Welcome to the Hundley Lab at Indiana University
Studying RNA Editing Regulation and Consequences on Gene Expression from C. elegans to humans
RNA Editing and ADARs
All cells of the human body contain the same genetic material, but have distinct functions and phenotypes due to variations in the messenger RNAs (and in turn the proteins) they express. Sequence alterations that change the genome-encoded information present in RNAs provide a powerful way to diversify the transcripts expressed in an organism’s cells over time. In addition to splicing, a major means to create diversity in RNA sequences is through enzymatic modification. RNA modifications are programmed in all organisms and influence many biological processes including metabolism, gene regulation, neuronal function, and immunity. Diverse classes of enzymes catalyze more than 100 different types of modifications in specific target RNAs. Next generation sequencing has allowed cataloging of these modifications and indicates RNA modification is altered in many diseases. However, a fundamental understanding of the molecular determinants that dictate when, where, and to what extent RNA editing occurs is lacking. In the Hundley lab, we are trying to address these fundamental questions and specifically focus on the ADAR family of enzymes. ADARs are essential in mammals and required for proper neuronal function in all animals. Consistent with this, ADARs are highly expressed in the nervous system of both C. elegans (worms) and humans. ADARs bind to double-stranded RNA, including small RNA precursors, long non-coding RNAs and double-stranded regions of mRNA, and convert adenosine (A) to inosine (I), a process commonly referred to as RNA editing.
A-to-I Editing and Impacts of Editing on Gene Expression
The most prevalent type of RNA editing in mRNA is the deamination of adenosine, with over 100 million editing events identified in the human transcriptome. Despite the fact that RNA editing is pervasive, it is still a poorly understood process. Deamination of adenosine (A) results in inosine (I), which has similar base-pairing properties as guanosine. Due to these differences in base-pairing, A-to-I editing can alter the amino acid encoded by a codon, modify splice sites and affect the interaction of the RNA molecule with itself or other RNAs, such as miRNAs and siRNAs. Thus, A-to-I editing in both coding and noncoding regions of mRNA can be biologically significant. Editing at individual sites is often less than 100%. Therefore, RNA editing generates multiple transcripts from a single genomic locus and is a major contributor to proteomic diversity and the control of gene expression. In addition, rather than serving as a static control of gene expression, A-to-I RNA editing provides a means to dynamically re-wire the genetic code during development and in a cell-type specific manner. Alterations in the levels of unedited to edited transcripts has been observed in a spectrum of central nervous system disorders (autism, stroke, epilepsy), neuropsychiatric diseases (chronic depression, bipolar disorder) neurodegenerative diseases (amyotrophic lateral sclerosis (ALS) and Alzheimer’s disease), and many types of cancer, including brain tumors (glioblastomas). However the editing levels do not directly correlate to the expression of ADAR proteins in many diseases, implying that other mechanisms to regulate RNA editing exist. In collaboration with the Yeo lab at UCSD, we have recently utilized next generation sequencing and molecular biology approaches to identify a major regulator of noncoding editing in C. elegans. Current efforts in the Hundley lab are focused on dissecting the regulatory mechanism and determining the conservation of this regulatory protein in human cells.
Regulation of A-to-I Editing
It has been proposed that modulating editing levels could serve as an efficient therapeutic to treat both cancers and many neuopathological diseases. However, as two editing enzymes are responsible for editing thousands of human genes, overexpression of ADARs could result in unwanted effects. Therefore, developing approaches that enhance editing of specific targets are likely better therapeutic strategies. However, it is not known how to affect such editing modulation. One long-term goal of the Hundley lab is to understand how the activity of ADARs can be modulated at specific places in RNA. In this regards, a major focus of the lab is to identify cellular factors and molecular mechanisms that regulate RNA editing. Rather than trying to identify disease-specific regulators, to get at these regulatory pathways, we are focusing on the fact that in an organism the extent of editing varies during development and between cell types. Interestingly, editing levels do not directly correlate with levels of the substrate mRNA or RNA editing enzymes. Thus, there are cellular factors that contribute to the spatiotemporal regulation of A-to-I editing. As ADARs target newly synthesized RNA, the speed of transcription and splicing can affect overall editing levels. In addition, other RNA binding proteins that bind to the same targets as ADARs can both positively and negatively impact editing levels. Current efforts in the lab are aimed at determining ADAR targets in the C. elegans nervous system. In addition, in collaboration with the lab of Ayelet Lamm, we are focusing on identifying developmental regulators of editing in C. elegans.
