Date of Completion

Spring 5-1-2018

Thesis Advisor(s)

Rosa Guzzo

Honors Major

Physiology and Neurobiology

Abstract

Cartilage is essential for the proper formation, growth, and function of long bones. In the process of endochondral ossification, cartilage serves a pre-cursor to long bone. Many studies have primarily focused on the transcription factors, growth factors, and signaling molecules that regulate this process. In recent years, epigenetic mechanisms have surfaced as key regulatory elements of gene expression. Some important epigenetic mechanisms include DNA methylation and post-translational modification of histone residues, such as histone acetylation and histone methylation. Our research focuses on a unique histone methyltransferases known as disruptor of telomeric silencing 1-like (Dot1L) and its role in embryonic and postnatal skeletal development. Genetic variants of Dot1L have been associated with skeletal growth, human height, and cartilage degeneration. Dot1L’s enzymatic activity catalyzes the methylation of lysine residue 79 in histone H3 and is associated with gene activation. There remains a gap in our knowledge regarding epigenetic regulators of cartilage development and endochondral ossification. For this reason, our research aims at understanding the role of Dot1L in regulating endochondral ossification in growth plate cartilage and its implications in skeletal growth. We utilize a Cre recombinase system to genetically inactivate the Dot1L gene in embryonic and postnatal cartilage and perform phenotypic and histological analyses and comparisons of the skeletons of control mice and mice expressing loss of Dot1L in cartilage. Results show that loss of Dot1L in mice expressing the Cre enzyme impairs skeletal growth. In addition, preliminary histological analyses of growth plate cartilage from mice with postnatal loss of Dot1L in cartilage suggest that Dot1L is important for controlling chondrocyte differentiation.

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