Douglas M. Anderson Ph.D.
Assistant Professor, Department of Medicine
Aab Cardiovascular Research Institute (CVRI) - Primary
Department of Pharmacology and Physiology - Secondary
2010 | Ph.D. | Molecular and Cellular Biology | Arizona State University, Tempe, AZ
2003 | B.S., summa cum laude | Biology | Arizona State University, Tempe, AZ
Awards & Honors
Award for Excellence in Postdoctoral Research, UT Southwestern Medical Center, Dallas, TX, 2015
Post-Doctoral Training & Residency
Postdoctoral Fellow, Laboratory of Eric N. Olson, Ph.D., UT Southwestern Medical Center, Dallas, TX 2010
Our lab investigates the regulatory pathways that control striated muscle development and function, and how defects in those pathways can give rise to human disease. The development of striated muscle is controlled by conserved networks of regulatory proteins and noncoding RNAs that coordinate the expression of genes involved in muscle growth, morphogenesis, differentiation and contractility. Our research focuses on the role of muscle-enriched RNA-binding proteins and long noncoding RNAs (lncRNAs) as novel regulators of muscle development and disease. Unexpectedly, we’ve found that many annotated lncRNAs, in fact, encode small functional proteins, called micropeptides, which play important roles in regulating intracellular signaling. By investigating the function of these regulatory proteins and noncoding RNAs, we aim to uncover novel insights into the regulatory mechanisms important for muscle biology. Our lab utilizes and generates a variety of biochemical and cell-based assays and both gain- and loss-of-function mouse models.
Project 1: Micropeptide control of calcium signaling in the cardiovascular system.
We recently discovered a 46 amino acid micropeptide, myoregulin (MLN), concealed within a muscle-specific RNA believed to be non-coding. MLN shares structural and functional similarity with phospholamban (PLN) and sarcolipin (SLN), two cardiac micropeptides that inhibit SERCA, the membrane pump that controls muscle relaxation by regulating calcium uptake into the sarcoplasmic reticulum (SR). MLN similarly interacts with SERCA and impedes calcium uptake into the SR (Figure 1A and B). Since PLN and SLN are expressed predominantly in the adult heart, MLN functions as the dominant regulator of SERCA in adult fast-type skeletal muscles. Consistent with this finding, genetic deletion of MLN in mice resulted in enhanced calcium handling and improved exercise performance.
In addition to the essential role that SERCA plays in regulating striated muscle contractility, SERCA plays an important role in regulating calcium signaling across diverse cell types, which do not express MLN, PLN or SLN. We have subsequently identified two additional transmembrane micropeptides, that we named endoregulin (ELN) and another-regulin (ALN), that overlap with the expression of SERCA isoforms in non-muscle cell types (Figure 1B). ELN overlaps with SERCA3 in endothelial and epithelial cells of vascular and visceral organs and ALN overlaps with the broadly expressed isoform SERCA2b. These findings reveal a general mechanism for the control of calcium handling across diverse cell types by a family of structurally and functionally related micropeptides. Considering the importance of intracellular calcium dynamics for many cellular processes (muscle relaxation, cardiac hypertrophy, smooth muscle relaxation, platelet cell activation, etc.), projects in my lab will focus on the role of these micropeptides in regulating the development and function of the cardiovascular system.
Project 2: Role of lncRNAs in cardiovascular development, function and disease.
Many RNA transcripts identified by deep sequencing are bona fide lncRNAs and do not appear to generate stable proteins. While challenging to study, recent advances in RNA probing techniques have allowed us to elucidate their function in vitro and in vivo. Interestingly, we’ve found that many lncRNA transcripts are located near essential cardiac-specific transcription factors and are required for normal development and survival (Figure 2). Using novel knockout approaches that prematurely stop the transcription of these RNAs, we have been able to assess their roles in vivo. Current projects in our lab include the study of cardiac-enriched lncRNAs and their role in heart development, function and disease.