Current Lab Members
Assistant Professor of Biochemistry and Molecular Biology, Medical Sciences Program, Indiana University School of Medicine
B.S. Chemistry, Eastern Illinois University
Ph.D. Biomolecular Chemistry, University of Wisconsin-Madison
Postdoctoral Fellowship, HHMI/University of Utah
Sarah Deffit, Ph.D.
Ph.D. Immunology, Indiana University School of Medicine
B.S. Biology and Chemistry, University of Colorado-Pueblo
Genome, Cell and Developmental Biology Graduate Student
B.S. Molecular and Cellular Biology, Cedarville University
Genome, Cell and Developmental Biology Graduate Student
B.Sc Molecular Biology and Biochemistry, University of Colombo, Sri Lanka
Biotechnology Master's Student
B.S. Biotechnology, Indiana University
B.S. Biology, Indiana University
Robert and Marjorie Mann Scholarship
STEM Summer Scholar
Former Lab Members
If you are missing from this list, please contact Heather and give her an update on where you are! She would love to hear from you.
Mike Washburn, Ph.D. (former graduate student) – currently a Research Scientist at Archer DX, Boulder CO
Emily Wheeler (former undergraduate student) – currently a graduate student at UCSD
Ellen Hallberg (former undergraduate student) – currently a medical student at St. Louis University
Jingyi Chen (former summer undergraduate exchange student) – currently a graduate student at The Scripps Research Institute
Amber Thomas (former graduate student) – currently a Lab Manager at Tempus
Nick McCrory (former volunteer researcher) – currently a graduate student at NC State
Brittany Levy (former undergraduate student) – currently a medical student at University of Cincinnati
Ashanti Matlock (former undergraduate student) – currently a graduate student at Ohio State University
Hundley Lab Publications
Oakes E, Anderson, Cohen-Gadol A, Hundley HA (2017) Adenosine Deaminase that Acts on RNA 3 (ADAR3) Binding to Glutamate Receptor Subunit B Pre-mRNA Inhibits RNA Editing in Glioblastoma, JBC, 2017 Mar 10; 292(10):4326-4335.
Washburn MC and Hundley HA (2016) Trans and cis factors affecting A-to-I RNA editing efficiency of a noncoding editing target in C. elegans, RNA, 2016 Feb 25.
Deffit SN and Hundley HA (2016) To edit or not to edit: Regulation of ADAR editing specificity and efficiency, WIREs RNA, Jan-Feb;7(1):113-27. doi:10.1002/wrna.1319.
Washburn MC and Hundley HA (2016) Controlling the editor: the many roles of RNA binding proteins in regulating A-to-I RNA editing, Advances in Experimental Medicine and Biology, volume 907: RNA Processing, 2016;907:189-213. doi:10.1007/978-3-319-29073-7_8.
Wheeler EC, Washburn MC, Major F, Rusch DB, Hundley HA (2015) Noncoding regions of C. elegans mRNA undergo selective adenosine to inosine deamination and contain a small number of editing sites per transcript, RNA Biology, 2015 Feb;12(2):162-74. doi:10.1080/15476286.2015.1017220.
Washburn MC, Kakaradov B, Sundararaman B, Wheeler E, Hoon S, Yeo GW, and Hundley HA (2014) The dsRBP and inactive editor, ADR-1, utilizes dsRNA binding to regulate A-to-I RNA editing across the C. elegans transcriptome, Cell Reports, Feb 27;6(4):599-607.
Hundley HA (2013) Regulation of gene expression through inosine-containing UTRs, In RNA Editing: Current Research and Future Trends, S. Maas, ed. (Horizon Press)
Bass B, Hundley H, Li JB, Peng Z, Pickrell J, Xiao XG, Yang L. (2012) The difficult calls in RNA editing, Nature Biotechnology, Dec 7;30(12):1207-9.
Capshew CR, Dusenbury KL and Hundley HA (2012) Inverted Alu dsRNA structures do not affect localization but alter translation of human mRNAs independent of RNA editing, Nucleic Acids Research (NAR), 2012 Sep 1;40(17):8637-45.
