Description:

The Department of Biochemistry and Molecular Genetics Departmental Seminar Series presents:

Alex Ruthenburg, PhD
Neubauer Family Foundation Assistant Professor
Molecular Genetics and Cell Biology, Biochemistry and Molecular Biology
University of Chicago

I will present several unpublished stories from my lab all thematically related by the use of biochemical fractionation to drive epigenetic pathway discovery. The first is centered on deciphering epigenetic pathways linked to MLL-rearranged leukemia, and the second vignette is our recent discovery of a new class of noncoding RNAs that act as enhancers.

Part 1: MLL1-rearrangements are thought to cause leukemia by inappropriately maintaining the expression of several transcription factors that promote self-renewal through epigenetic mechanisms. Both histone modifications, particularly the H3K79 methylation installed by the DOT1L enzyme, as well as 5-methylC adducts, such as 5-hydroxymethylC (5hmC) in DNA installed by the TET family of oxidases, play essential roles in both the initiation and progression of MLL-rearranged leukemias. As there are no known specific binding partners for these putative epigenetic marks, the pathways by which they act remain completely obscure, and consequently our understanding of the molecular mechanisms by which they allow MLL1-r-mediated cancer to develop and self-renew is limited. We have identified several highly-specific binding factors using fractionation biochemistry and validated the binding partners-- these discoveries now serve as critical inroads to understanding the pathways that emanate from these marks.

Part 2: Our biochemical fractionation of nuclei has revealed a class of previously unannotated long noncoding RNA species defined by their tight association with chromatin (cheRNA). This class of molecules is a far better predictor of cis-gene transcriptional activity than chromatin enhancer signatures and is distinct from eRNA (bi- directionally transcribed from enhancer elements). I will present recent evidence we have developed showing the generality of this phenomenon, the sharp tissue-specificity of cheRNA expression, and the direct role that the cheRNA molecules play in driving proximal coding gene transcription and other mechanistic insights.