Date of Award

2016

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Cell & Molecular Biology

First Advisor

Zhaolan Zhou

Abstract

Methylation of cytosine is an epigenetic mark essential for many cellular and

developmental processes. How methylation is interpreted into transcriptional regulation is not fully

understood, but previous studies have found that this process involves the methyl-CpG binding

domain (MBD) family of proteins. Three MBD proteins, MeCP2, MBD1 and MBD2, specifically

bind methylated cytosines and recruit different co-repressor complexes to regulate transcription

and chromatin states. Genetic studies also linked MeCP2 and MBD1 to neurodevelopmental

disorders in humans and mice. However, a role for MBD2 in the brain has not been described. In

this work, we characterized the phenotypes of mice lacking MBD2. We found that, unlike MeCP2

and MBD1, Mbd2 null mice behave similarly to wildtype littermates, with the exception of mildly

altered nesting and locomotor activity and reduced body weight. To investigate the underlying

cause of different functional requirements for the MBDs, we generated knockin mice in which

endogenous MBD2 and MBD1 are biotin-tagged. We systematically compared the spatiotemporal

expression patterns of the MBDs and found that MeCP2, MBD1 and MBD3 are primarily

expressed in the brain. In contrast, MBD2 is widely expressed throughout the body at young and

adult ages. In addition, the expression of MBD2 is upregulated in adult spleen and small intestine

compared to younger ages, while MBD1 and MBD3 are only enriched at early ages in the brain.

We also determined that MBD2 interacts with the NuRD complex ubiquitously across tissues. We

conclude that MBD2 is likely dispensable for brain function and instead may mediate NuRDrelated

functions primarily in peripheral tissues. Our study provides novel genetic tools and

reveals new directions to investigate MBD2 functions in vivo.

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