DOI

10.17077/etd.xyrjbbq9

Document Type

Dissertation

Date of Degree

Fall 2010

Degree Name

PhD (Doctor of Philosophy)

Degree In

Immunology

First Advisor

Rothman, Paul B.

First Committee Member

Colgan, John D.

Second Committee Member

Waldschmidt, Thomas J.

Third Committee Member

Weiss, Jerrold P.

Fourth Committee Member

Geyer, Pamela K.

Abstract

The B cell population is one of the key components of the adaptive immune system, which protects the host from a tremendous variety of pathogens by producing antibodies. B cells develop from hematopoietic stem cells through a pathway known as B lymphopoiesis. This is a process accompanied by intensive gene expression reprogramming. By the end, genes appropriate for the B lineage are activated and those that are not are continuously repressed. The regulation of lineage gene expression is conferred by a network of transcriptional regulators. Although some key components have been defined, more factors, especially those orchestrating the repression of non-B lineage genes, remain to be identified.

Chemically induced mutagenesis is a potent way of identifying genes with critical biological functions. Injection of n-ethyl-n-nitrosourea, a mutagen, has generated a unique point mutation in the mouse Gon4-like (Gon4l) gene that specifically causes a loss of peripheral B cells while maintaining the T cell population. The mutation is therefore named Justy for Just T cells. The goal of this thesis project is to analyze the Justy mice and provide insights into the mechanisms underlying the regulation of B lymphopoiesis.

The work presented here demonstrates that the protein encoded by Gon4l is essential for early B lymphopoiesis, which is likely through the repression of non-B lineage genes. Gon4l protein contains conserved domains implicated in transcriptional repression and associates in a complex with the transcriptional repression mediators Yin Yang 1 and Sin3a/HDAC1, after these proteins are transiently expressed in cell lines. When bound to DNA, Gon4l is capable of repressing a nearby promoter and this function correlates with its ability to form a complex. Therefore, these results suggest that Gon4l may function as a transcriptional regulator by employing its associated co-factors in the identified complex. Lastly, a wide spectrum of tumors developed in Justy mice, indicating that Gon4l can also act as a tumor suppressor.

Keywords

B lymphopoiesis, Gon4-like, Sin3a/HDAC1, transcriptional repression, tumorigenesis, YY1

Pages

xi, 146 pages

Bibliography

Includes bibliographical references (pages 131-146).

Copyright

Copyright 2010 Ping Lu

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