Alyssa R. Summers
Associate Professor of Biology,
Co-Chair of Biochemistry &
Director of Health Professions Program
B.A., Lawrence University; Ph.D., Vanderbilt University
Molecular Cell Biology, Molecular Genetics, Epigenetics, Genomics
RESEARCH & SCHOLARSHIP
My lab focuses on understanding how transcriptional networks regulate cell fates, tissue development and cancer.
In particular, we study how a chromatin modifying enzyme, called Hdac3, can regulate gene expression patterns that impact cell function.
To do this we use several mouse model systems that knock-out Hdac3 in specific tissues. In this lab we evaluate the role of Hdac3 in two biological systems: the mammary gland and the thymus.
Breast cancer is a complex disease that arises from both genetic and epigenetic alterations. Currently treatments involving histone deacetylase inhibitors (HDI) have emerged as a viable treatment options, particularly when combined with other systemic therapies. We aim to more fully elucidate the specific role that HDACs play in regulating breast cancer cell function during tumor progression. Using a conditional knock-out mouse model we have removed Hdac3 from the mammary gland and induced tumorigenesis using the viral gene polyoma middle T-antigen. Additionally, we use various pan-HDIs (such as SAHA and Depsipeptide) and a specific Hdac 3 inhibitor to evaluate cell motility, proliferation and death in a panel of breast cancer cell lines.
1.Mammary Gland Development: This project aims to determine the biological role of Hdac3 in mammary gland development from birth through lactation and involution. Due to the use of HDI in the treatment of cancer, as well as neurological disorders, it is imperative to understand the biological role of Hdac3 on normal cell function.
2.Breast Cancer Initiation and Progression: This project utilizes a mouse model and cell culture to examine the role that Hdac3 plays in tumor formation and progression.
T-CELL DEVELOPMENT PROJECT
Histone Deacetylase Complex 3 (Hdac3) is an epigenetic modifier that negatively regulates gene expression through the removal of acetyl groups from histone proteins. Due to the lethality of a total knock-out of this protein, we constructed a conditional knock-out mouse model that selectively removes Hdac3 in the thymus. Previous analysis in our lab showed that Hdac3 knock-out at an early stage of thymocyte development greatly reduced the number of functional peripheral T-cells. The majority of thymocytes became blocked in the immature Double Positive (DP) stage of development with limited expression of TCR, suggesting a crucial role for Hdac3 in T-cell maturation and function. Further analysis using Microarrays suggested a role for GIMAP proteins in this process, as 4 GIMAP genes were differentially expressed in the Hdac3 null thymoctyes. We are continuing to analyze the role of Hdac3 in T-cell development by examining GIMAPs and VDJ recombination of TCR alpha and beta genes.
1.T-cell regulation by GIMAP proteins: This projects focuses of the development and function of T-cells. GIMAPs were identified as potential genes regulated by Hdac3. We aim to determine the transcriptional role that Hdac3 plays in GIMAP expression and their functional consequences.
2.T-cell VDJ rearrangement and chromatin remodeling impact on TCR repertoire diversity: This project involves examining the function of Hdac3 in chromatin remodeling and how this impacts VDJ recombination and TCR (T-cell Receptor) expression. Efficient VDJ recombination impacts TCR diversity. The more diverse range of TCRs expressed on T-cells the better off we are at fighting off new pathogens, thus we aim to elucidate the role of Hdac3 in immune function.
Class 2012: Mary Emily Christensen, Logan Miller, and Laura Bownes
Class 2013: Carmen Rinio and Taylor Stavely
Class 2014: Nick Klus and Sarah Brown
Class 2015: Sydney Philpott, Andy Streiff, and Angelica DeFreitas
PUBLICATIONS and PRESENTATIONS
Summers AR, Stengel KR, Zhao Y, Klus N, Kaiser JF, Joyce S, Hiebert SW. Hdac3 is required for efficient passaged through ISP stage of thymocyte development. (in prep.)
Brown S, DeFreitas A, Philpott S, Summers AR. The role of Hdac3 in breast cancer cell function. (2014) Keystone Conference: Cancer Epigenetics
Summers AR, Fischer MA, Stengel KR, Zhao Y, Kaiser JF, Wells CE, Hunt A, Bhaskara S, Luzwick JW, Sampathi S, Chen X, Thompson MA, Cortez D, Hiebert SW. Hdac3 is essential for DNA replication in hematopoietic cells. Journal of Clinic Investigation (2013) V123 (7): 3112-23.
Nick K, Kaiser JF, Hiebert SW, Summers AR. Hdac3 is required for efficient selection of double positive thymocytes during T-cell development (2012) Keystone Conference: Chromatin Dynamics and Epigenetic Mechanisms
Bhaskara S, Knutson SK, Jiang G, Chandrasekharan MB, Wilson AJ, Zheng s, Yenamandra A, Locke K, Yuan J, Summers AR, Washington K, Zhou Z, Sun Z, Xia F, Khabele D, Hiebert SW. Hdac3 is essential for maintenance of chromatin structure and genome stability. Cancer Cell (2010) V18(5): 436-447.
Summers AR, Brown KA, Aakre ME, Arteaga C, Pietenpol JA, Moses HL, Cheng N. Epidermal Growth Factor Receptor plays a significant role in mediating Hepatocyte Growth Factor biological responses in mammary epithelial cells. Cancer Biology and Therapy (2007) V6(4): 561-570.
Summers AR, Law BL, Moses HL. Chapter: Transforming Growth Factor ß and Cancer, Cytokines in the Genesis and Treatment of Cancer. Edited by M. Caligiuri and M. Lotze. New Jersey: Humana Press Inc, 2007.