Abstract
Missense variants throughout ACTA2, encoding α-smooth muscle actin (αSMA), predispose to adult-onset thoracic aortic disease, but variants disrupting arginine 179 (R179) lead to smooth muscle dysfunction syndrome characterized by diverse childhood-onset vascular diseases. Here we show that αSMA localizes to the nucleus in wild-type smooth muscle cells (SMCs), enriches in the nucleus with SMC differentiation, and associates with chromatin remodeling complexes and SMC contractile gene promoters. The ACTA2 p.Arg179 αSMA variant shows decreased nuclear localization. Primary SMCs from Acta2SMC-R179C/+ mice are less differentiated than wild-type SMCs in vitro and in vivo and have global changes in chromatin accessibility. Induced pluripotent stem cells from participants with ACTA2 p.Arg179 variants fail to fully differentiate from neuroectodermal progenitor cells to SMCs, and single-cell transcriptomic analyses of an ACTA2 p.Arg179His participant’s aortic tissue show increased SMC plasticity. Thus, nuclear αSMA participates in SMC differentiation, and loss of this nuclear activity occurs with ACTA2 p.Arg179 pathogenic variants.
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Data availability
scRNA-seq datasets generated for this manuscript are available in the GEO under accession number GSE201091. The ATAC-seq dataset generated for this manuscript has been deposited in the GEO and is available under accession number GSE241055. All reagents and resources applicable to this study are available from the corresponding authors upon reasonable request. Source data are provided with this paper.
Code availability
No novel code or algorithm was generated for this study.
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Acknowledgements
This work was supported by an America Heart Association Merit Award (to D.M.M.), the National Heart, Lung and Blood Institute (RO1 HL146583 to D.M.M.), the Olivia Petrera-Cohen Research Fund (to D.M.M.), the John Ritter Foundation (to D.M.M.), Marylin and Frederick R. Lummis, MD, Fellowship in the Biomedical Sciences (to A.K.), National Institutes of Health (NIH) TL1TR003169 (to A.K.), NIH UL1TR003167 (to A.K.), NIH F32HL154681 (to A.J.P.), NIH R01HL157949 (to M.P.F.), British Heart Foundation awards RG/17/5/32936 and FS/18/46/33663 (to S.S.) and American Heart Association grant 20CDA35310689 (to C.S.K.). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Confocal microscopy was performed at the Center for Advanced Microscopy, Department of Integrative Biology and Pharmacology at McGovern Medical School, UTHealth. We thank G. Gabbiani and C. Chaponnier from the University of Geneva for their generosity in sharing the SKAfp and SMAfp peptides for this study.
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D.M.M. and C.S.K. designed the study. C.S.K. planned the individual experiments. C.S.K., A.K., S.M., X.y.D., C.K., J.E.E.P., M.S.B.B. and J.C. performed the cellular experiments. A.K. and A.J.P. obtained the sample and analyzed the scRNA-seq on mouse tissue. A.J.P. and M.P.F. obtained the sample and analyzed the scRNA-seq on participant tissue. C.S.K. and A.J.P. obtained the sample and analyzed the ATAC-seq on cultured SMCs. P.G. performed the integrated analysis combining scRNA-seq and ATAC-seq datasets. Y.Z. and X.S. consulted on nuclear actin functions and contributed to the design of experiments. S.S. reprogrammed a participant stem cell line and assisted with the stem cell differentiation protocol. D.M.M. and C.S.K. interpreted the data and drafted the manuscript. D.M.M. and M.P.F. obtained funding for this work.
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Extended data
Extended Data Fig. 1 αSMA localizes to the nucleus concurrently with SMC differentiation.
A) Quantitation of immunoblot in Fig. 1A shows that TGFβ1 stimulation for 48 h increases protein levels of αSMA in both the nucleus and cytosol, while PDGF-BB treatment for 24 h does not affect αSMA nuclear localization (n=3 independent experiments). Significance was assessed by one-way ANOVA followed by Tukey’s multiple comparisons test. B) Quantitation of the latrunculin (LtA) treatment immunoblot shown in Fig. 1C shows that depolymerization of actins by LtA treatment does not affect nuclear localization of actin, supporting that the observed nuclear localization is accurate (n = 4 independent experiments). Significance was assessed by Kruskal-Wallis test with Dunn’s multiple comparisons test. C) Quantitation of the NEPC to SMC differentiation timecourse immunoblot shown in Fig. 1G shows that αSMA levels in both the nucleus and cytosol increase around 15-20 fold during the differentiation. Over the same timecourse, β-actin levels do not dramatically change, and nuclear accumulation is lower than cytosolic (n = 4 independent experiments using 2 different control cell lines). All data are presented as mean ± standard deviation.
Extended Data Fig. 2 Forced nuclear localization of actins does not affect Mkl1 levels or localization.
