Alexander Tarakhovsky, MD, PhD

The Rockefeller University, NY

2012 B Cells, New Treatments

Alexander Tarakhovsky, MD, PhDTargeting of epigenetic readers to control lupus

The Study and What it Means to Patients

New to lupus, my team is exploring an entirely new therapeutic strategy one that aims to reverse autoimmunity by targeting proteins that switch on ‘bad’ genes in lupus B cells by a process called epigenetics.

Summary:
Could changes in gene activity that do not involve changes to the genetic code explain why the lupus immune system turns on the body? The role of such ‘epigenetic’ gene control in autoimmunity is just beginning to be explored. Drawing on our experience in B cell biology and epigenetics, my team will seek to uncover how B cell survival in lupus and in normal mice is controlled by modifications of DNA binding proteins. We will also test in mice an entirely new therapeutic approach for lupus that aims to reverse autoimmunity by targets a specific part of the cell’s epigenetic machinery.

Our work will use cutting-edge high throughput approaches to provide the first in depth analysis of epigenetic changes in lupus B cells. The Novel Research Grant from LRI is allowing us to explore an entirely new therapeutic approach  to lupus.

Scientific abstract:
Identification of genetic mechanisms responsible for initiation and progression of lupus is essential for the development of a novel approaches for treatment of this life-threatening disease. Regulation of gene expression depends largely on DNA-associated chromatin proteins. The chromatin exerts its influence on gene expression via epigenetic mechanisms. The latter are grossly governed by histone proteins, which control the assembly and function of multiple transcription complexes. The current study addresses two fundamentally novel aspects of lupus. First, it addresses the poorly understood epigenetic mechanism of the wild-type and a lupus-prone B cell survival driven by pro-survival ligand BAFF. Second, it describes a novel pharmacological approach for the regulation of gene expression by direct targeting of protein “readers” of epigenetic information. The proposed experiments bear significant promise for the discovery of novel mechanisms and treatment of lupus in mice, which could be potentially extended to human lupus. The analysis of epigenetic marks by ChIP sequencing and RNA sequencing are at the core of our studies. The Illumina HiSeq 2000 is a high-throughput DNA sequencing instrument capable of sequencing up to 55 gigabases per day. The proposed experiments will also employ in vitro B cell culture, analysis of B cell phenotype by FACS and in vitro assays that measure the degree of B cell activation. We will also conduct animal experiments and carry out a relatively large scale pharmacological analysis of the anti-lupus potential of a novel compound iBET, which has been discovered by us and has a selective activity towards a particular class of epigenetic regulators.