Insights into MBD2 function revealed by a novel genetic tagging approach / Kathleen H. Wood.

Format:

Book

Manuscript

Thesis/Dissertation

Author/Creator:

Wood, Kathleen H., author.

Contributor:

Zhou, Zhaolan, degree supervisor.

Bartolomei, Marisa S., degree committee member.

Jongens, Thomas A., degree committee member.

Kaestner, Klaus H., degree committee member.

Lengner, Christopher J., degree committee member.

University of Pennsylvania. Department of Cell and Molecular Biology, degree granting institution.

Language:

English

Subjects (All):

Penn dissertations--Cell and molecular biology.

Cell and molecular biology--Penn dissertations.

Local Subjects:

Penn dissertations--Cell and molecular biology.

Cell and molecular biology--Penn dissertations.

Physical Description:

x, 132 leaves : illustrations (some color) ; 29 cm

Production:

[Philadelphia, Pennsylvania] : University of Pennsylvania, 2016.

Summary:

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.

Notes:

Ph. D. University of Pennsylvania 2016.

Department: Cell and Molecular Biology.

Supervisor: Zhaolan Zhou.

Includes bibliographical references.

OCLC:

960101134