Research

The work in our lab focuses on understanding the molecular mechanisms for epigenetic memory and regulated gene expression through the study of chromatin and RNA. Transcription of RNA is a highly orchestrated and dynamic process controlled at several distinct steps. Synthesis of messenger RNA can be regulated at the level of RNA Pol II transcriptional initiation, promoter-proximal pausing, or functional elongation. Once a mature RNA is synthesized, its stability is controlled through factors such as its codon content, 5’ cap presence, and cellular localization. With such diverse strategies to control RNA transcript levels in a cell, it is unsurprising that each step is important in disease and therapeutic contexts. While RNAs are continuously transcribed and degraded in vivo, methods such as RNA-sequencing only provide us with a snapshot of RNA abundance. To reveal the rich regulated dynamics of the transcriptome, we have developed a suite of chemical approaches that make use of TimeLapse chemistry, a nucleotide recoding technique. We have also developed first-in-class bioinformatic tools designed to increase the power and rigor of analyses of nucleotide recoding sequencing (NR-seq) experiments. In order to investigate the interplay between chromatin and RNA, we use a wide range of approaches including the development of new chemical & biochemical technologies. Projects in our lab are frequently collaborative and integrate diverse areas including synthetic chemistry, cell biology, biochemistry, bioinformatics, and molecular biology. Most recently, our lab identified a novel histone post-translational modification in which cellular lysine residues are both methylated and acetylated on the same side chain to form Nε-acetyl-Nε-methyllysine (Kacme). We have shown that Kacme is found on histone H4 (H4Kacme) across a range of species and across mammalian tissues. Kacme is associated with marks of active chromatin, increased transcriptional initiation and is regulated in response to biological signals.