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Indiana University Bloomington

Heather HundleyHeather A. Hundley

Assistant Professor, Medical Science

Office: Jordan Hall 213

Phone: 812/855-0675

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Education

Ph.D., University of Wisconsin, 2005
Helen Hay Whitney Postdoctoral Fellow, University of Utah, 2005-2009

Research

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, 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.

One long-term goal of the Hundley lab is to understand how the activity of ADARs can be modulated at specific places in RNA. 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. In addition to identifying disease-specific regulators such as we recently did for glioblastoma (brain tumor), 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, dissecting the regulatory mechanism of specific RNA binding proteins and determining the conservation of this regulation in human cells.

We use a combination of biochemistry, genomics, and molecular and cellular biology in both worm and human systems to understand how RNA editing is regulated and the consequences of editing on both normal and cancer gene expression programs.

Representative 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.

  • One of the top 10 Accessed Articles in WIREs RNA for 2016

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 and Hundley HA (in press) Controlling the editor: the many roles of RNA binding proteins in regulating A-to-I RNA editing, in RNA processing: disease and genome-wide probing, G. Yeo ed. (Springer Press)

Washburn MC, Kakaradov B, Sundararaman B, Wheeler E, Hoon S, Yeo GW, 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, 2014 Feb 4; pii: S2211-1247(14)00028-X

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, 2012 Dec 7;30(12):1207-9.

Capshew CR, Dusenbury KL and Hundley HA (2012) Inverted Alu dsRNA structures do not affect localization but can alter translation efficiency of human mRNAs independent of RNA editing, Nucleic Acids Res., 2012 Sep 1;40(17):8637-8645.

Hundley HA and Bass BL (2010) ADAR editing in double-stranded UTRs and other noncoding RNA sequences, TIBS, 2010 Jul;35(7):377-383.

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.

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. (Science Express 2005 Mar 31).

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.