A,B) Immunostaining of NLS-infected SMCs with Mkl1 antibody (A) shows no change in Mkl1 localization or intensity with α-NLS or β-NLS infection, quantified in (B). n = 14 cells infected with empty vector (EV), 15 cells infected with β-NLS, and 11 cells infected with α-NLS across three independent staining experiments. Significance was assessed by one-way ANOVA with Tukey’s multiple comparisons test. All data are presented as mean ± standard deviation.
Extended Data Fig. 3 Mouse Acta2SMC-R179C/+ smooth muscle cells have decreased nuclear αSMA and are hypodifferentiated.
A) Quantitation of immunoblot in Fig. 4E shows significant and reproducible decreases in accumulation of contractile proteins in the Acta2SMC-R179C/+ cells compared with WT (n = 4 independent experiments). Significance was assessed by two-way ANOVA followed by Tukey’s multiple comparisons test. B) Quantitation of immunoblot in Fig. 4F shows decreased nuclear accumulation, of αSMA in the Acta2SMC-R179C/+ cells compared with WT. β-actin accumulation to the nucleus was variable across experiments (n = 4 independent experiments). Significance was assessed by two-way ANOVA followed by Tukey’s multiple comparisons test. C) Quantitation of immunoblot in Fig. 4G shows that LtA treatment further does moderately decrease nuclear accumulation of β-actin in Acta2SMC-R179C/+ cells but does not significantly affect αSMA nuclear accumulation (n = 3 independent experiments). Significance was assessed by two-way ANOVA followed by Tukey’s multiple comparisons test. D) Co-immunoprecipitation with Brg1 antibody confirms decreased association of both αSMA and β-actin with the Baf chromatin remodeling complex in in Acta2SMC-R179C/+ SMCs which is partially rescued by TGFβ1 treatment (n = 3 independent experiments). All data are presented as mean ± standard deviation.
Extended Data Fig. 4 Differential chromatin accessibility aligns with transcriptional changes in Acta2SMC-R179C/+ SMCs.
A) Distribution of chromatin accessibility peaks around the transcription start sites of nearby genes for peaks with increased accessibility in WT SMCs. B) Distribution of chromatin accessibility peaks around the transcription start sites of nearby genes for peaks with increased accessibility in Acta2SMC-R179C/+ SMCs. C) Visualization of integrated scRNA-seq and ATAC-seq datasets plots the log2FC in gene expression in vivo on the y-axis and the log2FC in chromatin accessibility in vitro on the x-axis. Genes indicated by dots inside the red circle have decreased accessibility and decreased expression in Acta2SMC-R179C/+ SMCs and were analyzed by GO enrichment analysis in Fig. 5H. Genes indicated by dots inside the blue circle have increased accessibility and increased expression in Acta2SMC-R179C/+ SMCs and were analyzed by GO enrichment analysis in Fig. 5H.
Extended Data Fig. 5 Genes with increased expression and accessibility in Acta2SMC-R179C/+ SMCs.
A) Genome browser view for the Klf4 gene shows chromatin accessibility increased in Acta2SMC-R179C/+ SMCs in vitro and transcript levels visualized in UMAP space and quantified shows increased expression in Acta2SMC-R179C/+ SMCs in vivo. B) Genome browser view for the Smad7 gene shows chromatin accessibility increased in Acta2SMC-R179C/+ SMCs in vitro and transcript levels visualized in UMAP space and quantified shows increased expression in Acta2SMC-R179C/+ SMCs in vivo. P values denote results of Wilcoxon rank sum test with Bonferroni correction for multiple comparisons between all ‘SMC 1’ (5,816 cells) and ‘SMC 2’ (3,229 cells) in the scRNAseq dataset. For all violin plots, line depicts median, hinges depict interquartile range, whiskers depict 1.5 interquartile ranges above and below the hinges. C) Quantitative RT-PCR validates shRNA-mediated knockdown of Smad7 in WT SMCs and shows knockdown of Smad7 increases expression of SMC contractile genes. Graph shows three technical replicates, representative of three independent experiments from three distinct lentiviral infections. Significance was assessed by unpaired, two-tailed t-test for each gene. All data are presented as mean ± standard deviation.
Extended Data Fig. 6 Genes with decreased expression and accessibility in Acta2SMC-R179C/+ SMCs.
A) Genome browser view for the Itga1 gene shows chromatin accessibility decreased in Acta2SMC-R179C/+ SMCs in vitro and transcript levels visualized in UMAP space and quantified shows decreased expression in Acta2SMC-R179C/+ SMCs in vivo. B) Genome browser view for the Synpo2 gene shows chromatin accessibility decreased in Acta2SMC-R179C/+ SMCs in vitro and transcript levels visualized in UMAP space and quantified shows decreased expression in Acta2SMC-R179C/+ SMCs in vivo. P values denote results of Wilcoxon rank sum test with Bonferroni correction for multiple comparisons between all ‘SMC 1’ (5,816 cells) and ‘SMC 2’ (3,229 cells) in the scRNAseq dataset. For all violin plots, line depicts median, hinges depict interquartile range, whiskers depict 1.5 interquartile ranges above and below the hinges.
