Debler Research
Contact
1020 Locust Street
JAH 411F
Philadelphia, PA 19107
The Debler Lab focuses on the structure and function of macromolecular machines and assemblies with a focus on genome maintenance and gene expression to understand their mechanism of action in health and disease at atomic resolution. We are particularly interested in understanding mechanisms of histone modifications and their recognition, as well as nucleosome remodeling. In addition to insights into the biology of these areas, our studies are aimed at providing a foundation for developing novel chemotherapeutic approaches, specifically against cancer and African sleeping sickness caused by the protozoan parasite Trypanosoma brucei.
Research Projects
Trypanosome Biology
Protozoan parasites termed kinetoplastids cause tremendous mortality and morbidity worldwide with more than half a billion people affected by their infections and represent masters of differentiation, as they seamlessly proceed through morphologically and physiologically distinct stages during their life cycles in different host organisms. Our research aims at dissecting the molecular machineries and mechanisms underlying gene expression, differentiation, and immune evasion in Trypanosoma brucei at atomic resolution. We seek to apply this knowledge in order to develop novel effective therapies for protozoan parasitic diseases.
Structure & function of chromatin regulators in protozoan parasites
It is well established that trypanosomes utilize a host of posttranscriptional mechanisms to regulate gene expression. However, we recently discovered that a class of chromatin regulators termed bromodomains is involved in life-cycle stage control, pointing towards an important, but thus far underappreciated role of transcriptional gene regulation in T. brucei. Specifically, we found that bromodomain inhibition in virulent bloodstream-form parasites in mammals leads to biochemical and physiological changes that are consistent with differentiation to the procyclic stage in the tse-tse insect vector. Our goal is to decipher the molecular mechanisms that regulate gene expression and other processes on the chromatin level in protozoan parasites.
Life-cycle stage reprogramming as a new strategy to combat protozoan parasitic diseases
African trypanosomiasis is a fatal parasitic disease that causes sleeping sickness in humans and n’agana in livestock. There is a significant unmet need for the development of efficacious anti-trypanosomal drugs, as the few drugs available have severe side effects, resistance is on the rise, and the pharmaceutical industry is generally less likely to invest in neglected tropical diseases. Based on our proof-of-principle discovery that a small molecule termed I-BET151 targeting Trypanosoma brucei chromatin proteins reprograms the life-cycle stage of the parasite from the virulent bloodstream form to a much less virulent insect-stage form that can be cleared by the immune system, we propose to develop this transformative approach into an effective chemotherapy for trypanosomiasis.
Immune evasion by monoallelelic expression of variant surface glycoprotein (VSG)
In the mammal, the African trypanosome resides extracellularly in its bloodstream form where it is densely covered with highly immunogenic Variant Surface Glycoprotein (VSG). By periodically switching this VSG from a repertoire of ~2500 distinct VSG genes by means of monoallelic expression, trypanosomes are masters of camouflage and successfully evade the immune system. This work will tackle the fundamental, long-standing question in eukaryotic biology of how allelic exclusion within a multi-gene family of alleles is achieved and will have profound implications for other fields, such as neuroscience (monoallelic expression of odorant receptors) and immunology (monoallelic expression of B-cell receptors).
Immune evasion by monoallelelic expression of variant surface glycoprotein (VSG)
In the mammal, the African trypanosome resides extracellularly in its bloodstream form where it is densely covered with highly immunogenic Variant Surface Glycoprotein (VSG). By periodically switching this VSG from a repertoire of ~2500 distinct VSG genes by means of monoallelic expression, trypanosomes are masters of camouflage and successfully evade the immune system. This work will tackle the fundamental, long-standing question in eukaryotic biology of how allelic exclusion within a multi-gene family of alleles is achieved and will have profound implications for other fields, such as neuroscience (monoallelic expression of odorant receptors) and immunology (monoallelic expression of B-cell receptors).
Cancer Biology
Transcriptional control of cell fate via the tumor suppressor p53
Cell fate decisions underlie critical biological processes like development, stress adaptation, the immune response, and malignant transformation. These cellular decisions depend on dynamic changes in the gene expression program. For most forms of cellular stress in humans, the p53 transcription factor is the central driver of adaptive gene expression programs. Interestingly, p53, like many key transcription factors, can trigger distinct cell fates in different contexts. We aim to resolve a central paradox in p53 biology: how can a single transcription factor that relies on a static code to recognize loci in the genome, drive multiple, distinct gene expression programs and cell fates?
Nucleosome Remodeling
Finally, we conduct mechanistic studies on ALC1 (amplified in liver cancer 1), also known as CHD1L, which is an ATP-dependent nucleosome remodeler involved in base excision repair. ALC1 is differentiated from other members of the ISWI-related remodelers by virtue of a C-terminal macrodomain, which possesses high intrinsic affinity for poly(ADP)-ribose (PAR) chains. Through its macrodomain, ALC1 is rapidly recruited to sites of DNA damage by PAR chains synthesized by PARP1/2. Macrodomain binding to PAR chains also relieves an autoinhibitory interaction between the macrodomain and ATPase domain of ALC1, which activates ATP hydrolysis and nucleosome sliding.