Complex processes such as development and disease progression are regulated by gene expression. The majority of gene expression is controlled through chromatin packaging. Heterochromatin Protein 1 (HP1) is an evolutionary conserved non-histone chromosomal protein required for chromatin packaging and gene expression. HP1 shows a non-uniform distribution on chromosomes, being enriched within centric heterochromatin and also localizing to telomeres and euchromatic sites. The long-term goal of this proposal is to determine the mechanisms of gene regulation by HP1 in a variety of chromatin contexts. HP1 exhibits the property of """"""""spreading"""""""" along the chromosome and silencing genes.
In Specific Aim 1, we propose HP1 tethering experiments and genetic screens in Drosophila to determine the mechanism of silent chromatin spreading. Recently, HP1 has been linked to the activation of both heterochromatin and euchromatic genes.
In Specific Aim 2, we propose to identify the sequences required for HP1 targeting. In addition, we will determine the role of HP1 in the expression of heterochromatic genes that normally reside in a repressive chromatin environment. Knowledge of HP1 function obtained from studies in Drosophila has important implications for breast cancer progression. We have shown that HP1Hsa, 1 of 3 HP1 family members in humans, is down-regulated in metastatic breast cancer cell lines and metastatic clinical samples. Modulation of HP1Hsa levels alters the invasive potential of breast cancer cells. Therefore, we hypothesize that HP1Hsa functions to regulate genes required for invasion and metastasis.
In Specific Aim 3, we will determine which genes are mis-regulated following knock-down of HP1Hsa levels and identify direct target genes by chromatin immunoprecipitation. The mechanism of HP1Hsa localization and function at such genes will be determined by a knock-down and replacement strategy where endogenous HP1Hsa is exchanged for mutant forms lacking specific functions. Collectively, these studies will expand our knowledge about the mechanisms of gene regulation by HP1 proteins and identify the molecular pathways that regulate metastasis. Relevance to Public Heath: Studies described here will identify the genes and molecular pathways involved in regulating breast cancer invasion/metastasis. Protein products encoded by such genes could represent new markers for metastatic progression and targets for therapy. ? ? ?
| Azzaz, Abdelhamid M; Vitalini, Michael W; Thomas, Andrew S et al. (2014) Human heterochromatin protein 1? promotes nucleosome associations that drive chromatin condensation. J Biol Chem 289:6850-61 |
| Geyer, Pamela K; Vitalini, Michael W; Wallrath, Lori L (2011) Nuclear organization: taking a position on gene expression. Curr Opin Cell Biol 23:354-9 |
| Dialynas, George; Speese, Sean; Budnik, Vivian et al. (2010) The role of Drosophila Lamin C in muscle function and gene expression. Development 137:3067-77 |
| Hines, Karrie A; Cryderman, Diane E; Flannery, Kaitlin M et al. (2009) Domains of heterochromatin protein 1 required for Drosophila melanogaster heterochromatin spreading. Genetics 182:967-77 |
| Wallrath, Lori L; Elgin, Sarah C R (2008) Stimulating conversations between HP1a and histone demethylase dKDM4A. Mol Cell 32:601-2 |
| Wallrath, Lori L; Nagy, Peter L; Geyer, Pamela K (2008) Editorial. Epigenetics of development and human disease. Mutat Res 647:1-2 |
| Yang, Hongbo; Pesavento, James J; Starnes, Taylor W et al. (2008) Preferential dimethylation of histone H4 lysine 20 by Suv4-20. J Biol Chem 283:12085-92 |
| Dialynas, George K; Vitalini, Michael W; Wallrath, Lori L (2008) Linking Heterochromatin Protein 1 (HP1) to cancer progression. Mutat Res 647:13-20 |
| Geyer, Pamela K; Wallrath, Lori L (2007) Heterochromatin: not just for silencing anymore: report of the Eighth International Conference on Drosophila Heterochromatin. Fly (Austin) 1:251-6 |
| Moss, Timothy J; Wallrath, Lori L (2007) Connections between epigenetic gene silencing and human disease. Mutat Res 618:163-74 |
Showing the most recent 10 out of 17 publications
