Epigenetics and chromatin
Ph.D. (Evolutionary and Population Biology) 2002 Washington University in St. Louis
My research focuses on understanding the mechanisms establishing and regulating epigenetic information, and how epigenetic systems ultimately contribute to gene regulation and disease. In addition to the genetic information encoded within the DNA, other forms of information exist in the cell. Epigenetic information is heritable, affects gene expression states and phenotypes, but is independent of DNA sequence. Examples of epigenetic systems include DNA methylation, histone modifications, and chromatin structure. These epigenetic systems play vital roles in gene regulation, and defects in epigenetic regulation have been implicated in a variety of human diseases including cancer. My lab uses the fruit fly Drosophila melanogaster as a model system to investigate epigenetic systems and their influence on development and gene regulation.
Currently, there are two on-going projects in the lab:
- 1. The regulation of H3K9 methylation
H3K9 methylation is a histone mark generally associated with silent regions of the genome and heterochromatin. In many eukaryotes including Drosophila, H3K9 methylation is generated by three classes of SET domain containing histone methyltransferases. In Drosophila, the action of SU(VAR)3-9, EGG, and G9a produces the genome-wide H3K9 methylation patters. However, how the three enzymes are coordinated and what their individual roles are is poorly understood. We are using molecular genetic, biochemical, and genomics approaches to answer these questions.
- 2. The HP1 protein family
Heterochromatin protein 1a (HP1a) was discovered as the first heterochromatin-associated protein. Its binding characterizes the heterochromatic regions of the fly genome, and homologs have been identified in species ranging from yeast to humans. The HP1a protein contains two conserved domains, the chromo domain, and the chromo-shadow domain. Based on this domain structure, four additional HP1 family proteins have been identified in Drosophila melanogaster. Of these, HP1B and HP1C, like HP1a, are ubiquitously expressed, while HP1D/RHINO and HP1E are restricted to the germline in females and males respectively. While HP1a binds large domains in heterochromatin, it also shows binding to active transcription start sites, where it is generally found in the company of HP1B and/or HP1C. We are using molecular genetic and genomics approaches to understand the relationship between HP1a, HP1B, and HP1C, and their effect on gene regulation.
Schwartz YB, Linder-Basso D, Kharchenko PV, Tolstorukov MY, Kim M, Li H, Gorchakov AA, Minoda A, Shanower G, Alekseyenka AA, Riddle NC, Jung YL, Gu T, Plachetka A, Elgin SCR, Kuroda MI, Park PJ, Savitsky M, Karpen GH, Pirrotta V. Nature and function of insulator protein binding sites in the Drosophila genome (2012) Genome Research 22(11):2188-98.
Riddle NC, Jung YL, Gu T, Alekseyenko AA, Asker D, Gui H, Kharchenko PV, Minoda A, Plachetka A, Schwartz YB, Tolstorukov MY, Kuroda MI, Pirrotta V, Karpen GH, Park PJ, and Elgin SCR. Enrichment of HP1a on Drosophila chromosome 4 genes creates an alternate chromatin structure critical for regulation in this heterochromatic domain (2012) PLoS Genetics 8(9):e1002954.
Alekseyenko AA, Ho JWK, Peng S, Gelbart M, Tolstorukov MY, Plachetka A, Kharchenko PV, Jung YL, Gorchakov AA, Larschan E, Gu T, Minoda A, Riddle NC, Schwartz YB, Elgin SCR, Karpen GH, Pirrotta V, Kuroda MI and Park PJ. Sequence-specific targeting of dosage compensation in Drosophila favors an active chromatin context (2012) PLoS Genetics 8(4):e1002646.
Kharchenko PV, Alekseyenko AA, Schwartz YB, Minoda A, Riddle NC, Ernst J, Sabo PJ, Larschan E, Gorchakov AA, Gu T, Linder-Basso D, Plachetka A, Shanower GA, Tolstorukov MY, Luquette LJ, Xi R, Jung YL, Park RW, Bishop EP, Canfield TP, Sandstrom R, Thurman RE, MacAlpine DM, Stamatoyannopoulos J, Kellis M, Elgin SCR, Kuroda MI, Pirrotta V, Karpen G, and Park PJ. Comprehensive analysis of the chromatin landscape in Drosophila melanogaster (2011) Nature 471:480-485.
Riddle NC*, Minoda A*, Kharchenko PV*, Alekseyenko AA, Schwartz YB, Tolstorukov MY, Gorchakov AA, Kennedy C, Linder-Basso D, Peach SE, Shanower GA, Zheng H, Jaffe JD, Kuroda MI, Pirrotta V, Park PJ, Elgin SCR, Karpen GH. Plasticity in patterns of histone modifications and chromosomal proteins in Drosophila heterochromatin (2011) Genome Research 21:147-163. *Co-first authors
Egelhofer TA, Minoda A, Klugman S, Linder-Basso D, Shanower GA, Kolasinska-Zwierz P, Alekseyenko AA, Cheung M-S, Day DS, Gadel S, Gorchakov AA, Gu T, Kharchenko PV, Kuan S, Latorre I, Luu Y, Ngo Q, Perry M, Rechtsteiner A, Riddle NC, Schwartz YB, Vielle A, Ahringer J, Elgin SCR, Kuroda MI, Park PJ, Pirrotta V, Ren B, Strome S, Karpen GH, Hawkins RD, and Lieb JD. Assessment of histone-modification antibody quality (2011) Nature Structural & Molecular Biology 18:91-93.
The modENCODE Consortium, et al. Identification of functional elements and regulatory circuits by Drosophila modENCODE (2010) Science 330:1787-1797. (NCR is a current member of the modENCODE Consortium)
Riddle NC, Jiang H, An L, Doerge RW, and Birchler JA. Gene expression analysis at the intersection of ploidy and hybridity in maize (2010) Theor Appl Genet 120:341-53.
Celniker SE et al for the modENCODE Consortium. Unlocking the secrets of the genome (2009) Nature 459:927-930. (NCR is a current modENCODE Consortium participant)
Brower-Toland B*, Riddle NC*, Jiang H, Huisinga KL, and Elgin SCR. Multiple SET methyltransferases are required to maintain normal heterochromatin domains in the genome of Drosophila melanogaster (2009) Genetics 181:1303-1319. *Co-first authors
Riddle NC, Shaffer CD, and Elgin SCR. A lot about a little dot – lessons learned from Drosophila melanogaster chromosome four (2009) Biochem Cell Biol 87:229-241.
Riddle NC, Leung W, Haynes KA, Granok H, Wuller J, and Elgin SCR. An investigation of heterochromatin domains on the fourth chromosome of Drosophila melanogaster (2008) Genetics 178:1177-1191.
Riddle NC, and Birchler JA. Comparative analysis of inbred and hybrid maize at the diploid and tetraploid levels (2008) Theor Appl Genet 116:563-576.
Riddle NC, and Elgin SCR. A role for RNAi in heterochromatin formation in Drosophila (2008) Curr Top Microbiol Immunol 320:185-209.