Epigenetic reprogramming of tumor and stem cell genomes by exogenous delivery of Transcription Factors
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1 Pilar Blancafort Associate Professor School of Anatomy, Physiology and Human Biology UWA! Epigenetic reprogramming of tumor and stem cell genomes by exogenous delivery of Transcription Factors The University of Western Australia (UWA) Opportunitoes for Research Collaborations December 4th, 2012
2 Outline! 1-Overview of Zinc Finger technology (Artificial Transcription Factors, ATFs) and their applications in cancer epigenetics! 2-Design of ATFs to epigenetically reprogram metastasis suppressor gene promoters & oncogenes! 3-Exogenous delivery of Transcription Factors (TFs) to reprogram the epigenetic landscape of breast epithelial tissues!
3 EPIGENETICS: changes to DNA/associated proteins that can alter gene expression without altering the DNA sequence "#$%&'(!)*#+!,-.+(&$&/(!!"#$%&'(( )*+,(( ( Tail Globular DNA methylation: 5-methylcytosine Histone modifications: methylation, acetylation, phosphorylation
4 Epigenetic marks act in a combinatorial manner (Histone Code) to activate/repress transcription Pol II complex Chromatin remodelers HAT +++ Active gene expression TATA nucleosome HDAC! Silenced gene expression Histone acetylation H3K4me ON H3K9me3 H3K27me H3K9me DNA me OFF
5 Design of chromatin remodeling factors to reprogram the epigenome of cancer cells EPIGENETIC ON SWITCH: TUMOR/METASTASIS SUPPRESSORS +++ nucleosome Active maspin expression Suppression of Tumor growth/motility EPIGENETIC OFF SWITCH: ONCO-TARGETS! Silenced SOX2 expression Suppression of Tumor growth Zinc Finger CM H3/H4 Ac H3K4 3me ON H3K9me3 DNA me OFF CM= Chromatin Modifiers
6 Objective: reprogram cancer cell behavior using sequence-specific DNA-binding proteins! Blancafort, P. et al. Proc. Natl. Acad. Sci. 2005; 102: ;!
7 Delivering master regulator TFs to investigate cancer etiology and disease progression! Beltran et al. Breast Cancer Res Sep 27;13(5):R94 l.
8 Engineering effector-specific DNA-binding proteins Chromatin remodeling enzymes ACTIVATOR DOMAIN RNA Polymerase Chromatin condensing enzyme(s) REPRESSOR DOMAIN CMD Histone modifications DNA methylation DNA recombination DNA cleavage
9 0+*'.*1&2%!(%!*+3! Nat Biotechnol. 2003; 21: ! Phenotypic selections of ATF libraries!
10 Reactivation of epigenetically dormant tumor suppressor 078!9:9;!./01!,234,&$#!!!!!!!!-$%,56!!!!!!!!"#$%$&'#!!!!!(")#'*(+,&'-! 45! <=)>"!&,#*'&!;5&'! B-#5,6,!C(D'E!:'+&#,6!
11 Design of ATFs recognizing specific 18-bp sequences in the maspin promoter ETS HRE ETS p53 p53 AP1 AATGGAGATCAGAGTACT ATF-452 GCAGTGGGCGTGGCGGTG ATF-126 TCGGTGGCGACGAAGACG ATF-97 Beltran A, et al. Oncogene Oct 23., 1-8.
12 ATF -126 reactivates maspin in cell lines that epigenetically silence the promoter MDA-MB-468 MDA-MB-231 Fold maspin mrna upregulation MDA-MB-468 CONTROL ATF -97 Maspin Tubulin ATF -126 ATF -452 ATF -126 NO-VP64 pmxvp64-ss ATF 30 6 ZF LIB MDA-MB-231 CONTROL ATF -97 ATF -126 ATF -452 ATF -126 NO-VP64 pmxvp64-ss ATF 30 6 ZF LIB MDA-MB-468 MDA-MB-231 Beltran A, et al. Oncogene Oct 23., 1-8; F$+!G,62'#!HI'#3!67789:;5787<=73!
13 ATF-126 induce tumor & metastasis suppression "JKLK<?! 4' - DOX + DOX CONTROL - DOX + DOX DOX removal ATF-126
14 Nanodelivery of ATF-126-encoded mrna:lipid protamine RNA nanoparticles H&I#J(I!! >KL<M'/%G*!/N,O! P2&%*/#'(! Q#D&$&/(! DSPE-PEG 2000 DSPE-PEG AA Anisamide (AA) Mean Fluorescence Intensity A777! GB77! G777! 6B77! 6777! 5B77! 5777! B77! 7! )55! "5B:! HRSTON! B77=! H(*'!L+-&2($.('.(!U'%('$#%V! :7! >7! B7! A7! G7! 67! 57! 7! % Tansfected W!)2*'$1(.%(I!! LPR (Lipid-Protamine-RNA)
15 LPR nanoparticles biodistribution in the tumor in vivo Untargeted LPRmCherry Targeted LPRcontrol mrna Targeted LPRmCherry Heart Liver Spleen Lung Kidney Tumor Fluorescence intensity + X*'Y!Z[!F-!"<\[!Z*'Y!Z[!K\*'Y!Q[!0+*'.*1&2%!P[!"-*'Y!Q3!?6756@3!F$+'2(+,#! HI'#,"E3!O6!/#';;3!