- Anderson DM*, Makarewich CA*, Anderson KM, Shelton JM, Bezprozvannaya S, Bassel-Duby R and Olson EN. (2016). Widespread control of calcium signaling by a family of SERCA-inhibiting micropeptides. Science Signaling 9: ra119. PMID: 27923914
- Anderson KM, Anderson DM, McAnally JR, Shelton JM, Bassel-Duby R and Olson EN. (2016). Transcription of the non-coding RNA upperhand controls Hand2 expression and heart development. Nature 539: 433-436. PMID: 27783597
- Anderson DM*, Cannavino J*, Li H, Anderson KM, Nelson BR, McAnally JR, Bezprozvannaya S, Liu Y, Lin W, Liu N, Bassel-Duby R and Olson EN. (2016). Severe muscle wasting and denervation in mice lacking the RNA binding protein ZFP106. Proceedings of the National Academy of Sciences USA 113: E4494-4503. PMID: 27418600
- Nelson BR*, Makarewich CA*, Anderson DM, Winders BR, Troupes CD, Wu F, Reese AL, McAnally J, Chen X, Kavalali ET, Cannon SC, Houser SR, Bassel-Duby R and Olson EN. (2016). A micropeptide encoded by a transcript annotated as long noncoding RNA enhances SERCA activity in muscle. Science 351:271-275. PMID: 26816378.
- Carroll KJ, Makarewich CA, McAnally J, Anderson DM, Zentilin L, Liu N, Giacca M, Bassel-Duby R and Olson EN. (2015). A mouse model for adult cardiac-specific gene deletion with CRISPR/Cas9. Proceedings of the National Academy of Sciences USA 113:338-343. PMID: 26719419.
- Anderson DM, Anderson KM, Chang CL, Makarewich CA, Nelson BR, McAnally JR, Kasaragod P, Shelton JM, Liou J, Bassel-Duby R and Olson EN. (2015). A micropeptide encoded by a putative long noncoding RNA regulates muscle performance. Cell 160: 595-606. PMID: 25640239.
- Nelson BR, Anderson DM and Olson EN. (2014). Small open reading frames pack a big punch in cardiac calcium regulation. Circulation Research 114:18-20. PMID: 24385504.
- Nelson BR, Wu F, Liu Y, Anderson DM, McAnally J, Lin W, Cannon SC, Bassel-Duby R and Olson EN. (2013). Skeletal muscle-specific T-tubule protein STAC3 mediates voltage-induced Ca2+ release and contractility. Proceedings of the National Academy of Sciences USA 110:11881-6. PMID: 23818578.
- Rowton M, Ramos P, Anderson DM, Rhee JM, Cunliffe HE and Rawls A. (2013). Regulation of mesenchymal-to-epithelial transition by PARAXIS during somitogenesis. Developmental Dynamics 242:1332-44. PMID: 24038871.
- Anderson DM, George R, Noyes MB, Rowton M, Liu W, Jiang R, Wolfe SA, Wilson-Rawls J and Rawls A. (2012). Characterization of the DNA-binding properties of the Mohawk homeobox transcription factor. Journal of Biological Chemistry. 287:35351-9. PMID: 22923612.
- Burnett LA, Anderson DM, Rawls A, Bieber AL and Chandler DE. 2011. Mouse sperm exhibit chemotaxis to allurin, a truncated member of the cysteine-rich secretory protein family. Developmental Biology 360:318-328. PMID: 22008793.
- Anderson DM, Beres BJ, Wilson-Rawls J and Rawls A. 2009. The homeobox gene Mohawk represses transcription by recruiting the Sin3A/HDAC co-repressor complex. Developmental Dynamics 238:572-580. PMID: 19235719.
- Book chapter: Anderson, DM (Author), Rawls, JA (Author) ,Rhee, JM (Author) . Development of Muscle and Somites. In: Inborn Errors of Development: The Molecular Basis of Clinical Disorders of Morphogenesis. Oxford University Press (2008). ISBN: 9780195306910
- William DA, Saitta B, Gibson JD, Traas J, Markov V, Gonzalez DM, Sewell W, Anderson DM, Pratt SC, Rappaport EF and Kusumi K. 2007. Identification of oscillatory genes in somitogenesis from functional genomic analysis of a human mesenchymal stem cell model. Developmental Biology 305:172-86. PMID: 17362910.
- Anderson DM, Arredondo J, Hahn K, Valente G, Martin JF, Wilson-Rawls J and Rawls A.(2006). Mohawk is a novel homeobox gene expressed in the developing mouse embryo. Developmental Dynamics 235:792-801. PMID: 16408284.