Scot J. Matkovich, Ph.D.

Assistant Professor
Internal Medicine
Cardiology

General Program

  • 314-362-7555

  • 8086

  • CSRB-NTA Room 825

  • smatkovi@WUSTL.EDU

  • microRNA, functional genomics, RNA sequencing, diabetes, pancreas, cardiomyopathy, heart, translational regulation

  • MicroRNA targeting in diabetes and cardiovascular disease

Research Abstract:

Building upon established techniques that utilize cell and animal models, together with RNA-sequencing and bioinformatic analyses, we seek to better understand the role of microRNAs (miRs) in regulating insulin secretion, the development of peripheral tissue insulin resistance, and the role of miRs in hypertrophied and diabetic hearts.
miRs have emerged in recent years as a fundamental part of the mammalian transcriptome that comprise critical regulators of mRNA translation. These endogenous, non-coding RNAs are expressed in distinct patterns during development and are highly regulated in disease states. To best explore their biology, their in vivo messenger RNA (mRNA) targets need to be known. However, accurate prediction of the mRNA targets that will be subject to regulation by a particular miR is complicated: 1) miR regulation of mammalian mRNAs only requires partial Watson-Crick base-pairing, 2) miR-mRNA pairing is only likely to occur at mRNA sites free of complex secondary structure, and 3) the degree of miR suppression will depend on the expression level of both the miR and its mRNA target, and in this respect miRs expressed in more than one cell type may well have different preferred targets in different cells.
Many groups are working to explore the therapeutic potential of miRs, since artificial molecules able to inhibit the normal activity of miRs (antagomiRs) can be readily introduced in vivo. Understanding the mRNA networks regulated by miRs in cell- and tissue-specific contexts will be critical to effective use of such therapies, and requires unbiased investigation of potential mRNA targets. A key component of our research strategy is to use RISC-sequencing, a novel next-generation sequencing technique that examines the flux of mRNAs between the transcriptome and the RISC-associated RNA pool and identifies mRNAs that are targeted to the RISC. In combination with miR and translationally competent mRNA expression analyses using deep sequencing, and both sequence-based and structure-based algorithms for predicting miR-binding sites, we aim to discover new regulatory events mediated by miRs in cardiovascular disease and diabetes.

I have ongoing collaborations both inside and outside Washington University, some in the field of miRs, and others employing both coding and noncoding transcriptome analysis in disease models using RNA-sequencing.

Selected Publications:

Matkovich SJ*, Grubb DR, McMullen JR, Woodcock EA. Chronic contractile dysfunction without hypertrophy does not provoke a compensatory transcriptional response in mouse hearts. PLoS One 2016;11:e0158317. * corresponding author

Matkovich SJ*, Dorn GW II, Grossenheider TC, Hecker PA. Cardiac disease status dictates functional mRNA targeting profiles of individual microRNAs. Circ Cardiovasc Genet. 2015;8:774-84. * corresponding author

Gong G, Song M, Csordas G, Kelly DP, Matkovich SJ, Dorn GW II. Parkin-mediated mitophagy directs perinatal cardiac metabolic maturation in mice. Science 2015;350:aad2459.

Jacovetti C, Matkovich SJ, Rodriguez-Trejo A, Guay C, Regazzi R. Postnatal β-cell maturation is associated with islet-specific microRNA changes induced by nutrient shifts at weaning. Nat Commun. 2015;6:8084.

Holley CL, Li MW, Scruggs BS, Matkovich SJ, Ory DS, Schaffer JE. Cytosolic accumulation of small nucleolar RNAs (snoRNAs) is dynamically regulated by NADPH oxidase. J Biol Chem. 2015;290:11741-8.

Matkovich SJ*, Edwards JR, Grossenheider TC, de Guzman Strong C, Dorn GW, 2nd* (2014). Epigenetic coordination of embryonic heart transcription by dynamically regulated long noncoding RNAs. Proc Natl Acad Sci USA. 111:12264-12269. * co-corresponding authors

Hu Y*, Matkovich SJ*, Hecker PA, Zhang Y, Dorn GW, II (2012). Epitranscriptional orchestration of genetic reprogramming is an emergent property of stress-regulated cardiac microRNAs. Proc Natl Acad Sci USA. 109:19864-9. * equal contribution

Matkovich SJ*, Hu Y, Eschenbacher WH, Dorn LE, Dorn GW, 2nd*. (2012). Direct and indirect involvement of microRNA-499 in clinical and experimental cardiomyopathy. Circ Res. 111:521-31. * co-corresponding authors

Dorn GW, 2nd, Matkovich SJ, Eschenbacher WH, Zhang Y. (2012). A human 3` miR-499 mutation alters cardiac mRNA targeting and function. Circ Res. 110(7):958-67.

Matkovich SJ, Wang W, Tu Y, Eschenbacher WH, Dorn LE, Condorelli G, Diwan A, Nerbonne JM, Dorn GW, 2nd. (2010). MicroRNA-133a protects against myocardial fibrosis and modulates electrical repolarization without affecting hypertrophy in pressure-overloaded adult hearts. Circ Res. 106:166-175.

Last Updated: 9/6/2016 9:26:38 AM

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