-fasting
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CHALLENGES - INFERENCES
Ò Study population and sample differences
Ò Confounding/effect modification É lifestyle, sex (infant), race, age
Ò Time dependent (disease course) changes
Ò Target (gene) identification – functional validation É Complex relationships É Loops
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CHALLENGES: THERAPEUTIC APPLICATIONS
Ò miRNA mimics are unstable,
Ò Selective targeting may be difficult, broad systemic effects
Ò Maintaining physiological levels of therapeutic miRNAs: over-inhibition or over-expression
Ò Delivery systems
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CURRENT AREAS OF WORK
Ò Integration with other –omics (e.g. genomics, metabolomics, proteomics)
Ò Placenta-specific miRNAs in urine
Ò Histo-pathologic and/or imaging correlates of miRNA expression
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ACKNOWLEDGMENTS
Ò Naya Frederick Ò Tanya Sorenson Ò Dejene Abetew
• Michelle Williams • Mahlet Tadesse • Eric Rimm • Andrea Baccarelli
• Aedin Cassidy • Peter Curtis • Sarah Edwards
• David Willoughby • Kumaravel
Chidambaram
• Lei He • Peter Bartolomeo • George Campbell
UW • David Siscovick • Colin Pritchard • Luke Wander • Tim Thornton