Date of Award
Doctor of Philosophy (PhD)
Cell & Molecular Biology
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.
Wood, Kathleen, "Insights into Mbd2 Function Revealed by a Novel Genetic Tagging Approach" (2016). Publicly Accessible Penn Dissertations. 2103.