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Volume 25, Issue 12, Pages 2705-2714 (December 2017) Development and Mechanism of Small Activating RNA Targeting CEBPA, a Novel Therapeutic in Clinical Trials for Liver Cancer Jon Voutila, Vikash Reebye, Thomas C. Roberts, Pantelitsa Protopapa, Pinelopi Andrikakou, David C. Blakey, Robert Habib, Hans Huber, Pal Saetrom, John J. Rossi, Nagy A. Habib Molecular Therapy Volume 25, Issue 12, Pages 2705-2714 (December 2017) DOI: 10.1016/j.ymthe.2017.07.018 Copyright © 2017 The Author(s) Terms and Conditions

Figure 1 Nucleotide Walk on CEBPA saRNA Hotspots in HepG2 Cells (A) Schematic showing location and orientation of CEBPA mRNA and antisense transcript GenBank: AW665812, with approximate locations of AW1 and AW2 hotspots. (B) Expression of CEBPA mRNA for each sequence transfected at 50 nM relative to mock transfected cells. (C) Expression of albumin mRNA for each sequence transfected at 50 nM relative to mock transfected cells. Error bars represent SEM. Molecular Therapy 2017 25, 2705-2714DOI: (10.1016/j.ymthe.2017.07.018) Copyright © 2017 The Author(s) Terms and Conditions

Figure 2 Mechanism of Action of AW1-51 saRNA in HepG2 Cells (A) Relative luciferase activity representing C/EBP protein activity after transfection with 10 nM AW1-51 saRNA. (B) qPCR for CEBPA mRNA on nascent transcripts isolated from nuclear run-on after 10 nM AW1-51 saRNA transfection. (C) qPCR for CEBPA mRNA after transfection with 10 nM AW1-51 duplexes with a 5′ inverted abasic modification on the indicated strand. (D) qPCR for CEBPA mRNA after transfection with 10 nM AW1-51 saRNA with mutations in the seed region. (E) qPCR for CEBPA mRNA after transfection with 10 nM AW1-51 saRNA with mutations in the center of the duplex. (F) qPCR for GenBank: AW665812 RNA after transfection with 10 nM AW1-51. Statistical significance shown for the indicated condition compared to NC transfection: *p < 0.05; **p < 0.01; ***p < 0.001. Error bars represent SEM. Molecular Therapy 2017 25, 2705-2714DOI: (10.1016/j.ymthe.2017.07.018) Copyright © 2017 The Author(s) Terms and Conditions

Figure 3 Activity of CEBPA-51 in the HCC Lines HepG2 and Hep3B (A) qPCR for CEBPA and ALB mRNA after transfection with 10 nM CEBPA-51. (B) Western blot for C/EBP-α after transfection with 10 nM CEBPA-51. (C) WST-1 assays over a 96-hr time course after transfection with 10 nM CEBPA-51. Statistical significance shown for CEBPA-51 compared to FLUC transfection: *p < 0.05; **p < 0.01. Error bars represent SEM. Molecular Therapy 2017 25, 2705-2714DOI: (10.1016/j.ymthe.2017.07.018) Copyright © 2017 The Author(s) Terms and Conditions

Figure 4 Mechanism of Action of CEBPA-51 in HepG2 Cells (A) Western blot after co-immunoprecipitation of Ago1–4 and biotinylated CEBPA-51. (B) qPCR for CEBPA mRNA after transfection of 10 nM CEBPA-51 wild-type and Ago2 knockout MEFs. (C) qPCR at the CEBPA locus after chromatin immunoprecipitation with biotinylated CEBPA-51. The CEBPA-51 target site is approximately 3 kb downstream of the CEBPA TSS. (D) qPCR for CTR9 mRNA after transfection with CTR9 siRNA and qPCR for CEBPA mRNA after co-transfection of CTR9 siRNA and CEBPA-51. Statistical significance shown for the indicated condition compared to FLUC transfection: **p < 0.01. Error bars represent SEM. Molecular Therapy 2017 25, 2705-2714DOI: (10.1016/j.ymthe.2017.07.018) Copyright © 2017 The Author(s) Terms and Conditions