4524A Thomas Hall

Campus Box 7615
North Carolina State University
Raleigh, NC 27695
919.513.0528 (voice)
919.515.7867 (fax)
mike_sikes@ncsu.edu


Courses

MB 441 : Immunology


Publications

 

Michael Sikes
Associate Professor

Developmental Immunology


Research Brief

V(D)J schematic The human genome contains no more than 30,000-50,000 different genes. Despite this limitation, our lymphocytes recognize an almost limitless array of different pathogens by expressing more than 1 billion different antigen receptors. Since it would be impossible for any one cell to have so many antigen receptor genes, we have evolved a process of gene rearrangement, known as V(D)J recombination, that assembles antigen receptor genes from large pools of coding segments in developing lymphocytes. Each new assembly of coding segments results in an antigen receptor that recognizes a single antigen. Although this process of gene rearrangement is a very powerful mechanism for generating a large diversity of finished genes from a limited amount of starting material, the ability to recombine DNA sequences is inherently dangerous. In fact, many cancers begin when uncontrolled DNA rearrangement alters the expression of a specific growth factor gene. To safeguard against inappropriate rearrangements, V(D)J recombination is tightly regulated during lymphocyte development such that genes encoding the T cell receptor (TCR) are only rearranged in developing T cells, and developing B cells only rearrange genes that encode the immunoglobulin (Ig) molecules.

Evidence suggests that the patterning of V(D)J recombination is regulated by precisely timed changes in the accessibility of individual coding segments to the recombinase proteins. My research focuses on dissecting the tissue- and development-specific regulation of V(D)J recombination using complementary approaches in isolated cell lines and transgenic mice. To isolate the changes associated with recombinational accessibility, I have engineered a novel recombinase-inducible cell system in which the expression of Green Fluorescent Protein (GFP)-tagged recombinase can be easily monitored using fluorescent microscopy or FACS.

By analyzing the rearrangement of modified substrates in this cell line, we are beginning to define the minimal control elements critical to each stage of antigen receptor gene assembly. Biochemical and molecular analyses allow us to decipher the mechanism by which each control element alters recombinational accessibility. To date, these studies have defined a clear role for transcriptional promoters and enhancers in regulating both antigen receptor transcription and recombination. Insights gained from these initial cell-based studies will guide targeted mutagenesis of endogenous antigen receptor genes in the mouse, and allow us to test emerging models of recombinational control in the context of normal lymphocyte development.


Biographical Sketch

Mike was born and raised in Bryant Arkansas, a once tiny town outside of Little Rock famous for its proximity to the Reynolds and Alcoa bauxite mines (aluminum comes from bauxite ore). From the time he was a small child, Mike pursued two the passions of music and science and dreamed becoming a famous drummer/biologist. Upon graduation from Bryant High School in 1986, Mike opted to forgo his musical plans to follow his two older brothers into the biology program at the University of Arkansas at Little Rock, and worked closely with his oldest brother, Robert Sikes, studying the food habits of the nine-banded armadillo. Despite the undeniable allure of the armadillo, classes in cell and developmental biology convinced Mike that his real scientific interests were grounded in the complex gene regulation systems that drive the development of multicellular organisms.

After college, Mike earned his doctorate degree in the Cell Biology Department at Baylor College of Medicine in Houston, Texas. His graduate research focused on the characterization of novel methods for delivering gene therapeutics in live animals. While in Houston, Mike met his future wife, Suzanne Sessoms, and upon graduation in 1995, followed Suzanne to Vanderbilt University, where he took a postdoctoral position with Dr. Eugene Oltz in the Department of Microbiology and Immunology. Working with Dr. Oltz as a fellow (four years), and later a junior faculty member (3 years), Mike s research focused on understanding the mechanisms that drive a unique form of gene regulation, termed V(D)J recombination, which allows lymphocytes to defend against literally billions of different pathogens. In January of 2003, Mike was appointed as an assistant professor in the Department of Microbiology at North Carolina State University. His current research is focused on determining the complex pathways by which chromatin surrounding individual DNA sequences is modified to facilitate or inhibit V(D)J recombination during lymphocyte development. Mike and Suzanne maintain a love for the outdoors, and Mike still thinks of starting another band.