Mission Statement: Our goal is to discover the principles and mechanisms that control expression of genes, with the benefit to society that this knowledge will enhance our understanding of the causes of disease and advance therapeutic strategies to correct deleterious gene expression.
Summary: Our goal is to understand how messenger RNAs are regulated. Regulation of translation, degradation and localization of mRNAs contributes to the enormous dynamic range of protein expression. Misregulation can cause disease, developmental defects, or death. Sequence specific RNA-binding factors, both protein and small RNAs, play a central role in mRNA regulation. Our research focuses on two important classes of regulatory proteins: PUF proteins and deadenylases
PUF proteins: We study PUF proteins, a family of regulators that bind certain mRNAs with exquisite specificity and repress their expression. PUF proteins have diverse biological roles in development, stem cell proliferation, and fertility. PUFs also control neurological processes including motor neuron function, learning and memory formation. Our goals are to identify the mRNAs that PUF proteins regulate and determine the molecular mechanism of repression. To accomplish this, we use a combination of biochemistry, genetics, bioinformatics, transcriptomics, and high throughput assays in multiple organisms including Humans and Drosophila. This research has direct impact on genetic mechanisms that control development, neurological function, and cancer.
Deadenylases: Ribonucleases play critical roles in regulating mRNAs. Deadenylases are specialized ribonucleases that degrade the poly(Adenosine) tails of mRNAs. Regulation of poly(A) tail length is emerging as a critical control point for translation and mRNA degradation in a wide variety of biological contexts. Indeed, we found that specific deadenylases play a central role in PUF regulation. PUF proteins enhance deadenylation of the mRNAs they bind by directly recruiting the deadenylase enzyme complex.
The versatility of regulation by deadenylation is greatly expanded in higher eukaryotes through diversification of deadenylases. For instance, humans possess twelve deadenylase orthologs. Genetic analysis indicates that each deadenylase controls unique biological functions including cell division and growth, metabolism, development, bone morphogenesis and anti-viral responses. We are exploring the questions: how many active deadenylases are there, do their catalytic activities differ, which mRNAs do they act upon, and how are their activities controlled?
National Institutes of Health 1R01GM105707
American Cancer Society Research Scholar Grant
- Elizabeth Abshire - Graduate Student, American Heart Predoctoral Fellow, co-mentored with Raymond Trievel
- Brian Alzua - Graduate Student
- Rene Arvola - Graduate Student, NSF Graduate Research Fellow
- Rebecca Haugen - Graduate Student
- Kelsey Hughes, Ph.D. – Postdoctoral Scientist
- Isioma Enwerem, Ph.D. - Postdoctoral Scientist
Weidmann CA, Qiu C, Arvola RM, Lou TF, Killingsworth J, Campbell ZT, Tanaka Hall TM, Goldstrohm AC. 2016. Drosophila Nanos acts as a molecular clamp that modulates the RNA-binding and repression activities of Pumilio. Elife. 2016 Aug 2;5. pii: e17096. doi: 10.7554/eLife.17096. PMID: 274826
Tzu-Fang Lou, Chase Weidmann, Jordan Killingsworth, Traci Hall, Aaron Goldstrohm, and Zachary Campbell. Integrated analysis of RNA-binding protein complexes using in vitro selection and high-throughput sequencing and sequence specificity landscapes (SEQRS). Methods. Protein-RNA: Structure Function and Recognition. Editors: Yael Mandel and Gabriele Varani. 2016. In Press
Kearse MG, Green KM, Krans A, Rodriguez CM, Linsalata AE, Goldstrohm AC, Todd PK. (2016). CGG Repeat-Associated Non-AUG Translation Utilizes a Cap-Dependent Scanning Mechanism of Initiation to Produce Toxic Proteins. Mol Cell. S1097-2765(16)00178-7 PMID: 27
Rene Arvola, Elizabeth Abshire, Jen Bohn and Aaron Goldstrohm. Post-transcriptional mechanisms of gene regulation. (2015) Post-transcriptional Regulation of Endocrine Function. Editors: Aaron Goldstrohm and K.M.J. Menon. Springer, Philadelphia, USA.
Chase Weidmann, Nathan Raynard, Nathan Blewett, Jamie Van Etten, Aaron Goldstrohm. (2014) The RNA binding domain of Pumilio antagonizes poly-adenosine binding protein and accelerates deadenylation. RNA. 20:1298-1319. http://rnajournal.cshlp.org/content/early/2014/06/18/rna.046029.114.abst...
Joel Hrit, Nathan Raynard, Jamie Van Etten, Kamya Sankar, Adam Petterson, and Aaron C. Goldstrohm. (2014) In Vitro Analysis of RNA Degradation Catalyzed by Deadenylase Enzymes. Methods in Molecular Biology. 1125:325-39.
