Biochemistry Graduate Program

Lab

Biology Bldg. 327
Hundley Lab website

Awards

• Outstanding Research Mentor, Indiana University School of Medicine-Bloomington, 2022
• Bodil Schmidt-Nielson Fund, 2021
• Salisbury Cove Research Foundation Award, 2021
• Trustee Teaching Award, IUSM
• Bergmann Prize, US-Israel Binational Science Foundation
• American Cancer Society Research Scholar Award
• Helen Hay Whitney Postdoctoral Fellowship, 2006-2009

Research

RNA plays a central role in the expression of genes in all organisms. Understanding how the cell decides which RNAs to express at a given time is a fundamental question in biology. Work in the Hundley lab is centered on a conserved family of proteins, called ADARs, which can affect gene expression through both binding RNA and modifying specific nucleotides (referred to as RNA editing). Both RNA editing and RNA binding are essential functions of human ADARs and dysregulated in over 35 human diseases.

Deciphering the fundamentals of RNA recognition by ADARs: As ADARs can effectively rewrite the genetic code, the recognition of target RNAs must be tightly controlled. Work in the Hundley lab is focused on understanding the in vivo rules that govern ADAR interactions with target RNAs. We use a number of biochemical and genomic techniques to profile both RNAs bound by ADARs as well as those edited by ADARs. Recently, we have also become intrigued by how ADAR recognition of target RNAs can be influenced by changes in the environment to dynamically regulate gene expression and RNA editing.

Regulation of RNA editing: In many diseases and across human tissues during normal development, ADAR expression does not directly correlate with the extent of editing at individual adenosines. Furthermore, spatiotemporal editing patterns vary for individual genes, suggesting that specific factors bind target mRNAs to regulate editing in vivo. To date, we have demonstrated that the editing-deficient members of the ADAR family can influence substrate recognition and editing in both the model organism C. elegans and human glioblastoma (brain cancer) cell lines. Our ongoing work is focused on identifying additional proteins that regulate editing (particularly in a tissue-specific manner) as well as understanding how subcellular localization and other cellular processes (ex. transcription, RNA modification by other enzymes, etc.) alter ADAR function.

Connecting tissue-specific mechanisms of gene regulation to organismal physiology: ADARs play important roles in diversifying the transcriptome. We take advantage of the genetic amenability of the model organism C. elegans to not only monitor ADARs effects on different tissues, but also dissect the molecular mechanisms of how ADARs edit and/or bind RNA uniquely in specific tissues and connect that information to impacts on organismal behavior and/or survival. We have done extensive work on how ADARs bind and edit transcripts in the nervous system and revealed mechanisms that regulate sensing of chemicals and survival to hypoxia (low oxygen). We are also actively exploring how ADARs sense and respond to pathogen infection and impacts of ADARs on other tissues, including the germline.

Oncogenic roles of ADARs: Defects in editing are known to result in misexpression of both tumor suppressors and oncogenes in many cancer types. Our work has focused on the regulation of editing in glioblastoma, a malignant form of brain cancer. We have shown that ADAR3, a deaminase-deficient member of the ADAR family, is a key regulator of RNA editing and expression of ADAR3 is elevated in tissue isolated from glioblastoma patients. Most recently, we have demonstrated that ADAR3 expression results in a gene expression program that provides glioblastoma cells with resistance to irradiation and temozolomide, two standard-of-care therapies. Going forward, we want to understand how ADAR3 expression and activity are regulated and the molecular targets of ADAR3 in glioblastoma.

Research Areas

Chromatin, Chromosomes, and Genome Integrity
Developmental Mechanisms and Regulation in Eukaryotic Systems
Genomics and Bioinformatics

Publications