Enzymatic Regulation by Crosstalk Interactions Governs The Dynamics of Histone H3 Lysine 4 Methylati...

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" Enzymatic Regulation by Crosstalk Interactions Governs The Dynamics of Histone H3 Lysine 4 Methylation "
Feng, Vanessa Muir, Tom W.

Document Type	:	Latin Dissertation
Language of Document	:	English
Record Number	:	1052829
Doc. No	:	TL51946
Main Entry	:	Feng, Vanessa
Title & Author	:	Enzymatic Regulation by Crosstalk Interactions Governs The Dynamics of Histone H3 Lysine 4 Methylation\ Feng, VanessaMuir, Tom W.
College	:	Princeton University
Date	:	2019
Degree	:	Ph.D.
student score	:	2019
Note	:	119 p.
Abstract	:	Methylation of lysine 4 on histone H3 (H3K4) plays a critical role in the maintenance of active gene expression at genes important for differentiation and cellular identity. The dynamics of this crucial histone post-translational modification (PTM) are tightly regulated by the methyltransferases and demethylases responsible for depositing or removing H3K4 methylation respectively. Through their identities are known, the precise mechanisms that recruit these enzymes to their target genes and the local chromatin environmental cues that direct their enzymatic activities have yet to be fully elucidated. To study the effect of local histone PTMs on deposition of H3K4 methylation, we employed a high-throughput biochemical assay that utilizes a DNA-barcoded mononucleosome library to profile the H3K4 methyltransferase complex MLL1. Many chromatin effector proteins possess conserved protein domains that engage nucleosome features, and this technology allowed us to assay the effects of diverse combinations of histone PTMs and other nucleosome modifications on MLL1 activity. The results of this work show that the MLL1 core complex is stimulated on acetylated nucleosome substrates. Antagonistic to MLL1, KDM5B is a histone demethylase specific for H3K4 that contains three PHD reader domains in addition to its catalytic jumonji C domain. Although PHD1 of KDM5B is known to bind the unmodified H3 tail, it is unknown whether this binding can regulate the catalytic activity of the demethylase. To address this, we utilized chemically defined chromatin substrates to demonstrate that KDM5B demethylase activity is stimulated by binding of the unmodified H3 tail and this stimulation is dependent upon recognition by PHD1. Furthermore, we employ designer chromatin substrates to demonstrate that this activation is limited to distances where the stimulating motif and substrate are confined within the same nucleosome array. Together, these findings further our understanding of the mechanisms that maintain the borders separating transcriptionally active and silent chromatin domains.
Descriptor	:	Chemistry
Added Entry	:	Muir, Tom W.
Added Entry	:	Princeton University