Heather Hundley Lab
Current Hundley Lab Members:
Heather A. Hundley, Ph.D.- Principal Investigator (click here to view Dr. Hundley’s faculty webpage)
Mike C. Washburn- Genome, Cell and Developmental Biology Ph.D. student
Eimile Oakes- Genome, Cell and Developmental Biology Ph.D. student
Ellen Hallberg- Undergraduate researcher, Biology Honors Thesis
Current Research Interests:
Active research projects ongoing in my lab are focused on understanding the biological impact of double-stranded RNA and RNA editing on post-transcriptional regulation of gene expression in both normal and cancerous cells. We use a combination of biochemistry, genomics/genetics and molecular biology in both the model organism Caenorhabditis elegans (microscopic worms) and human cell lines to address our questions.
Proper control of gene expression is critical for the normal development of all organisms. Errors in regulating mRNA (post-transcriptional gene expression) account for over 20% of all human genetic diseases, including many types of cancer. Post-transcriptional gene regulation is governed by the interactions of trans-acting factors with cis-acting elements, which are typically found within the noncoding or untranslated regions (UTRs) of mRNA. Our lab is interested in understanding how a family of proteins called ADARs recognize and modifies double-stranded regions within UTRs to regulate gene expression.
ADARs are highly expressed in the nervous system of both worms and humans. ADARs bind to double-stranded RNA (dsRNA) and convert adenosine (A) to inosine (I), a process called RNA editing. Current estimates range from over 400,000 to 1 million A-to-I editing events in noncoding regions of the human transcriptome. Global hypoediting of these events has been reported in many neuropathological diseases, including epilepsy, schizophrenia, amyotrophic lateral sclerosis, and many types of cancer, including glioblastomas (brain tumors). However the levels of the ADAR proteins are not altered in disease, implying that other mechanisms to regulate ADAR-mediated RNA editing exist. 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 lab are focused on dissecting the regulatory mechanism and determining the conservation of this regulatory protein in human cells.
In addition to RNA editing, our lab is interested in how both ADARs and dsRNA elements affect post-transcriptional gene regulation. We have previously shown that C. elegans ADR-1 regulates translation of neuronal mRNAs in an editing independent manner. Furthermore, our work has provided the first data that double-stranded structures within UTRs affect translation of human mRNAs in many cancer cell lines and the C. elegans nervous system. Our current goal is to dissect the mechanisms that both ADR-1 and double-stranded RNA structures utilize to repress translation in neurons, by both determining co-factors required for the translational repression and identifying the endogenous neuronal mRNAs regulated by this mechanism.
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, 2014 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. (2013) http://www.horizonpress.com/rna-editing
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 can alter translation efficiency of human mRNAs independent of RNA editing, Nuc. Acids Res. , 2012 Sep 1;40(17):8637-8645.
Hundley HA and Bass BL (2010) RNA editing in double-stranded UTRs and other noncoding RNA sequences, TIBS, 2010 Jul;35(7):377-83.
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. (Science Express 2005 Mar 31).
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.