Jamie Van Etten, Trista Schagat, and Aaron Goldstrohm. (2013) A Guide to Design and Optimization of Reporter Assays for 3' Untranslated Region Mediated Regulation of Mammalian Messenger RNAs. Methods. 63:110-118. http://www.sciencedirect.com/science/article/pii/S1046202313001266
Jamie Van Etten, Trista Schagat, Joel Hrit, Chase Weidmann, Justin Brumbaugh, Joshua Coon, and Aaron Goldstrohm. (2012) Human Pumilio proteins recruit multiple deadenylases to efficiently repress messenger RNAs. Journal of Biological Chemistry. 287, 36370-36383
PMID: 22955276 http://www.jbc.org/content/early/2012/09/06/jbc.M112.373522.abstract
- Most read JBC RNA paper
Nathan Blewett and Aaron Goldstrohm. (2012) A Eukaryotic Translation Initiation Factor 4E-Binding Protein Promotes mRNA Decapping and is Required for PUF Repression. Molecular and Cellular Biology. 32: 4181-4194 PMID: 22890846 http://mcb.asm.org/content/32/20/4181.full
Chase Weidmann and Aaron Goldstrohm. (2012) Drosophila Pumilio protein contains multiple autonomous repression domains that regulate mRNAs independently of Nanos and Brain Tumor. Molecular and Cellular Biology. 32(2):527-40
Nathan Blewett, Jeff Coller and Aaron Goldstrohm. (2011) A quantitative assay for measuring mRNA decapping by splinted ligation reverse transcription polymerase chain reaction: qSL-RT-PCR. RNA. 17(3):535-43 PMID:21220548 http://rnajournal.cshlp.org/content/early/2011/01/10/rna.2436411
Nayoung Suh, Sarah L. Crittenden*, Aaron Goldstrohm*, Brad Hook, Beth Thompson, Marvin Wickens and Judith Kimble. (2009) FBF and its control of gld-1 expression in the C. elegans germline. Genetics. (* coauthors) PMID: 19221201 http://www.genetics.org/cgi/content/full/181/4/1249
Aaron Goldstrohm and Marvin Wickens. (2008) Multifunctional deadenylase complexes diversify mRNA control. Nature Reviews Molecular Cell Biology. 9, 337-344. PMID: 18334997 http://www.nature.com/nrm/journal/v9/n4/full/nrm2370.html
Aaron Goldstrohm, Brad Hook and Marvin Wickens. (2008) Regulated deadenylation in vitro. Methods in Enzymology. 448:77-106. PMID: 19111172 http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B7CV2-4V6YK6M-B...
Brad Hook, Aaron Goldstrohm, Daniel Seay, and Marvin Wickens. (2007) Two yeast PUF proteins negatively regulate a single mRNA. Journal of Biological Chemistry. 282, 15430-15438.
PMID: 17389596 http://www.jbc.org/content/282/21/15430.long
Aaron Goldstrohm, Daniel Seay, Brad Hook, and Marvin Wickens. (2007) PUF protein mediated deadenylation is catalyzed by Ccr4p. Journal of Biological Chemistry. 228, 109-114.
PMID: 17090538 http://www.jbc.org/content/282/1/109.long
Aaron Goldstrohm, Brad Hook, Daniel Seay, and Marvin Wickens. (2006) PUF proteins bind Pop2p to regulate mRNAs. Nature Structural and Molecular Biology. 13, 533-539.
PMID: 16715093 http://www.nature.com/nsmb/journal/v13/n6/abs/nsmb1100.html
- Commentary: R. Wharton and A. Aggarwal. (2006) mRNA regulation by PUF domain proteins. 2006. Science STKE. Sept. 20.
Miguel Sánchez Alvarez*, Aaron Goldstrohm*, Mariano Garcia-Blanco, and Carlos Suñé. (2006) The human transcription elongation factor CA150 localizes to splicing factor-rich nuclear speckles and assembles transcription and splicing components into complexes through its amino and carboxyl regions. Molecular and Cellular Biology. 26, 4998-5014. (*coauthors)
PMID: 16782886 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1489151/?tool=pubmed
Marvin Wickens and Aaron Goldstrohm. (2003) A Place to Die, a Place to Sleep. Science. 300, 753-755. PMID: 12730589 http://www.sciencemag.org/cgi/content/full/300/5620/753
Aaron Goldstrohm, Todd Albrecht, Carlos Suñé, Mark Bedford, and Mariano Garcia-Blanco. (2001) The human transcription elongation factor CA150 interacts with RNA Polymerase II and the pre-mRNA splicing factor SF1. Molecular and Cellular Biology. 21. 7617-7628.
