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The role of chromatin regulation in gene expression: analyzed through the phenotype characterization of Chd6 ATPase-/- mice and methylation status of the human globin locus.

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Call No.	QH599 .L38 2009
Author	Lathrop, Melissa Jeanne.
Title	The role of chromatin regulation in gene expression: analyzed through the phenotype characterization of Chd6 ATPase-/- mice and methylation status of the human globin locus.
Date	2009
Abstract	Epigenetic regulation of gene expression is a developing field of study with many potential therapeutic applications. Chromatin remodeling is necessary for proper mammalian development, and misregulation of this process is associated with many human diseases. Three mechanisms by which chromatin structure is modified include methylation of the DNA, covalent modification of histone tails, and repositioning of nucleosomes by ATP dependant chromatin remodeling enzymes. To further increase our knowledge of the mechanisms and proteins involved in the modification of chromatin structure I undertook two projects; the role of DNA methylation in the regulation of human β-globin gene expression, and analysis of the Chd6 ATPase-/- mouse. Methylation status of the human β-globin gene promoters correlates with the expression pattern of the individual genes. However an extensive locus wide analysis of the methylation pattern in primary human tissue has not been performed. We used bisulfite sequencing to assay the locus across four time points in development, observing the methylation status CpGs within adult bone marrow, fetal liver, and two stages of embryonic stem cell derived primitive-like erythroid cells. The development of large domains of hypomethylation coincides with expression of the globin genes. These domains are found to fall within domains of histone modifications commonly found at active transcription sites. These domains further suggest that extensive loss of methylation plays a key role in the high levels of expression found in some tissue specific non-CpG island genes. The CHD protein family is a member of the SNF2 superfamily of chromatin remodeling enzymes. Members of the third subfamily of CHD proteins are not thoroughly characterized, and mutations in several are associated with disease in humans. CHD6 is a DNA dependent ATPase which functions within a large protein complex at sites of transcription initiation. To investigate the role of Chd6 in regulation of gene expression a mouse with deletion of the ATPase domain was developed. The Chd6 ATPase-/- mouse had no observable anatomic defect, but behavioral analysis identified an ataxia phenotype. The data suggests that CHD6 is a candidate gene for three human ataxias which by linkage mapping are near the CHD6 gene on chromosome 20q12.
Description	ix, 151 leaves : ill. 28 cm.
Format	application/pdf
Advisor	Fiering, Steve N., Lowrey, Chris, Tevosian, Sergei, Rhodes, Harker, Paulson, Robert
Subject	Chromatin -- Structure. DNA -- Methylation. Globin genes -- Expression. Adenosine triphosphatase. Proteins -- Chemical modification.
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.278

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	The Role of Chromatin Regulation in Gene Expression: Analyzed Through the Phenotype Characterization of Chd6 ATPase-/- Mice and Methylation Status of the Human Globin Locus A Thesis Submitted to the Faculty In partial fulfillment of the requirements for the degree of Doctor of Philosophy in Microbiology and Immunology by Melissa Jeanne Lathrop DARTMOUTH COLLEGE Hanover, New Hampshire June 2, 2009 Examining Committee: _________________________________ (Chair) Steven Fiering, Ph.D. _________________________________ Chris Lowery, M.D. _________________________________ Sergei Tevosian, Ph.D. _________________________________ C. Harker Rhodes, M.D. ________________________________ Brian W. Pogue, Ph.D. _________________________________ Dean of Graduate Studies Robert Paulson, Ph.D.

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The role of chromatin regulation in gene expression: analyzed through the phenotype characterization of Chd6 ATPase-/- mice and methylation status of the human globin locus.

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