Initiating Events in Direct Cardiomyocyte Reprogramming

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Initiating Events in Direct Cardiomyocyte Reprogramming Kimberly Sauls, Todd M. Greco, Li Wang, Meng Zou, Michelle Villasmil, Li Qian, Ileana M. Cristea, Frank L. Conlon  Cell Reports  Volume 22, Issue 7, Pages 1913-1922 (February 2018) DOI: 10.1016/j.celrep.2018.01.047 Copyright © 2018 The Author(s) Terms and Conditions

Cell Reports 2018 22, 1913-1922DOI: (10.1016/j.celrep.2018.01.047) Copyright © 2018 The Author(s) Terms and Conditions

Figure 1 Induced Cardiomyocyte Proteomic Analysis (A) First, retroviruses packaged with either a pMXs-DsRed (Red) construct or a pMXs-MGT (green) construct, were generated. Freshly generated virus was used to transduce MEFs (<p5). Nuclei were isolated from transduced MEFs at 48 and 72 hr post-transduction and then subjected to quantitative TMT MS/MS analysis to identify and quantify proteomic changes. (B) Comparison of proteins quantified by TMT-based proteomics at 48 and 72 hr post-transduction. (C) Hierarchical clustering of log2 TMT abundance ratios (MGT/DsRed) visualized as a heatmap showing increased (red), decreased (blue), and unchanged (gray) TMT ratios. Missing values were indicated in white. Heatmap clusters were assigned from a specific dendrogram depth. Cell Reports 2018 22, 1913-1922DOI: (10.1016/j.celrep.2018.01.047) Copyright © 2018 The Author(s) Terms and Conditions

Figure 2 Extracellular Matrix Protein Networks Are Predominantly Upregulated at Both 48 and 72 hr Post-reprogramming (A) Gene set enrichment analysis of TMT protein ratios found that proteins annotated to the PANTHER protein class extracellular matrix protein (n = 70) were on average significantly upregulated at both 48 (blue circles, p < 8.43E-6) and 72 hr (orange circles, p < 6.3E-4) compared to the distribution of all proteins (orange and blue lines). (B and C) The functional connectivity and relative abundance of the proteins annotated to extracellular matrix protein networks was visualized by STRING analysis. Node color indicates average relative increase (yellow) or decrease (blue) in protein abundance at 48 and 72 hr post-transduction. Black node color indicates the protein was not detected at that time point. Extracellular matrix (ECM) protein abundance was similarly increased at both time points, although on average the magnitude was greater at 48 hr. Cell Reports 2018 22, 1913-1922DOI: (10.1016/j.celrep.2018.01.047) Copyright © 2018 The Author(s) Terms and Conditions

Figure 3 Translation Factor Networks Are Strongly Downregulated at 48 hr Post-reprogramming but Then Rebound at 72 hr (A) Gene set enrichment analysis of TMT protein ratios found proteins annotated to the PANTHER protein translation factors (n = 46) were on average significantly downregulated at 48 hr (blue circles, p < 1.79E-08) but not at 72 hr (orange circles) compared to the distribution of all proteins (orange and blue lines). (B and C) The functional connectivity and relative abundance of the proteins annotated to translational protein networks was visualized by STRING analysis. Node color indicates average relative increase (yellow) or decrease (blue) in protein abundance at 48 and 72 hr post-transduction. Individual protein abundances were strongly decreased at 48 hr, but less so at 72 hr when all proteins showed <50% change. Cell Reports 2018 22, 1913-1922DOI: (10.1016/j.celrep.2018.01.047) Copyright © 2018 The Author(s) Terms and Conditions

Figure 4 Chromatin-Associated Protein Networks Are Predominantly Downregulated at 72 hr Post-reprogramming (A) Gene set enrichment analysis of TMT protein ratios found proteins annotated to the PANTHER protein class chromatin/chromatin-binding proteins (n = 38) were on average significantly downregulated at 72 hr (orange circles, p < 4.5E-10) but not at 48 hr (blue circles) compared to the distribution of all proteins (orange and blue lines). (B and C) The functional connectivity and relative abundance of the proteins annotated to chromatin protein networks was visualized by STRING analysis. Node color indicates average relative increase (yellow) or decrease (blue) in protein abundance at 48 and 72 hr post-transduction. Black node color indicates the protein was not detected at that time point. Cell Reports 2018 22, 1913-1922DOI: (10.1016/j.celrep.2018.01.047) Copyright © 2018 The Author(s) Terms and Conditions

Figure 5 Temporal Changes in ECM, Translation, and Chromatin Binding Protein Networks (A–D) Western blot analysis was performed on nuclear fractions of MEFs transduced with either MGT or DsRed and were probed with antibodies against representative proteins in each class. (A) Nid2 an extracellular matrix protein and (B) Agrin at 72 hr post-infection (C) SMARCC1 and (D) HMGB1, chromatin-associated proteins, at 48 post-transduction. Densitometry quantification reveals changes in levels of proteins examined are consistent with the TMT proteomic results. These changes were significant for both Nid2, Agrin, and SMARCC1 (p < 0.05). (E) Schematic overview of infection and summary of the changes in relative protein abundances at 48 and 72 hr post-transduction. Data are represented as mean ± SEM. Cell Reports 2018 22, 1913-1922DOI: (10.1016/j.celrep.2018.01.047) Copyright © 2018 The Author(s) Terms and Conditions