Dr. Heather Miller earned her B.S. in Molecular Biology/ Biotechnology from Clarion University of Pennsylvania in 2003. She went on to earn her Ph.D. in Molecular Genetics and Microbiology from Duke University in the laboratory of Dr. Mariano Garcia-Blanco. Here, she studied the roles of Tat-specific factor 1 (Tat-SF1) in both HIV-1 and human gene expression. To gain more teaching experience, she also completed a Certificate in Teaching College Biology. After defending in 2009, Heather came to NC State as a Teaching Postdoctoral Associate. She has taught multiple biotechnology courses here over the last two and half years and has mentored several undergraduate researchers.
My research interests are in RNA biology, particularly the processes of transcription and splicing. I study how these processes are regulated at the molecular level and how they are functionally coupled. I am investigating a human transcription-splicing factor called Tat specific factor 1 (Tat-SF1). This relatively understudied protein not only functions in both transcription and alternative processing of human genes, but is also a host factor for human immunodeficiency virus (HIV-1).
Transcription and processing in HIV-1
As a retrovirus, HIV-1 contains a single-stranded RNA genome that is reverse-transcribed and integrated into the host cell’s genome. It relies heavily on host cell transcription, processing, and translation machinery to propagate. The virus is remarkable in that it encodes over 40 different mRNAs from a genome consisting of one single, 9kb strand. These mRNA isoforms are generated in part by alternative splicing. Using RNA interference (RNAi), I demonstrated that Tat-SF1 depletion inhibited HIV-1 infectivity, but was not required for HIV-1 to transcribe its genome. Instead, Tat-SF1 depletion altered the ratios of different HIV-1 mRNA isoforms. So, although it seemed clear that Tat-SF1 was indeed utilized by the virus to propagate, the data showed that it was used post-transcriptionally (Miller et al., 2009). The mechanism behind this is still unknown, and could be explained by a role in alternative splicing, altered stability, or export of HIV-1 RNA. Recent work by undergraduate summer researchers aimed to elucidate which of these roles Tat-SF1 plays. Furthermore, since the protein contains two RNA recognition motifs, we are investigating a possible direct or indirect interaction with the HIV-1 genome.
Transcription and processing in humans
Although the literature on Tat-SF1 has centered on this protein’s role in HIV-1 gene expression, I also set out to determine the cellular target genes of Tat-SF1. I have studied the human transcriptome using specialized microarrays that report on overall mRNA levels (changes in synthesis and/or degradation) as well as alternatively processed mRNA isoform levels (Miller et al, 2011). This large study provided vast amounts of information on Tat-SF1-regulated processes and identified over 500 human genes whose mRNA levels are altered by Tat-SF1 depletion. Gene ontology analyses pointed to many interesting pathways with evidence of Tat-SF1 intervention, including insulin-signaling, the cell cycle, and nucleic acid metabolism. Putative binding motifs were also identified within the thousands of genes that were analyzed. Research under my mentorship will continue to analyze this microarray data to gain further insight into how Tat-SF1 functions in human gene expression.
(* denotes undergraduates as co-authors):
Carson, S., Miller, H.B., and Witherow, D.S. (2012) Molecular Biology Techniques: A Classroom Laboratory Manual, 3rd ed., Burlington, MA: Elsevier Academic Press. Elsevier
Miller, H.B., Carson, S.B. (2012) A contemporary, laboratory-intensive course on mRNA transcription and processing. Biochemistry and Molecular Biology Education. 40, 88-89. [PubMed]
Miller, H.B., Witherow, D.S., and Carson, S.B. (2012) Student learning outcomes and attitudes when biotechnology lab partners are of different academic levels. CBE-Life Science Education (in press).
Stolarchuk, C.*, Dent, M.*, and Miller, H.B. (2012) Human Tat specific factor 1 modulates HIV-1 RNA levels. The Journal of Young Investigators (in press).
Miller, H.B., Robinson, T.J., Gordan, R.A., Hartemink, A.J., and Garcia-Blanco, M.A. (2011) Identification of Tat-SF1 cellular targets by exon array analysis reveals dual roles in transcription and splicing. RNA. 17, 665-674. PubMed
Miller, H.B., Saunders, K.O., Tomaras, G.D., Garcia-Blanco, M.A. (2009) Tat-SF1 is not required for Tat transactivation but does regulate the relative levels of unspliced and spliced HIV-1 RNAs. PLoS One. 4(5): e5710. doi: 10.1371/journal.pone.0005710. PubMed
Seth, P., Miller, H.B., Lasda, E.L., Pearson, J.L., Garcia-Blanco, M.A. (2008) Identification of an intronic splicing enhancer essential for the inclusion of FGFR2 exon IIIc. Journal of Biological Chemistry. 283, 10058-67. PubMed
Taylor, J.L., Bennett, H.N., Snyder, B.A., Moore, P.S., Chang, Y. (2005) Transcriptional analysis of latent and inducible Kaposi's sarcoma-associated herpesvirus transcripts in the K4 to K7 region. Journal of Virology. 79, 15099-106. PubMed
In her spare time, Heather enjoys spending time with her two dogs, Dustin and Daisy. She has played in several sand volleyball leagues in the Triangle and loves being outdoors. Heather especially likes visiting the beaches of North Carolina with her husband.
Heather has accepted a position as Assistant Professor of Biochemistry at High Point University, starting August 2012!!!