Small RNA-directed heterochromatin establishment – SMARHTEST

Heterochromatin is a closed and mostly transcriptionally repressed state of chromatin, which is critical for gene silencing, cell differentiation and genome maintenance. Although how heterochromatin is maintained through cell proliferations is well understood, how heterochromatin is formed in the first place is still poorly understood. This is largely because there are very few biological models in which we can separately study the process of heterochromatin establishment from its maintenance. The programmed DNA elimination in the ciliated protozoan Tetrahymena can be synchronously induced in laboratory in a large scale and heterochromatin is established de novo during this process. Therefore, Tetrahymena DNA elimination serves as a unique model for heterochromatin initiation and spreading processes that can be studied genetically and biochemically. The goal of this proposal is to understand the heterochromatin establishment process using this DNA elimination as a model. Our previous studies demonstrated that heterochromatin establishment on eliminated sequences in Tetrahymena is dependent on an RNA interference mechanism. In this proposal, I aim to understand: 1) how small RNAs interact with chromatin to recruit the initial set of heterochromatin components; 2) how the initial set of heterochromatin components induces production of the secondary small RNAs that leads to propagation of heterochromatin; and 3) how the spreading of heterochromatin is stopped precisely at the borders of eliminated sequences. I am confident that this proposed study will provide several novel insights for the basic molecular mechanisms of heterochromatin establishment. In addition, because heterochromatin is suggested to be important for genome integrity, development, aging and cancer progression, I believe the results obtained by the proposed project will eventually aid in improving human health.