Dr. Joseph Miano grew up in Chili, a suburb of Rochester, New York. He graduated from Gates-Chili High School in 1980 and, following one year of playing junior hockey in Western New York and Southern Ontario, he attended SUNY Cortland and graduated in 1986 with dual degrees in Biology and Physical Education (Exercise Science). His undergraduate research, performed in 1983-86 under the tutelage of David Berger and Jim Starzec, investigated the effects of psychological stress or voluntary exercise on fatty streak formation in the aorta of spontaneously hypertensive rats. His PhD research, in Experimental Pathology at New York Medical College under the mentorship of Michael Stemerman, involved the identification of genes rapidly turned on following experimental balloon angioplasty. His post-doctoral training was done with Eric Olson at the MD Anderson Cancer Center in Houston Texas where he cloned and characterized several smooth muscle-restricted promoters and initiated the study of retinoids in the blood vessel wall. He was recruited to the University of Rochester in 1999 following a three year appointment at the Medical College of Wisconsin where he developed a passion for the human genome. A major research aim in the Miano Lab has been to decipher the small snippets of codes in our genome that dictate how genes involved in cardiovascular disease are either turned up or down. Much like a thermostat controlling the heat in a home, cells normally have exquisite control over the level of gene activity. Diseases of the heart and blood vessels occur when this 'geneostat' control runs awry. Thus, identifying and understanding how certain genetic codes control genes turning on and off is a foundation for developing novel methods of predicting and perhaps treating various diseases of the body. Dr. Miano's lab was among the first wave of labs in 2013 to exploit the revolutionary CRISPR genome editing technology for purposes of altering the mouse genome and, within a year, the lab generated the first CRISPR animal model carrying subtle mutations in a control element that turns on a gene (Cnn1). To date, Dr. Miano has published over 100 research papers that focus on the control of gene expression in smooth muscle cells of the blood vessel wall. He previously served as Associate Editor of ATVB and Consulting Editor of Circulation Research. He is a Fellow of the American Heart Association and a member of the Vascular Cell and Molecular Biology Study Section at NIH.
Links of interest for the lay public:
Research Gate https://www.researchgate.net/home
Dr. Joseph M. Miano received his Ph.D. in Experimental Pathology from New York Medical College in 1992. His post-doctoral training was done in Eric Olson's laboratory at the University of Texas M.D. Anderson Cancer Center where he cloned and characterized several smooth muscle-restricted promoters and initiated the study of retinoids in the vessel wall. Prior to his appointment at the U of R, Dr. Miano was an Assistant Professor in the Department of Physiology at the Medical College of Wisconsin where his genomics interests were developed and cultivated through collaborative work with Howard Jacob's lab. Dr. Miano served as an editorial board member for several journals and was Associate Editor of ATVB and a Consulting Editor for Circulation Research. He is a Fellow of the American Heart Association and a member of the Vascular Cell and Molecular Biology Study Section at NIH.
The human genome is replete with functional information, including millions of transcription factor binding sites (TFBS) that bind some 1400 transcription factors and several classes of non-coding RNA genes, particularly the rapidly growing class of long non-coding RNA (lncRNA). Thus, the long-held notion that the human genome is made up largely of "junk DNA" has been debunked and a new era has emerged to elucidate the functionality of the non-protein coding genome which comprises 98% of our blueprint of life.
Though the ENCODE Consortium and other big genome projects have been a magnificent kick-start for this new endeavor, much remains to be learned across the ~250 distinct cell types that make up the human body, especially under stress conditions that simulate disease processes. Accordingly, research in the Miano Lab is focused broadly on the vascular smooth muscle cell (VSMC) and how this cell type's differentiation program is controlled through both key TFBS and lncRNAs. Much of the work revolves around a DNA-binding transcription factor called serum response factor (SRF), its TFBS known as a CArG box, and an SRF cofactor called Myocardin (MYOCD), which his lab first showed to be a potent stimulus for the VSMC differentiation program. Current funded projects involve the study of a protein-coding gene (AKAP12A) that is a direct target of the SRF-Myocardin switch; the regulation of MYOCD and its role in vascular diseases; and the elucidation of the CArGome (all functional CArG boxes in the genome).
The latter project is also aimed to gain insight into CArG-SNPs that may be linked to human diseases. Since the vast majority of the >3.6 million CArG boxes punctuating the human genome fall in intergenic or intronic sequence space where "pervasive transcription" is known to occur, the lab initiated several screens to define known and novel lncRNAs in human VSMC. A major focus of the lab is obtaining functional insight into a novel lncRNA (SENCR) enriched in vascular cells as well as a number of known and novel lncRNAs that are regulated by SRF and/or MYOCD. The project pipeline involves a systematic series of experiments to define expression of lncRNAs in human tissues and cell lines; elucidating full length transcripts by RACE; defining spatial localization of lncRNAs by RNA-FISH; ascertaining potential regulatory sequences within lncRNAs (e.g., microRNA binding site, TFBS, etc); defining lncRNA promoters and the signaling molecules that converge upon regulatory sequences therein; defining altered transcriptomes by RNA-seq following loss-of-function with dicer substrate siRNAs directed to several regions of a lncRNA; and lncRNA interaction studies with other RNAs or proteins to begin understanding mechanistic aspects of lncRNAs. The Miano Lab utilizes state-of-the-art tools in genetics (e.g., HDR-mediated genome editing with CRISPR-Cas9), genomics, bioinformatics, and molecular biology to elucidate regulatory element and lncRNA biology in experimental and clinically relevant settings.
Leimgruber C, Quintar AA, Peinetti N, Scalerandi MV, Nicola JP, Miano JM, Maldonado CA. "Testosterone Rescues the De-Differentiation of Smooth Muscle Cells Through Serum Response Factor/Myocardin." Journal of cellular physiology.. 2017 Oct 0; 232(10):2806-2817. Epub 2017 Apr 10.
Musunuru K, Lagor WR, Miano JM. "What Do We Really Think About Human Germline Genome Editing, and What Does It Mean for Medicine?" Circulation. Cardiovascular genetics.. 2017 Oct 0; 10(5)
Halim D, Wilson MP, Oliver D, Brosens E, Verheij JB, Han Y, Nanda V, Lyu Q, Doukas M, Stoop H, Brouwer RW, van IJcken WF, Slivano OJ, Burns AJ, Christie CK, de Mesy Bentley KL, Brooks AS, Tibboel D, Xu S, Jin ZG, Djuwantono T, Yan W, Alves MM, Hofstra RM, Miano JM. "Loss of LMOD1 impairs smooth muscle cytocontractility and causes megacystis microcolon intestinal hypoperistalsis syndrome in humans and mice." Proceedings of the National Academy of Sciences of the United States of America.. 2017 Mar 28; 114(13):E2739-E2747. Epub 2017 Mar 14.
Books & Chapters
Chapter Title: Muscle: Fundamental Biology and Mechanisms of Disease
Book Title: Vascular smooth muscle cell phenotypic adaptation
Author List: Miano JM
Edited By: Hill, J.A. and Olson, E.N
Published By: Academic Press2012
Chapter Title: Retinoids and interferons as antiangiogenic cancer drugs
Book Title: Antiangiogenic Agents in Cancer
Author List: Clifford, J.L., Miano, J.M., and Lippman, S.M
Edited By: Teicher, B.A.
Published By: Humana Press1999
Chapter Title: Radiation hybrid (RH) mapping of human smooth muscle-restricted genes.
Book Title: Molecular Biology of Vascular Disease.
Author List: Miano, J.M.*, Garcia, E. and Krahe, R.
Edited By: Baker, A.H.
Published By: Humana Press1999
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