16 LPR nanoparticles encapsulating ATF-126 inhibit ovarian cancer xenograft growth in vivo Tumor Volume (mm 3 ) LPR-AA-ATF-126 LPR-AA-Control VC LPR-mATF LPR-Control VC * **!-Maspin!-HA!-"-actin Tumor samples Days after tumor inoculation Lara H, Wang Y, Beltran AS, Juarez-Moreno K, Yuan X, Kato S, Leisewitz AV, Cuello-Fredes M, Licea AF, Connolly DC, Huang L, Blancafort J Biol Chem. (2012)
17 Hereditable de novo silencing of the SOX2 oncogene in breast cancer 6ZFs! Dnmt3a! rel Sox2 mrna expression MCF7 0.0 DOX * * DOX removal! ctrl ctrl 598DNMT3a 598DNMT3a 598DNMT3a DNMT3a DNMT3a 598SKD 598SKD 598SKD DOX removal! Relative ATP release t= empty Control! ZF SKD! SKD 598DNMT3A! ZF-552 DNMT3a DNMT3a DNMT3A! 0hrs 48hrs 96hrs 144hrs 192hrs DOX removal! F%&+]('E-2Y!F!'&!,+L! PBQ!!?6756@!!
18 ZFs-Dnmt3a fusions promote hereditable DNA methylation in the SOX2 promoter SOX2 amplicon 6ZFs Dnmt3a ZF-598-Dnmt3a ZF-552-Dnmt3a Control ZF-598E74A ZF-598-Dnmt3a ZF-552-Dnmt3a ZF-552-E74A Dnmt3a MCF-7 ZF-598-Dnmt3a % mecpg -Dox +Dox Dox Removal
19 -717 6ZFs -552 Dnmt3a -342 ZF-552! DNMT3a! -598 ZF-598! DNMT3a! ZF-598! 3a E74A! MCF7!
20 Hereditable de novo silencing of the SOX2 oncogene in tumor models A Tumor volume mm control -DOX -598 control +DOX 598Dnmt3a -Dox P= *** P= ** 598Dnmt3a +Dox 598Dnmt3a+Dox Removal 10x 10x 10x Control +Dox SOX2 amplicon control +Dox 598Dnmt3a +Dox 598Dnmt3a Dox Removal 598Dnmt3a +Dox 598Dnmt3a Dox Removal
21 Therapeutic effect of LPR nanoparticles in tumor models "-.-("&/'01%&( "-.-("&/'01%&( BC8%+( 2*&0'+(0'33( 45"6'&'10*337(+'5+%6+*88'9(0'33( $%(0E'8%$E'+*57F +*9"*1%&(
22 T&'.+-$#&'$! ATFs re-activate epigenetically silenced genes (maspin tumor suppressor)!!!!!!! ATFs induce directional DNA-methylation/ demethylation patterns along the target promoters (epigenetic re-writers) that can be used to reprogram complex genomes and discover genes involved in phenotype specification
23 )\*'^$!)&_33!!! Adriana Sujey Beltran Ashley Rivenbark Angela Russo Xinni Yuan Bine Stolzenburg Karla O Juarez Haydee Lara NCI/NIH American Lung Association DoD V-Foundation Breast SPORE Golfers Against Cancer LCC-UNC-CH Chuck Perou, LCCC, Pathology Aleix Prat LCCC Pathology Brian Strahl UNC Biochemistry Lee Graves, Pharmacology Paul Lizardi Yale Dep Pathology!!
24 ATFs induce directional demethylation patterns in the H157 NSCLC cell line Percent Methylation NCI-H ZF-97 VP64 ZF NCI-H157 + ATF NCI-H157 + ATF-126 Percent Methylation Percent Methylation Nucleotide position Nucleotide position Beltran A & Blancafort P. Epigenetics 2011
25 Specificity of 6ZFs in breast cancer cell lines by ChIP-Seq P(YYV!`!L*2'\*/!a!H*b!c2#//(2!dFT!!
26 LPR nanoparticles are regulate endogenous maspin!-ha LPR-AA-Control LPR-AA-ATF-126!-Maspin Molecular Beacon LPR-AA-Control LPR-AA-ATF-126 Lara H, Wang Y, Beltran AS, Juarez-Moreno K, Yuan X, Kato S, Leisewitz AV, Cuello-Fredes M, Licea AF, Connolly DC, Huang L, Blancafort J Biol Chem. (2012)
27 Nucleosome +++ Active transcription Onco-target ON e.g MYC Enhancer H3K4me H3K9/27Ac H3K9me 5meC TALe-binding site Epigenetic-OFF switches Proximal Promoter Epigenetic Silencing domain Engineered DNA-binding domain epitale Stable epigenetic silencing Onco-target OFF
28 0*$(I!&'!eD2(I#.%(If!E#'I#'Y!$D(.#J.#%V!&1!%\(!KL!\(+#.($! 6ZF! Sequence motif! Gene! Target Sequence! Score! -552! &'()%!"#!!!#####$##$#$$% *+,-% -598! &'()% #$$#####!##!#####$% *.,+% -4203! &'()%!""!!#!#!##!####!!% *.,/0%
29 Reprogramming: change in the genomic architecture that leads to changes in gene expression and phenotype specification! Histone DNA double helix Nucleosomes H3 H2B H2A H4 Chromatin Solenoid Chromatin loop: ~100,000 bp DNA
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