Reading and Writing DNA Methylation in the Mammalian Brain Daniel Connolly

Format:

Book

Thesis/Dissertation

Author/Creator:

Connolly, Daniel, author.

Contributor:

University of Pennsylvania. Neuroscience., degree granting institution.

Language:

English

Subjects (All):

Neurosciences.

Genetics.

0317.

0369.

Local Subjects:

Neurosciences.

Genetics.

0317.

0369.

Physical Description:

1 electronic resource (157 pages)

Contained In:

Dissertations Abstracts International 86-07B

Place of Publication:

Ann Arbor : ProQuest Dissertations and Theses, 2024

Language Note:

English

Summary:

DNA methylation is a chemical modification of cytosine nucleotides essential for the regulation of genome function in mammals. Although its roles in embryonic development and cellular differentiation have been well-studied, far less is known about how DNA methylation regulates brain function, despite the fact that mutations in the DNA methylation machinery lead to profound neurologic dysfunction in humans. Here, we explored the roles of DNA methylation in postmitotic neurons of the brain by selectively disrupting both the predominant "writer" (DNMT3A) and "reader" (MeCP2) of DNA methylation in mice. We found that loss of DNMT3A-catalyzed DNA methylation leads to broad changes in gene expression, influencing MeCP2 occupancy across the genome as well as impacting the activity of both the Polycomb repressive complex and COMPASS family member proteins. Additionally, we characterized the molecular consequences of a loss-of-function mutation in MeCP2 that leads to Rett syndrome, a progressive neurodevelopmental disorder. We found that MeCP2 dysfunction results in gradual accumulation of subtle transcriptional changes across postnatal life, preferentially affecting highly-methylated genes with minimal chromatin signatures of Polycomb repression. Taken together, our results provide insights into the multifaceted roles of de novo DNA methylation in brain function, suggesting that DNA methylation works in tandem with histone modifications to maintain precise gene expression in neurons across postnatal life. These findings expand our knowledge of the pathogenesis of neurological disorders involving impaired readout of DNA methylation in the brain

Notes:

Source: Dissertations Abstracts International, Volume: 86-07, Section: B.

Advisors: Zhou, Zhaolan Joe Committee members: Song, Hongjun; Marsh, Eric D.; Wu, Hao; Li, Mingyao; Zhou, Wanding

Ph.D. University of Pennsylvania 2024

Local Notes:

School code: 0175

ISBN:

9798302183088

Access Restriction:

Restricted for use by site license