PMID: 11604498 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC99933/?tool=pubmed
Aaron Goldstrohm, Arno Greenleaf, and Mariano Garcia-Blanco. (2001) Co-transcriptional Splicing of Pre-messenger RNAs: Considerations for the Mechanism of Alternative Splicing. Gene. 277, 31-47. PMID: 11602343 http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T39-445G6X8-3...
Carlos Suñé, Aaron Goldstrohm*, Junmin Peng, David Price, and Mariano Garcia-Blanco. (2000) An in vitro transcription system that recapitulates EIAV Tat-mediated inhibition of HIV-1 Tat activity demonstrates a role for P-TEFb and associated proteins in the mechanism of Tat activation. Virology. 274, 356-366. (* coauthors)
PMID: 10964778 http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WXR-45BCFG2-6...
Sherry Carty, Aaron Goldstrohm, Carlos Suñé, Mariano Garcia-Blanco, and Arno Greenleaf. (2000) Protein-interaction modules that organize nuclear function: FF domains of CA150 bind the phosphor-CTD of RNA polymerase II. Proceedings of the National Academy of Sciences. 97, 9015-902.
PMID: 10908677 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC16813/?tool=pubmed
Albert Chen, Sara Wong, Gabriel Martinez-Santibanez, Angelina Londono-Joshi, Paula Wishart, Aaron Goldstrohm. Cold E-mails and Hot Coffee: Take action on your career. Science Careers, June 18, 2015. http://sciencecareers.sciencemag.org/career_magazine/previous_issues/articles/2015_06_18/caredit.a1500157
Albert Chen, Sara Wong, Gabriel Martinez-Santibanez, Angelina Londono-Joshi, Paula Wishart, Aaron Goldstrohm. Cold E-mails and Hot Coffee: Offer Value to Build Your Network From Zero. Science Careers, June 26, 2015. http://sciencecareers.sciencemag.org/career_magazine/previous_issues/articles/2015_06_25/caredit.a1500163
Sara Wong, Albert Chen, Gabriel Martinez-Santibanez, Angelina Londono-Joshi, Paula Wishart, Aaron Goldstrohm. Cold E-mails and Hot Coffee: Build Skills with the Informational Interview. Science Careers, July 2, 2015 http://sciencecareers.sciencemag.org/career_magazine/previous_issues/articles/2015_07_02/caredit.a1500168
Gabriel Martinez-Santibanez, Albert Chen, Sara Wong, Angelina Londono-Joshi, Paula Wishart, Aaron Goldstrohm. Cold E-mails and Hot Coffee: Skill Building and Implementation on Campus. Science Careers, July 15, 2015 http://sciencecareers.sciencemag.org/career_magazine/previous_issues/articles/2015_07_15/caredit.a1500179
For a complete list of PubMed publications, click HERE
Goldstrohm Lab Alumni
- Joel Hrit, Biochemistry 2012, Honors Thesis - now Graduate Student, Univ. of California San Francisco
- Kamya Sankar, Biochemistry 2010, Honors Thesis - now Medical Student, Wayne State Univ.
- Adam Petterson, Biochemistry 2010, Univ. Chicago - now employed by Illumina
- Kelly Compton, UROP Student 2013
- Nathan Raynard, M.S., Graduate Student 2011-2014, Genetics Training Program
- Nathan Blewett, Ph.D., Graduate Student 2008-2013, CMB Training Program - now Postdoctoral Scientist at NIH
- Isabel Georges - Undergraduate Student 2013
- Jamie Van Etten, Ph.D., Graduate Student 2010-2013 - now Postdoctoral Scientist at University of Minnesota
- Paul Del Rizzo, Ph.D., Postdoctoral Fellow 2013-2014, co-mentored with Dr. Raymond Trievel – now a senior scientist at Cayman Chemical.
- Chase Weidmann, Ph.D., Graduate Student 2010-2015, Genetics Training Program – now a Postdoctoral Fellow at Univ. of North Carolina, Chapel Hill
- Brittany Bowman, Ph.D., Postdoctoral Fellow 2014-2015 – now a Postdoctoral Fellow at Univ. of North Carolina, Chapel Hill
- Jennifer Bohn - Graduate Student, Univ. of Michigan
- Michael Kearse, Ph.D. - Kirschstein NRSA Postdoctoral Fellow, co-mentored with Dr. Peter Todd - now postdoctoral fellow at Univ. of Pennsylvania
- Jordan Killingsworth - Undergraduate Student
- Thishan DeSilva – Undergraduate Student 2015, now veterinary student at Ohio State University
- May Tsoi - Research Lab Technician at Univ. of Michigan