Research Chromatin organization plays a key role in many cellular processes, including gene expression, genome stability, and cell differentiation. Misregulation of chromatin structure and function underlies a variety of diseases, including cancer. My primary research interest is to understand the fundamental principles of chromatin organization, particularly how small RNAs and epigenetic marks contribute to development and disease. Toward this goal, we have chosen to study the fission yeast (Schizosaccharomyces pombe) through a combination of approaches, including genetics, cell biology, biochemistry and genomics. Fission yeast has recently emerged as one of the premiere models for chromatin study. In this simple, genetically tractable model organism, many epigenetic components are highly conserved. As in mammalian cells, chromatin in fission yeast can be classified as euchromatin and heterochromatin. While euchromatin is genetically active and loosely packed, heterochromatin is defined cytologically as regions that are highly condensed through the cell cycle. Heterochromatin, mainly composed of transposable elements and repeats, is essential for many fundamental processes, such as gene silencing, chromosome segregation and genome integrity. In fission yeast, heterochromatin includes peri-centromere, telomere and mating-type region. Specific epigenetic marks are enriched in heterochromatin region, particularly the methylation of H3 at lysine 9 (H3K9), a mark conserved from fission yeast to human. Clr4, a member of the SUV39 family histone methyltransferase, catalyzes H3K9 methylation. This modification serves as a binding site for Swi6, a structural and functional homolog of metazoan Heterochromatin Protein 1 (HP1). A WD repeat protein, Rik1, is in a complex with Clr4 (Fig. 1A). Rik1 shares homology to the DNA damage binding protein DDB1, and is important for heterochromatin silencing and H3K9 methylation. We identified two novel silencing factors, Dos1/Clr8 and Dos2/Clr7 (delocalization of Swi6), through a visual genetic screen for mutations delocalizing Swi6-GFP (Fig. 1B). Dos1 is a WD repeat protein while Dos2 contains a zinc finger domain. Both were found in the complex containing Clr4 and Rik1. Recently, we discovered that Dos1 also interacts with a conserved H3K4 histone demethylase, responsible for removing H3K4 methylation in heterochromatin, which explains why H3K4 methylation is depleted in that region (Fig. 1A). Small interference RNAs (siRNAs) is essential for heterochromatin assembly and H3K9 methylation. Two key complexes are required for RNAi processing: RITS (RNA-induced transcriptional silencing), which contains Argonaute, and RdRP (RNA-dependent RNA polymerase). Heterochromatin siRNA is cell cycle-dependent: at S phase, heterochromatin transcripts are transiently expressed, and subsequently processed into siRNAs by RITS and RDRC complexes. The small RNAs, in concert with silencing factors, including Dos1, Dos2, Rik1 and Lid2, promote heterochromatic H3K9 methylation by Clr4.
Our current research has particularly focused on the following key questions in the field of epigenetics: How are epigenetic marks, particularly in heterochromatin, established and maintained? What is the mechanism used to coordinate different epigenetic marks? How are epigenetic marks faithfully inherited during the cell cycle? How are small RNAs regulated and how does their generation impact chromatin function? Job Opportunities Post-doctoral and research assistant positions are available in Dr. Li’s laboratory. Areas of Research/Interest epigenetics, chromatin Fellowships/Honors Memorial Research Scholarship, University of Texas at Austin, 2002 Publications Mikel Zaratiegui, Stephane Castel, Danielle V. Irvine, Anna Kloc, Jie Ren, Fei Li, Elisa de Castro, Laura Marín, An-Yun Chang, Derek Goto , W. Zacheus Cande, Francisco Antequera, Benoit Arcangioli, and Rob Martienssen. RNAi promotes heterochromatic silencing through replication-coupled release of RNA pol II. Nature (In press). Email update requests to fas.bio.computing@nyu.edu . |
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