Connecting the Dots: Unraveling the Role of DOT1L in a Novel Neurodevelopmental Disorder Marissa Jane Maroni

Format:

Book

Thesis/Dissertation

Author/Creator:

Maroni, Marissa Jane, author.

Contributor:

University of Pennsylvania. Neuroscience., degree granting institution.

Language:

English

Subjects (All):

0317.

0369.

Local Subjects:

0317.

0369.

Physical Description:

1 electronic resource (194 pages)

Contained In:

Dissertations Abstracts International 87-07B

Place of Publication:

Ann Arbor : ProQuest Dissertations and Theses, 2025

Language Note:

English

Summary:

Chromatin regulators are disproportionately mutated in individuals with neurodevelopmental disorders (NDDs). DOT1L, a histone methyltransferase, is one such protein in which individuals with monoallelic variants in DOT1L display global developmental delay, attention deficit hyperactivity disorder, and varying congenital anomalies. Despite this, the impact of monoallelic loss of DOT1L in neuronal function remains unclear. Here, we sought to define the effects of DOT1L and the posttranslational mark DOT1L deposits, methylation on histone H3 lysine reside 79 (H3K79me), in neuronal function. We applied bulk and single-nucleus RNA-sequencing, ChIP-sequencing, imaging, multielectrode array recordings, mass spectrometry, embryonic stem cell models, and behavioral analysis of zebrafish and multiple mouse models. We identified 16 individuals with NDDs and monoallelic DOT1L variants. We found that variants in DOT1L are clustered in the catalytic domain and demonstrate that specific variants cause loss of DOT1L methyltransferase activity. In primary cortical neurons, Dot1l knockdown disrupts the transcription of synaptic genes, neuronal branching, the expression of a synaptic protein, and neuronal activity. Further in the cortex, monoallelic Dot1l loss causes H3K79me2 depletion and sex-specific transcriptional responses. Using both zebrafish and mouse models, we found behavioral disruptions that include developmental deficits and sex-specific social behavioral changes. Finally, in mouse embryonic stem cell-derived neurons, we found that H3K79me regulates the transcriptional landscape and modulates global levels of the histone variant H3.3 in these neurons. Cumulatively, this work contributes to our understanding of how changes to the chromatin landscape can contribute to NDDs

Notes:

Advisors: Korb, Erica Committee members: Hart, Michael; Bartolomei, Marisa; Bhoj, Elizabeth; Elefant, Felice

Source: Dissertations Abstracts International, Volume: 87-07, Section: B.

Ph.D. University of Pennsylvania 2025

Vendor supplied data

Local Notes:

School code: 0175

ISBN:

9798276007229

Access Restriction:

Restricted for use by site license