Investigating the Cellular Phenotypes of the H3.3 Associated Neurodevelopmental Disorder Bryant-Li-Bho Syndrome Kelly Clark

Format:

Book

Thesis/Dissertation

Author/Creator:

Clark, Kelly, author.

Contributor:

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

Language:

English

Subjects (All):

Genetics.

Bioinformatics.

Cellular biology.

Neurosciences.

0369.

0715.

0379.

0317.

Local Subjects:

Genetics.

Bioinformatics.

Cellular biology.

Neurosciences.

0369.

0715.

0379.

0317.

Physical Description:

1 electronic resource (160 pages)

Contained In:

Dissertations Abstracts International 86-12B

Place of Publication:

Ann Arbor : ProQuest Dissertations and Theses, 2025

Language Note:

English

Summary:

Bryant-Li-Bhoj syndrome (BLBS) is a mixed neurodevelopmental-neurodegenerative syndrome characterized by developmental delay, intellectual disability, and multiple congenital anomalies. BLBS is caused by germline variants in H3-3A and H3-3B, which encode histone 3.3 (H3.3). There are 70 known BLBS causative variants which span both genes. To further understand the cellular effects of this broad array of variants, we first investigated in BLBS patient-derived dermal fibroblasts the proliferative phenotype of BLBS in which cells senesce prematurely after a phase of hyperproliferation. We found that while the premature senescence phenotype was consistent across variants, the cause of senescence appears to diverge between variants. Some variants, particularly those which affect H3.3 chaperone binding, result in shortened telomeres, while others exhibit increased DNA damage. We then explored the transcriptional profile of BLBS dermal fibroblasts and found that the most dysregulated pathways across variants are developmental pathways, including neurodevelopmental pathways. We found that, while many genes are differentially regulated in only cells with one causative variant, these variant-specific dysregulated genes converge on developmental processes, cell cycle regulation, and metabolic pathways. This aberrant gene expression may be due to several disrupted regulatory mechanisms, including transcription factor binding, chromatin accessibility, histone post-translational modifications, and DNA methylation. To evaluate DNA methylation as a potential biomarker for BLBS diagnosis, we used a whole-genome methylation microarray to evaluate the DNA methylation in dermal fibroblasts and whole blood. We found that we are unable to identify a consistent DNA methylation profile in BLBS fibroblasts or blood, suggesting that DNA methylation may not be an effective biomarker for BLBS and that gene dysregulation in BLBS may not be primarily mediated by DNA methylation. This analysis of some of the most fundamental cellular phenotypes of BLBS, proliferation, gene expression, and DNA methylation, offer new insight into the mechanisms of BLBS and the convergence of its many causative variants. This thesis work provides a new understanding of BLBS at the cellular level, thus building a foundation for future studies on key cellular pathways that are dysregulated in BLBS

Notes:

Source: Dissertations Abstracts International, Volume: 86-12, Section: B.

Advisors: Bhoj, Elizabeth Committee members: Jordan-Sciutto, Kelly; Wang, Kai; Bucan, Maja; Greenberg, Roger

Ph.D. University of Pennsylvania 2025

Local Notes:

School code: 0175

ISBN:

9798280760721

Access Restriction:

Restricted for use by site license