What We Do
The First Advances in Precision Medicine (APM 2021) Conference:
Transgenerational Inheritance of Epigenetic Information
The notion of the transgenerational inheritance of environmentally acquired traits has been a subject of heated debate for centuries. Almost 100 years after the first spectacular observation of transgenerational inheritance of acquired traits by Paul Kammerer, we are yet to recognize the existence of such Lamarckian inheritance. Here, we have created an epigenome editing toll-kit that enables us to precisely modify and edit various epigenetic marks at an organismal level. We have strong evidence that the modified epigenetic marks can be inherited from a dividing mother cell to the daughter cells and, more importantly, from one generation to the next. Pourkarimi’s lab research focuses on understanding the mechanism underlying such epigenetic transmission. We use cutting-edge technology such as epigenome editing tool kit, SILAC based proteomics, and forward and reverse genetic screens to tackle such a fundamental question in epigenetic.
Epigenetic modifiers, such as those defining genetic enhancers and promoters, are associated with DNA replication origins. Surprisingly, a fertilized zygote inherits these modifications from the parental generation. That makes us how such important epigenetic modification can be inherited from one generation to the next! This critical question keeps us motivated and awake. We use a multidisciplinary approach to find the answer!
Understanding the Role of Chromatin Modifiers in DNA Damage-Induced Apoptosis and DNA repair
We have a long-lasting interest in identifying novel DNA damage-induced cell cycle arrest and apoptosis regulators. Post-translational histone proteins are the key elements that regulate gene expression while controlling chromatin compaction. These heritable modifications are essential for maintaining the higher-order chromatin structure and play critical roles in genome stability and DNA repair. We have recently identified novel chromatin-associated proteins whose knockdown results in hypersensitivity to cancer drugs such as Hydroxyurea (HU). Upon DNA damage, Chk1, Checkpoint kinase 1, is activated through the function of DNA damage sensors such as ATM and ATR. Chk1 activation inhibits CDK1, leading to cell cycle arrest and apoptosis. In this project, students will perform a different genome-wide RNAi screen to identify genes that cause hypersensitivity or resistance to genotoxic agents such as HU upon depletion. Using a high-throughput reverse genetic approach combined with cutting-edge imaging technology and genomics approach, we aim to identify new players of the DNA damage repair that work at the apex of DNA damage sensing and the DNA repair pathway genotoxic induced apoptosis.
Electron micrograph of an isolatted C. elegans germaline, 24 hours post gamma radiation. Cells marked with astrics show classical feature of an apoptotic cell death, Mahmoud Izadi et al, 2021.
Characterizing the human disease-causing mutations in a model system
Cancer cells have a profound and rapid cell division pace, which will constrain cells to adjust their rate of protein synthesis while adapting to the limited nutrition availability in their microenvironment. Thus, targeting translation machinery components by therapeutics can serve as the Achilles’ heel for tumor cells, opening doors and strategies for cancer therapy. Mutations in the translational machinery component, including the component of a ribosomal complex, and the protein family responsible for loading tRNA with their corresponding amino acids, are seen in cancer patients. Aminoacyl tRNA synthetases (Aars) are a family of proteins responsible for loading the correct amino acid to its cognate tRNA, a crucial and limiting factor during protein synthesis.
Although at a first superficial glance, they are housekeeping genes essential for ensuring the high fidelity of translation, a mutation in Aars is associated with various human diseases such as neurological disorders and cancer. The gain of function mutation of some of the members of the Aars protein family is reported to be associated with cancer progression and metastasis.
My lab uses C. elegans as a tractable genetics system to model human diseases like cancer and autoimmune disorders. This project aims to uncover the non-canonical function of aminoacyl tRNA synthetase relevant to cancer. We have recently identified a novel function of some of the members of the Aars protein family in cell cycle progression and programmed cell death in C. elegans. Using genetics and biochemical approaches, we investigated how mutations of Aars proteins can promote cancer and other human diseases.
Establishing an all-in-one Toolkit for Epigenome Editing
Using epigenome engineering, we can modify the epigenome landscape. At Pourkarimi lab we are continually investing in developing a new all in one toolkit for epigenome editing.
