Serum Response Factor-dependent MicroRNAs Regulate Gastrointestinal Smooth Muscle Cell Phenotypes

Overview

Journal Gastroenterology

Specialty Gastroenterology

Date 2011 Apr 9

PMID 21473868

Citations 38

Authors

Chanjae Park

Grant W Hennig

Kenton M Sanders

Jonathan H Cho

William J Hatton

Doug Redelman

Jong Kun Park

Sean M Ward

Joseph M Miano

Wei Yan

Seungil Ro

Affiliations

Soon will be listed here.

Abstract

Background & Aims: Smooth muscle cells (SMCs) change phenotypes under various pathophysiological conditions. These changes are largely controlled by the serum response factor (SRF), a transcription factor that binds to CC (A/T)6 GG (CArG) boxes in SM contractile genes. MicroRNAs (miRNA) regulate transitions among SMC phenotypes. The SMC miRNA transcriptome (SMC miRNAome) and its regulation by SRF have not been determined.

Methods: We performed massively parallel sequencing to identify gastrointestinal (GI) SMC miRNA transcriptomes in mice and humans. SMC miRNA transcriptomes were mapped to identify all CArG boxes, which were confirmed by SRF knockdown and microarrays. Quantitative polymerase chain reaction was used to identify SMC-phenotypic miRNAs in differentiated and proliferating SMCs. Bioinformatics and target validation analysis showed regulation of SMC phenotype by SRF-dependent, SMC-phenotype miRNAs.

Results: We cloned and identified GI miRNA transcriptomes using genome-wide analyses of mouse and human cells. The SM miRNAome consisted of hundreds of unique miRNAs that were highly conserved among both species. We mapped miRNAs CArG boxes and found that many had an SRF-dependent signature in the SM miRNAome. The SM miRNAs CArG boxes had several distinct features. We also identified approximately 100 SMC-phenotypic miRNAs that were induced in differentiated or proliferative SMC phenotypes. We showed that SRF-dependent, SMC-phenotypic miRNAs bind and regulate Srf and its cofactors, myocadin (Myocd) and member of ETS oncogene family Elk1.

Conclusions: The GI SMC phenotypes are controlled by SRF-dependent, SMC-phenotypic miRNAs that regulate expression of SRF, MYOCD, and ELK1.

Citing Articles

SRF SUMOylation modulates smooth muscle phenotypic switch and vascular remodeling.

Xu Y, Zhang H, Chen Y, Pober J, Zhou M, Zhou J Nat Commun. 2024; 15(1):6919.

PMID: 39134547 PMC: 11319592. DOI: 10.1038/s41467-024-51350-5.

miR-10b-5p rescues leaky gut linked with gastrointestinal dysmotility and diabetes.

Zogg H, Singh R, Ha S, Wang Z, Jin B, Ha M United European Gastroenterol J. 2023; 11(8):750-766.

PMID: 37723933 PMC: 10576606. DOI: 10.1002/ueg2.12463.

Functional Implications and Clinical Potential of MicroRNAs in Irritable Bowel Syndrome: A Concise Review.

Bravo-Vazquez L, Medina-Rios I, Marquez-Gallardo L, Reyes-Munoz J, Serrano-Cano F, Pathak S Dig Dis Sci. 2022; 68(1):38-53.

PMID: 35507132 PMC: 9066399. DOI: 10.1007/s10620-022-07516-6.

Role of microRNAs in Disorders of Gut-Brain Interactions: Clinical Insights and Therapeutic Alternatives.

Singh R, Zogg H, Ro S J Pers Med. 2021; 11(10).

PMID: 34683162 PMC: 8541612. DOI: 10.3390/jpm11101021.

Micro-organic basis of functional gastrointestinal (GI) disorders: Role of microRNAs in GI pacemaking cells.

Singh R, Wei L, Ghoshal U Indian J Gastroenterol. 2021; 40(2):102-110.

PMID: 33738768 DOI: 10.1007/s12664-021-01159-7.

References

Xie C, Huang H, Sun X, Guo Y, Hamblin M, Ritchie R . MicroRNA-1 regulates smooth muscle cell differentiation by repressing Kruppel-like factor 4. Stem Cells Dev. 2010; 20(2):205-10. PMC: 3128754. DOI: 10.1089/scd.2010.0283. View

Miano J . Serum response factor: toggling between disparate programs of gene expression. J Mol Cell Cardiol. 2003; 35(6):577-93. DOI: 10.1016/s0022-2828(03)00110-x. View

Rothman A, Kulik T, Taubman M, Berk B, Smith C, Nadal-Ginard B . Development and characterization of a cloned rat pulmonary arterial smooth muscle cell line that maintains differentiated properties through multiple subcultures. Circulation. 1992; 86(6):1977-86. DOI: 10.1161/01.cir.86.6.1977. View

