GSBS Dissertations and Theses

Publication Date


Document Type

Doctoral Dissertation

Academic Program

Cancer Biology


Molecular, Cell and Cancer Biology

First Thesis Advisor

Merav Socolovsky, Ph.D., M.B.B.S.


Erythropoiesis, DNA Methylation


In the mammalian genome, 5‟-CpG-3‟ dinucleotides are frequently methylated, correlating with transcriptional silencing. Genome-wide waves of demethylation are thought to occur only twice during development, in primordial germ cells and in the pre-implantation embryo. They are followed by de novo methylation, setting up a pattern that is inherited throughout development. No global methylation changes are thought to occur during further somatic development, although methylation does alter at gene-specific loci, contributing to tissue-specific patterns of gene expression. Here we studied DNA methylation in differentiating mouse erythroblasts in vivo using several approaches including genomic-scale, reduced representation bisulfite sequencing (RRBS). Surprisingly, demethylation at the erythroid-specific β-globin locus was coincident with a wave of global DNA demethylation at most genomic elements, including repetitive elements and genes silenced in erythropoiesis. Over 30% of total methylation is irreversibly lost during erythroid differentiation. Demethylation occurred through a passive mechanism, requiring the rapid DNA replication triggered with the onset of erythroid terminal differentiation. Global loss of DNA methylation was not associated with a global increase in transcription, as determined by GeneChip analysis. We propose that global demethylation is a consequence of cellular mechanisms required for the rapid demethylation and induction of β-globin and other erythroid genes. Our findings demonstrate that, contrary to previously held dogma, DNA demethylation can occur globally during somatic cell differentiation, providing a new experimental model for the study of global demethylation in development and disease.



Rights and Permissions

Copyright is held by the author, with all rights reserved.