Date of Award

2021

Degree Type

Thesis

Degree Name

Master of Science (MS)

Department

Molecular and Cellular Biochemistry Program

Abstract

The chromatin regulator MLLT3 recognizes target genes through the YEATS domain that identifies post-translationally modified histones, with preference for crotonyl and acetyl marks, and recruits different multiprotein effector complexes through its C-terminal domain to target genes. To study the role of MLLT3 in gene regulation, the Zeleznik-Le and Hemenway labs developed Mllt3 whole-body knockout (Mllt3;Rosa26-CreERT2) mice. These mice have a hematopoietic stem cell phenotype and an unexpected obesity and hepatic steatosis phenotype. It was unknown whether these phenotypes were from liver intrinsic effects or influenced by other parts of the body. To study this fatty liver phenotype further, Mllt3;Alb-Cre were generated that have a liver specific Mllt3 knockout. RNA-sequencing was done livers isolated from these mice aged around 13 weeks. Bioinformatic Gene Ontology Pathway (GO) Analysis of the RNA-sequencing data identified significant changes in the expression of hexose and monosaccharide metabolism genes following Mllt3 deletion in male but not female mice. Based on the RNA-sequencing and Gene Ontology Results, we hypothesized that Mllt3 regulates hexose and monosaccharide metabolic processes and mitochondrial function within the liver. For my thesis project, more detailed quantitative RT-PCR of the differentially expressed genes in these pathways identified age and sex related expression changes in Mllt3;Alb-Cre mice. Changes in mitochondrial function and quantity were also studied in the context of an Mllt3 liver specific knockout. Mitochondrial function, tested by Seahorse Assays, indicated no significant alteration in primary liver tissue from Mllt3;Alb-Cre mice at one year of age. There was a change in mitochondrial quantity following Mllt3 deletion, with age and sex differences as well. Overall, a liver specific Mllt3 knockout affects hexose metabolism and mitochondrial quantity with age and sex differences. This reveals a critical role of Mllt3 in the maintenance of normal metabolic homeostasis.

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Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.

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