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Structure/function analyses of the murine -globin locus through trageted mutations.

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Call No.	QP552.G5 H8 2005
Author	Hu, Xiao, 1970-
Title	Structure/function analyses of the murine -globin locus through trageted mutations.
Date	2005
Abstract	Genes at the mammalian β-globin loci are arranged in the order of their developmental activation. Expression of individual genes at this locus is controlled by gene proximal and distal cis -regulatory elements. This thesis focused on the function of the locus structure in gene regulation at the multigenic murine β-globin locus. The prominent gene distal cis-regulatory element at the β-globin locus is the locus control region (β-LCR), which contains a series of DNase I hypersensitive sites (5 ' HSs) upstream of the structural genes. The β-LCR is required for physiological level transcription of all the β-like globin genes. The cores of the individual 5 ' HS sites have been proposed to be important for the structure and function of the β-LCR in transgenic constructs. We studied the core element of the 5 ' HS2 site within the β-LCR at the endogenous murine β-globin locus. The activities of the 5 ' HS2 core were examined by differentiating ES cells in which the 5 ' HS2 core element was deleted through homologous recombination (HR) in vitro and in 5 ' HS2 core knockout mice. Our study demonstrated that deletion of the murine 5 ' HS2 core caused minimal to mild changes of transcription from all the β-like globin genes and did not affect the formation of the remaining 5 ' HS sites within the LCR. Our data do not support the hypothesis that the core of the 5 ' HS site is required for the general LCR structure and near normal activity and suggest that individual 5 ' HS sites at the murine β-LCR function independently and additively. Expression of individual genes at the β-globin locus is developmentally controlled, a process known as the β-globin switch. It has been observed that transcription of one β-globin gene can interfere with transcription of the other β-globin genes when linked to the LCR in cis , a phenomenon known as transcriptional interference (TI). An LCR-gene competition model has been proposed to explain the relationships among genes at the β-globin locus. It has been hypothesized that transcription of the embryonic and fetal genes suppresses the transcription of the adult genes during the embryonic and fetal development stages, respectively. In this thesis, we mutated the endogenous murine β-globin locus to investigate (1) how transcription of one murine embryonic gene affects the other embryonic genes and (2) how transcription of the murine embryonic genes affects the fetal/adult genes at the embryonic development stage. Transcription of the β-like globin genes was studied in a series of mice with promoter deletions at the murine embryonic genes, Ey and βh1 (ΔEy, Δβh1 and ΔEyΔβh1).
Description	xiii, 181 leaves : ill. 28 cm.
Format	application/pdf
Advisor	Steve N. Fiering.
Subject	Globin genes -- Expression. Genetic markers. Genetic transcription -- Regulation. Mutation (Biology).
College	Dartmouth Medical School -- Department of Microbiology and Immunology.
Issuing Body	Dartmouth Dissertations are made available through the Dartmouth Digital Library.
Degree	Thesis (Ph.D.)--Dartmouth College.
Copyright	All rights reserved. No part of this book may be reproduced in any form by any electronic or mechanical means without permission in writing from the author.
DOI	http://dx.doi.org/10.1349/ddlp.84

Title	Page 1
Format	application/pdf
Issuing Body	Dartmouth Dissertations are made available through the Dartmouth Digital Library.
Degree	Thesis (Ph.D.)--Dartmouth College.
Full Text	Structure/Function Analyses of the Murine β- Globin Locus through Targeted Mutations A Thesis Submitted to the Faculty In partial fulfillment of the requirements for the Degree of Doctor of Philosophy In Microbiology and Immunology By Xiao Hu DARTMOUTH COLLEGE Hanover, New Hampshire May 31st, 2005 Examining Committee: (Chair) Nancy Speck, Ph.D (Advisor) Steve Fiering, Ph.D. Christopher Lowrey, M.D. Eric Bouhassira, Ph.D Charles Barlowe, Ph.D Dean of Graduate Studies

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