Kent W, Sugnet C, Furey T, Roskin K, Pringle T, Zahler A . The human genome browser at UCSC. Genome Res. 2002; 12(6):996-1006. PMC: 186604. DOI: 10.1101/gr.229102. View

Lewis B, Burge C, Bartel D . Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell. 2005; 120(1):15-20. DOI: 10.1016/j.cell.2004.12.035. View

Chow N, Bell R, Deane R, Streb J, Chen J, Brooks A . Serum response factor and myocardin mediate arterial hypercontractility and cerebral blood flow dysregulation in Alzheimer's phenotype. Proc Natl Acad Sci U S A. 2007; 104(3):823-8. PMC: 1783398. DOI: 10.1073/pnas.0608251104. View

Cordes K, Sheehy N, White M, Berry E, Morton S, Muth A . miR-145 and miR-143 regulate smooth muscle cell fate and plasticity. Nature. 2009; 460(7256):705-10. PMC: 2769203. DOI: 10.1038/nature08195. View

Nakamura K, Maki N, Trinh A, Trask H, Gui J, Tomlinson C . miRNAs in newt lens regeneration: specific control of proliferation and evidence for miRNA networking. PLoS One. 2010; 5(8):e12058. PMC: 2920319. DOI: 10.1371/journal.pone.0012058. View

Krek A, Grun D, Poy M, Wolf R, Rosenberg L, Epstein E . Combinatorial microRNA target predictions. Nat Genet. 2005; 37(5):495-500. DOI: 10.1038/ng1536. View

10.

Miano J, Cserjesi P, Ligon K, Periasamy M, Olson E . Smooth muscle myosin heavy chain exclusively marks the smooth muscle lineage during mouse embryogenesis. Circ Res. 1994; 75(5):803-12. DOI: 10.1161/01.res.75.5.803. View

11.

Boettger T, Beetz N, Kostin S, Schneider J, Kruger M, Hein L . Acquisition of the contractile phenotype by murine arterial smooth muscle cells depends on the Mir143/145 gene cluster. J Clin Invest. 2009; 119(9):2634-47. PMC: 2735940. DOI: 10.1172/JCI38864. View

12.

Xin H, Rishniw M, Ji G, Kotlikoff M . Smooth muscle expression of Cre recombinase and eGFP in transgenic mice. Physiol Genomics. 2002; 10(3):211-5. DOI: 10.1152/physiolgenomics.00054.2002. View

13.

Niu Z, Li A, Zhang S, Schwartz R . Serum response factor micromanaging cardiogenesis. Curr Opin Cell Biol. 2007; 19(6):618-27. PMC: 2735128. DOI: 10.1016/j.ceb.2007.09.013. View

14.

Davis B, Hilyard A, Nguyen P, Lagna G, Hata A . Induction of microRNA-221 by platelet-derived growth factor signaling is critical for modulation of vascular smooth muscle phenotype. J Biol Chem. 2008; 284(6):3728-38. PMC: 2635044. DOI: 10.1074/jbc.M808788200. View

15.

Cooper S, Trinklein N, Nguyen L, Myers R . Serum response factor binding sites differ in three human cell types. Genome Res. 2007; 17(2):136-44. PMC: 1781345. DOI: 10.1101/gr.5875007. View

16.

Xin M, Small E, Sutherland L, Qi X, McAnally J, Plato C . MicroRNAs miR-143 and miR-145 modulate cytoskeletal dynamics and responsiveness of smooth muscle cells to injury. Genes Dev. 2009; 23(18):2166-78. PMC: 2751981. DOI: 10.1101/gad.1842409. View

17.

Ro S, Yan W . Small RNA cloning. Methods Mol Biol. 2010; 629:273-85. PMC: 3052395. DOI: 10.1007/978-1-60761-657-3_17. View

18.

Ji R, Cheng Y, Yue J, Yang J, Liu X, Chen H . MicroRNA expression signature and antisense-mediated depletion reveal an essential role of MicroRNA in vascular neointimal lesion formation. Circ Res. 2007; 100(11):1579-88. DOI: 10.1161/CIRCRESAHA.106.141986. View

19.

Liu N, Bezprozvannaya S, Williams A, Qi X, Richardson J, Bassel-Duby R . microRNA-133a regulates cardiomyocyte proliferation and suppresses smooth muscle gene expression in the heart. Genes Dev. 2008; 22(23):3242-54. PMC: 2600761. DOI: 10.1101/gad.1738708. View

20.

Owens G, Kumar M, Wamhoff B . Molecular regulation of vascular smooth muscle cell differentiation in development and disease. Physiol Rev. 2004; 84(3):767-801. DOI: 10.1152/physrev.00041.2003. View