Welcome to the Hundley Lab at Indiana University

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.

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.

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.

The last week of July wrapped up with three poster sessions---the Indy worm meeting where undergrad Olivia Abraham made her poster deput, the IU-Bloomington Office of Engaged Learning poster session where undergrad Amanda Lawson presented her summer research on ADAR3, and last but not least, the Indiana Medical Student Program for Research and Scholarship poster session where (nearly) MS2 students Obi Nwosu and Anna Dudley presented their summer research and Obi took home an honorable mention prize for his poster! Thanks to all in the lab for a great summer of research-

Heather attended the 2018 Post-transcriptional Gene Regulation Gordon Conference and presented a poster on the lab's work on a new mode of substrate recognition for the ADAR enzymes.

The lab is awarded a Ralph W. and Grace M. Showalter Trust grant to gain additional preliminary data for a new project on RNA-mediated regulation of innate immune gene expression and pathogen resistance!

Heather chairs the Noncoding RNA session at the 2018 C. elegans Small RNA, Pathogenesis, Aging and Metabolism meeting!

Heather presented the lab's work on neural editing and chemotaxis at the C. elegans Neuro 2018 meeting.

The Hundley lab welcomes undergraduate Amanda Lawson to the lab for her summer Women in STEM LLC project!

Graduate student Suba Rajendren led off the talks in the RNA Editing and Modification session at the 2018 RNA Society meeting. Great job telling your exciting story on ADAR substrate RNA recognition!

GCDB graduate student, Reshma Kurup joins the Hundley lab--welcome Reshma!

Graduate student Suba Rajendren wins a travel award from RNA Society to attend the annual RNA Society meeting in Berkeley, California. Congrats Suba!

Heather had a wonderful visit to Case Western Reserve University and presenting the lab's work at the RNA Center.

Suba Rajendren is awarded the Doane and Eunice Dahl Wright fellowship for 2018. Congrats Suba!

Heather visits Purdue Cancer Center to talk about the lab's recent work.

Heather presents the labs' work on RNA editing in the worm nervous system to the Department of Biology at Ball State University.

The Hundley lab makes the short journey to Indianapolis to attend the 2017 Rustbelt RNA meeting.

Congrats to Suba for her honorable recognition poster prize! Great job Suba!

Suba and Eimile present their research at the 2017 IUSM Biochemistry and Molecular Biology Research Day

Congrats to Pranathi and Eimile on the publication of their Methods in Molecular Biology Chapter on Methods to Detect A-to-I RNA Editing--This is a great resource for anyone attempting to examine A-to-I RNA editing of cellular RNAs!

Sarah's exciting paper on neural cell RNA-seq was accepted at eLIFE! This work wouldn't have been possible without a great collaboration with the Yeo lab and many Hundley lab members past and present (Aidan, Suba, Pranathi, Mike and Emily). Congrats to all!

Eimile and Heather receive a pilot grant to identify more ADAR3 regulated targets in glioblastoma!

Khorana Scholar, Britya Ghosh, finished her summer research project on RNA Editing in glioblastoma.

Pranathi completes her Masters Research in Biotechnology by completing the construction of 24 RNA-seq libraries! We will miss you Pranathi-

Undergraduate Haider Al-Awadi defends his undergraduate thesis research in the Chemistry Department

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!

Congrats to grad student Eimile Oakes and undergraduate student Ashley Anderson on publication of their study of the role of ADAR3 in glioblastoma in JBC!

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!