Extended Data Fig. 7 Participant-derived ACTA2 p.Arg179 SMCs are less differentiated than controls.
A) Demographic and genotype information for patient and control lines used in this study. B) Quantitation of immunoblot from Fig. 6A reveals significant decreases in contractile protein accumulation in ACTA2 p.R179C patient SMCs compared with control SMCs (n = 4 independent experiments). Significance was assessed by one-way ANOVA with Sidak’s multiple comparisons test. C-E) Immunoblot showing decreased contractile protein accumulation is a consistent finding across three ACTA2 p.R179 patient lines (C), quantified in (D,E). Graph shows biological replicates- each dot represents one patient or control line. Significance in (D) ( + /- TGFβ1) was assessed by two-way ANOVA with Tukey’s multiple comparisons test. Significance in (E) (no TGFβ1) was assessed by unpaired, two-tailed t-tests per protein. Grey bars/black dots represent control and green bars/dots represent ACTA2 p.R179. All data are presented as mean ± standard deviation.
Extended Data Fig. 8 Participant-derived ACTA2 p.Arg179 SMCs have decreased nuclear αSMA compared with controls.
A) Quantitation of immunoblot from Fig. 6C shows a significant decrease in αSMA nuclear accumulation in patient-derived ACTA2 p.R179C SMCs compared with controls. β-actin accumulation to the nucleus was variable and not significantly altered (n = 3 independent experiments). Significance was assessed by repeated measures one-way ANOVA followed by Tukey’s multiple comparisons test. B,C) Immunoblot showing decreased nuclear accumulation of αSMA is a consistent phenotype across three ACTA2 p.R179 patient lines (B), quantified in (C). Graph shows biological replicates- each dot represents one patient or control line. Significance was assessed by unpaired, two-tailed t-test for each condition (cytosol, nucleus) for each protein. D) Quantitation of immunoblot from Fig. 6D shows a significant increase in cytosolic αSMA and decrease in αSMA nuclear accumulation in patient-derived ACTA2 p.R179 NEPCs compared with controls. β-actin accumulation to the nucleus was not significantly altered (n = 3 independent experiments). Significance was assessed by unpaired, two-tailed t-test for each condition (cytosol, nucleus) for each protein. E) Co-immunoprecipitation with BRG1 antibody confirms decreased association of both αSMA and β-actin with the BAF chromatin remodeling complex in ACTA2 p.R179C SMCs. Grey bars/black dots represent control and green bars/dots represent ACTA2 p.R179. All data are presented as mean ± standard deviation.
Extended Data Fig. 9 Expression of skeletal α-actin can compensate for loss of nuclear αSMA in Acta2-/- cells.
A) Immunostaining for αSMA shows partial disruption of αSMA filaments in SMCs with the ACTA2 p.R179C pathogenic variant. B) Subcellular fractionation immunoblot of Acta2 KO mouse SMCs shows that sarcomeric actin (encoded by ACTA1 and known to be expressed in Acta2 KO SMCs as a compensatory mechanism for loss of αSMA) in these cells can go into the nucleus. C) Quantitative RT-PCR confirms that ACTA2 Crispr-edited iPSC-derived SMCs do not have increased expression of ACTA1. Graph shows three technical replicates, results are representative of three independent experiments. All data are presented as mean ± standard deviation.
Extended Data Fig. 10 Integrated ACTA2 p.R179H and Marfan syndrome (MFS) aortic scRNAseq data.
A) Complete dataset following reciprocal PCA data integration demonstrating representation of all major cell clusters in both datasets. Red arrow indicates SMC cluster selected for downstream analysis. B) Expression plot of MYH11 confirming SMC identity for selected cluster. C) Overlaid UMAP plot for ACTA2 p.R179H and MFS SMCs demonstrating overrepresented sub-populations in ACTA2 patient (black arrows). D) Expression of ‘typical’ SMC modulation markers (FN1, COL1A1) with gradient of expression in both patients. E) Expression of representative altered SMC phenotypic trajectory markers in ACTA2 patient (see Fig. 7I) not activated in MFS SMCs. F) Activation of TGFβ1-responsive gene SERPINE1 is not observed in ACTA2 p.R179H SMCs as compared to MFS.
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Kwartler, C.S., Pedroza, A.J., Kaw, A. et al. Nuclear smooth muscle α-actin participates in vascular smooth muscle cell differentiation. Nat Cardiovasc Res 2, 937–955 (2023). https://doi.org/10.1038/s44161-023-00337-4
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DOI: https://doi.org/10.1038/s44161-023-00337-4
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