In order for estrogen receptor (ER)to activate gene transcription it must overcome a repressivechromatin structure. ER does this by recruiting to the promoter enzymes that either covalently modifychromatin or remodel it into a more permissive state. Only recently has it become apparent that allchromatin is not homogenous. Histone variants replace their canonical histone counterparts in specificregions of the genome. The effect of histone variants on gene regulation is largely unknown. However,preliminary data indicates that the histone variant macroH2A is involved in ER-regulated transcription inbreast cancer cells. MacroH2A has also been implicated in the epigenetic silencing of transcription that occurs during Xinactivation. Recently, macroH2A was shown to bind to the nicotinamide adenine dinucleotide (NAD+)metabolites ADP-ribose (ADPR) and O-acetyl-ADP-ribose (OAADPR). This finding implicates macroH2Aas a target of exciting signaling events in two NAD+-dependent pathways: the turnover of poly(ADP-ribose)polymerase (PARP)-synthesized poly(ADP-ribose) (PAR) chains by poly(ADP-ribose)glycohydrolase(PARC) and deacetylation of proteins by SIRT1.The objective of these studies is to achieve a better understanding of both the causes of macroH2Aincorporation at estrogen target genes (Aim1) and effects of macroH2A incorporation at these genes(Aim2). Toward this end,a variety of biochemical cell-based,and bioinformatic approaches will be usedincluding Chromatin immunoprecipition (ChIP), ChlP-chip, expression analysis, RNAi, protein-proteininteraction assays, enzyme assays,and DMA motif finding algorithms. Estrogen signaling through the ER plays important roles in normal physiological processes such assexual development and fertility. However, estrogen also promotes the growth and progression of breastcancer and has a protective effect from heart disease, stroke and osteoporosis. Therefore, anunderstanding of the mechanism by which macroH2A regulates the transcription of ER target genes willprovide insights into the progression of these diseases.
| Hussey, Kristine M; Chen, Hongshan; Yang, Christine et al. (2014) The histone variant MacroH2A1 regulates target gene expression in part by recruiting the transcriptional coregulator PELP1. Mol Cell Biol 34:2437-49 |
| Gamble, Matthew J; Frizzell, Kristine M; Yang, Christine et al. (2010) The histone variant macroH2A1 marks repressed autosomal chromatin, but protects a subset of its target genes from silencing. Genes Dev 24:21-32 |
