Histone Modifications Govern Inducible Gene Expression and Cell Fate Determination

The wrapping of DNA around histone proteins (chromatin) compacts the eukaryotic genome while allowing for regulated access to DNA. Post-translational modifications of histone proteins play an important role in regulating gene expression through the identification and interpretation of the chemical moiety on the histone and the temporal recruitment/activation of proteins that catalyze the addition or removal of these modifications. These events are poorly understood for one such modification - histone lysine methylation - in the context of inducible gene expression and cancer stem cell maintenance. To better define how histone lysine methylation regulates inducible gene expression, I examined the role of H3 lysine 79 methylation (H3K79me) in response to janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling. DOT1L (Disruptor of Telomeric silencing 1 Like) is an evolutionarily conserved histone methyltransferase responsible for H3K79 methylation, and is a key regulator of gene activation. Depletion of DOT1L decreased gene transcription and H3K79 methylation at STAT1-dependent genes.. To understand if a STAT1- DOT1L interaction was required for STAT1-dependent gene transcription, I identified the interacting region of DOT1L. My findings indicate that a novel STAT1-DOT1L interaction is required for JAK-STAT dependent gene expression, and provide new mechanistic insights into DOT1L's role in inducible transcription. In embryonic stem cells, genes required for cell fate determination are silenced by a unique chromatin signature in which both H3K4 and H3K27 methylation are present at their promoters. To investigate whether cancer stem cells also use H3K4 and H3K27 methylation to regulate their promoters, I generated chromatin state maps for these modifications in a pediatric cancer stem cell line. Surprisingly, unlike in embryonic stem cells, I found that H3K4 and H3K27 methylation associates with some genes that are transcriptionally active. These findings suggest iii that H3K4 and H3K27 methylation in cancer stem cells may have additional, previously uncharacterized functions in regulating gene expression. Histone methylation provides key epigenetic information for a cell's transcriptional program and reflects regulated transcriptional changes that occur during development. My research contributes to understanding the mechanism by which histone methylation regulates both inducible gene expression and gene expression that governs cell fate decisions.

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