Biochemistry & Molecular Biology,
Keck School of Medicine
USC / Norris Comprehensive Cancer Center
- Gene Regulation/Transcription
- Cancer Cell Biology
- Signal Transduction
- Protein Chemistry/Enzymology
Research OverviewIn human cells, the DNA is compacted into the nucleus as a complex structure known as chromatin. The basic repeating unit of chromatin is the nucleosome, which consists of 147 bp of DNA wrapped around a histone octamer containing two copies each of the histones H2A, H2B, H3 and H4. All DNA-templated reactions occurring in the context of chromatin require remodeling activities that counterbalance the repressive nature of chromatin. Two major remodeling processes are post-translational modifications of histone N-terminal domains (e.g., acetylation, methylation, phosphorylation and ubiquitylation) and exchange of histone variants (e.g., H2A.Z, H2AX, macroH2A, H2A-Bbd, H3.3 and CENP-A) into and out of chromatin.
Our long-term goal is to gain mechanistic insights into how histone modifications and variants regulate critical epigenetic events to attenuate various cellular malignancies, especially cancer development. To investigate these aspects, we have established powerful protocols to interrogate the cellular function of histone modifications and variants as a signal which would facilitate the recruitment/retention of epigenetic regulators at their target sites in chromatin. Using these experimental systems, current research efforts are mainly directed towards understanding how such diverse histone modifications and variants are localized to specific regions of chromatin under a distinct condition and how modified histones and incorporated variants influence epigenetic pathways in cell growth and differentiation.
1. Histone modifications: Although the underlying mechanism has not been unraveled, an emerging body of evidence supports that specific histone modifications serve as marks for the recruitment of effector molecules to activate downstream signaling events. In this project we are trying to identify and characterize factors which recognize a unique pattern of histone modifications within nucleosomal context to potentiate or antagonize gene transcription.
2. Histone variants: Histone variants have the ability to substitute their canonical counterparts and to establish chromatin domains with specific functional properties. In this project we are aiming to compare the localization patterns of histone variants between different cell types and to uncover the perturbation of replication-independent variant exchange in cancer cells. This project employs multiple approaches including ChIP-seq and gene expression profiling.
3. Linker histone H1: So far, most studies have focused on the contribution of linker histone H1 as a structural component of chromatin. However it is becoming apparent that H1 also acts as a specific gene regulator (e.g., p53 target genes) by interacting with many different non-histone proteins. Our current efforts are aimed at understanding the role of individual H1 isoforms in specific gene transcription and the molecular basis for the observed function.