Hundley HA and Bass BL (2010) RNA editing in double-stranded UTRs and other noncoding RNA sequences, TiBS, 2010 Jul;35(7):377-83.
Before Coming to IU
Hundley HA, Krauchuk AA, Bass BL (2008) C. elegans and H. sapiens mRNAs with edited 3’ UTRs are present on polysomes, RNA, 2008 Oct;14(10):2050-2060.
Bass BL, Hellwig S, Hundley HA. (2005) A nuclear RNA is cut out for Translation, Cell, 2005 Oct21;123(2):181-183.
Rauch T, Hundley HA, Pfund C, Wegrzyn RD, Walter W, Kramer G, Kim SY, Craig EA, Deuerling E (2005) Dissecting functional similarities of ribosome-associated chaperones from Saccharomyces cerevisiae and Escherichia coli, Molecular Microbiology, 2005 Jul;57(2):357-65.
Hundley HA, Walter W, Bairstow S, Craig, EA. (2005) Human Mpp11 J-protein: Ribosome-tethered Molecular Chaperones Are Ubiquitous, Science, 2005 May 13; 308(5724):1032-4.
Craig EA, Eisenman HE, Hundley HA. (2003) Ribosome-tethered molecular chaperones: the first line of defense against protein misfolding? Current Opinion in Microbiology 2003 Apr; 6(2):157-62.
Hundley H, Eisenman H, Walter W, Evans T, Hotokezaka Y, Wiedmann M, Craig E. (2002) The in vivo function of the ribosome-associated Hsp70, Ssz1, does not require its putative peptide-binding domain. Proc Natl Acad Sci 2002 Apr 2;99(7):4203-8.
Take a look and enjoy!
Master's student Pranathi Vadlamani wins first place in the poster competition at the Hutton Honors College Research Symposium. Congrats Pranathi!
Graduate students Suba and Eimile receive a Women in Science Travel Award from the IU Provost's Office to support their trip to the 2017 RNA Editing Gordon Research Conference in Ventura, CA.
Suba was also selected to give an oral presentation at that 2017 RNA Editing Gordon Research Seminar.
Congrats Suba and Eimile!
Biochemistry Graduate Student, Justin Peterson joins the Hundley lab. Welcome Justin!
Dr. Sarah Deffit was awarded an NIH F32 NRSA Postdoctoral Fellowship for her studies in the Hundley lab. Congrats Sarah!
Thanks to Pranathi, Suba, Haider and Eimile on helping to introduce our Brownie troop visitors to science in the Hundley lab (and liquid nitrogen!)
The Hundley lab enjoyed a journey to the 2016 Rustbelt RNA meeting in Cleveland Ohio with postdoc, Sarah Deffit, presenting her exciting neural editing data in an oral presentation and Suba, Eimile, Pranathi and Haider presenting posters.
Graduate student Suba Rajendren passes her prelim- Congrats Suba!
Heather is awarded the Bergmann Prize from the US-Israel Binational Science Foundation. In addition, the Lamm and Hundley labs are awarded a joint research grant from the US-Israel Binational Science Foundation to study the developmental regulation of editing in C. elegans.
STEM Summer Scholar Emilia Oben, a junior undergraduate from Jackson State University, joins the Hundley lab for a summer research experience. Welcome Emilia!
Emilie presents her thesis research at the Simon Cancer Research Day in Indianapolis.
Sarah is awarded a CTSI Postdoc Challenge grant to perform pilot studies at the IUB-Flow Cytometry Core and the IUB- Center for Genomics and Bioinformatics. Congrats Sarah!
Haider is awarded the Robert and Marjorie Mann Scholarship to continue his undergraduate project in the lab this summer. Congrats Haider!
Ashley is awarded the STEM Summer Scholars Institute scholarship to continue her undergraduate project in the lab this summer. Congrats Ashley!
IUB-undergraduate, Pranathi Vadlamani joins the lab to get a head start on her biotechnology master’s project. Welcome Pranathi!
Emilie presents her thesis research at the American Society for Cell Biology meeting in San Diego.
Dr. Washburn defends his thesis research and graduates from Indiana University. Congrats Mike!