Epigenetic switches: molecular mechanisms underlying transitions between epigenetic states

Funding Type: 
Basic Biology II
Grant Number: 
RB2-01602
ICOC Funds Committed: 
$0
Disease Focus: 
Epilepsy
Neurological Disorders
Stem Cell Use: 
Embryonic Stem Cell
Public Abstract: 
Life begins with single fertilized zygote that through the process of differentiation gives rise to every cell type in human body. Amazingly the embryonic stem cells and induced pluripotent cells retain that potential and thus provide exciting hope for therapeutic applications. In the process of differentiation cells “make a decision” and “learn” what their job in the body is and often have to remember that decision for a lifetime, while retaining the ability to interact with their environment. In our proposal aims at investigating the nature of this cellular memory and plasticity and at understanding the mechanism by which certain genes are turned on or turned off during differentiation. Scientific evidence suggests that an indexing system exists that is based on chemical modifications of proteins organizing DNA into chromatin to regulate gene expression. Some of these modifications act as signals marking particular genes to be active, while others mark inactive genes. This indexing system needs maintenance and there are specialized proteins, called chromatin modifying enzymes that maintain chromatin modifications, thus acting as a “memory”. However, chromatin modifying machines are also capable of switching one indexing state (e.g. active) to another (e.g. inactive) at a particular gene locus in response to a signaling event. We recently discovered a novel chromatin modifying complex, that may work in mediating such epigenetic switches during development and embryonic stem cell differentiation. We propose here to test the hypothesis that this complex enzyme is indeed a switch, to investigate the exact mechanism of the switch at the molecular level and determine which regions of genome are the targets for the switch complex at different times during differentiation. We anticipate that these studies will advance our understanding of basic biological processes underlying the developmental decisions of differentiating stem cells. Such advancements could contribute to improvements in stem cell derived therapies.
Statement of Benefit to California: 
Since the nature of basic science is to tackle the “unknown unknowns” we can’t make specific promises for short-term health benefits to the residents of California. Nevertheless, research proposed here addresses fundamental questions regarding mechanisms of gene regulation in stem cells and during human development and thus, in the long-term, it is likely to have a high impact on development of cell replacement therapies, for harnessing the potential of personalized medicine and for identification of novel drug targets to combat cancer and age-related diseases. Other tangible and immediate benefits for the community include: - creations of at least 2 new jobs in a high skill sector - contribution to the training of new workforce in a set of unique skills in human stem cell technology - creation of new intellectual property that would benefit local institution and by extension local community. - boosting local economy since we buy our supplies from local vendors whenever possible.
Progress Report: 
  • We have been developing new methods to identify the products of stems cells that are differentiated in tissue culture dished. We are focusing on generating a specific type of neuron - cortical interneuron. To this end, we have identified specific sequences in the human genome that drive gene expression in the immature cortical interneurons. Results from the first year of our work provide evidence that our method to use these gene expression elements is working to help us identify cortical interneurons.
  • We have identified 5 gene regulatory elements (enhancers) that can promote gene expression in a specific type of neuronal precursor and neuron. We found that these enhancers can be used to aid in the identification and isolation of these types of cells from embryonic stem cells. In other studies, our group is testing the feasibility of using these types of cells to ameliorate neurological disorders, such as epilepsy.
  • We have identified 5 gene regulatory elements (enhancers) that can promote gene expression in a specific type of neuronal precursor and neuron. We found that these enhancers can be used to aid in the identification and isolation of these types of cells from embryonic stem cells. In other studies, our group is testing the feasibility of using these types of cells to ameliorate neurological disorders.

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