Beyond Argonaute: understanding microRNA

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Jul 14, 2014 - Genes Transcription Factor of DNA Binding Sites & Gene Regulation - BIOBASE Biological ... Find an example via RPPA or mutations. 45 ...
Beyond Argonaute: understanding microRNA dysregulation in cancer and its effects on protein interaction and transcriptional regulatory networks Sara JC Gosline, PhD ISMB – Late Breaking Research July 14, 2014

microRNAs (miRNAs) • Transcribed in nucleus • Processed by Dicer • Forms silencing complex with argonaute (Ago2) and GW182 • Binds 3’ untranslated region (UTR) of mRNA

Drosha Nucleus Cytoplasm Dicer

• Causes premature degradation of mRNA

AAAA

GW182

Ago2 1

Seed region sequence complementarity enables computational prediction of targets

AAAA

GAUGGAG CUACCUCA

AAAA

2

-2

-1 0 1 mRNA expression change 12h after miR-7 over-expression

2

miR-7 Targets Other mRNA

0

0.0

miR-7 Targets Other mRNA

Number of mRNA 1000 2000 3000 4000 5000 6000

Fraction less than value 0.8 0.6 0.2 0.4

1.0

miRNAs impose modest fold change

-2

-1 1 0 mRNA expression change 12h after miR-7 over-expression

Grimson et al., Mol. Cell 2007

3

2

1.0

Yet miRNAs are implicated in many biological processes

0.0

Let-7 Targets Other mRNA

-2

-1 0 1 mRNA expression change 32h after let-7 over-expression

2

0

Fraction less than value 0.8 0.6 0.2 0.4

Number of mRNA 2000 4000 6000

Let-7 Targets Other mRNA

-2

-1 1 0 mRNA expression change 32h after let-7 over-expression

Selbach et al., Nature 2008

2

4

Available  Cancer  Types

#  Cases  Shipped by  BCR

#  Cases with  Data*

Date  Last  Updated (mm/dd/yy)

200

200

02/04/14

The Cancer Genome Atlas (TCGA) Acute  Myeloid  Leukemia  [LAML]

6/26/2014

Cancer Details - Breast invasive carcinoma: Case Counts - Data Portal

Adrenocortical  carcinoma  [ACC]

80

80

06/13/14

Bladder  Urothelial  Carcinoma  [BLCA]

412

366

06/25/14

Brain  Lower  Grade  Glioma  [LGG]

516

516

06/25/14

1064

06/24/14

257

06/25/14

Breast  invasive  carcinoma  [BRCA] Home

Download  Data

Tools

About  the  Data

1101

Publication  Guidelines

Cervical  squamous  cell  carcinoma  and  endocervical Home  >  Cancer  Details adenocarcinoma  [CESC]

308

Cholangiocarcinoma  [CHOL]

36

0

 

Colon  [COAD] carcinoma  samples:   Target  adenocarcinoma  number  of  Breast  invasive

462

450

06/23/14

185

176

06/15/14

Anno

Breast invasive carcinoma: Case Counts 500  (number  subject  to  change)

Esophageal  carcinoma  [ESCA] Breast  invasive  carcinoma  [BRCA] Cases Glioblastoma  multiforme  [GBM]

Total

Exome

1064

1032

1

SNP

Methylation

1059531 1044

mRNA

miRNA

1048 521

1041

https://tcga-data.nci.nih.gov/tcga/ N/A N/A N/A N/A N/A N/A

Organ-­Specific  Controls2

Head  and  Neck  squamous  cell  carcinoma  [HNSC] 528 528 1 Raw  exome  data  are  available  at  CGHub.  Variant  calling  data  are  available  via  the  links  under  Exome  above.

Clinical 1001 06/23/14 N/A

06/25/14

We focus on six cancers with >50 mRNA and miRNA levels

2 Organ-­Specific  Controls  are  derived  from  donor  material  taken  from  individuals  not  matched  to  the  tumors  in  this  study.  Specifically,

these  tissues  would  be  from [KICH]  individuals  that  did  not  have  cancer  but  were  able66  to  donate  tissue  for  other  autopsy Kidney  Chromophobe 66  reasons  (e.g.  rapid 06/25/14

5

We can search for miRNAs with expression correlated with survival

High miRNA levels correlate with better outcome Low miRNA levels correlate with better outcome

Cancer

miRNAs associated with prognosis (p