Noncoding RNAs in Cell Fate Determination

Noncoding RNAs in Cell Fate Determination

Funding Type: 
New Faculty I
Grant Number: 
RN1-00529
Award Value: 
$2,985,894
Stem Cell Use: 
Embryonic Stem Cell
Status: 
Closed
Public Abstract: 
Statement of Benefit to California: 
Progress Report: 

Year 1

All the cells in the human body carry the same genetic information in the form of DNA. The process of choosing which genes are stably switched ON or OFF, termed epigenetics, determines whether a cell will become a brain cell, heart cell, or skin cells. This work seeks to understand the epigenetic control when stem cells become differentiated cells. In the previous funding period, we have uncovered mechanisms governing the choice between self-renewal (a stem cell copying itself to make more stem cells) versus differentiation (a stem cell becoming a specialized cell and no longer dividing). An enzyme named UTX is a histone demethylase, which function by changing the packaging of DNA in cells, termed chromatin. We discovered that in differentiated cells, but not embryonic stem cells, UTX controls genes that makes cells stop dividing and differentiate. One of these UTX target genes includes RB, a gene that is important to prevent cancerous growth. The next goals are to understand how UTX and other enzymes that open up chromatin are deployed to specific genes to control stem cell behavior. We suspect that a new type of genes termed long noncoding RNAs are the key guiding mechanisms for enzymes to specific genes.

Year 2

The human body is composed of thousands of cell types, which all came originally from embryonic stem cells. Although all these cell types have the same genetic blueprint, different genes are active in different cells in order to give each its distinctiveness. The process by which the genes remember whether they are in liver, brain, or skin cells is called “epigenetics.” A central problem in regenerative medicine is to understand the epigenetic program so that human embryonic stem cells can be efficiently turned into the cell types required for each specific patient. Conversely, by manipulating the epigenetic program, adult cells may be reprogrammed into primitive cells that can turn into other cell types to repair diseased or damaged tissues. The goal of the proposed research is to better understand the epigenetic program in human embryonic stem cells and adult cells. We want to tap into the natural mechanisms by which the body normally “remembers” what kinds of cells reside in each tissue and apply them to regenerative therapies. Specifically, the research will study the roles of a newly discovered type of genes, termed “noncoding RNAs”, in stem cell epigenetics. A better understanding of how cells remember their own fates can improve regenerative medicine in several ways. First, by appreciating the roles of noncoding RNAs in this process, specific noncoding RNAs can be used as markers to track and predict when cells are acquiring or forgetting specific cell fates. For instance, it may be possible to learn from the pattern of noncoding RNAs that an embryonic stem cell is ready to become brain cells, which can be used to treat a patient with stroke. Second, beyond tracking cell fate, noncoding RNAs may be used to directly manipulate stem or adult cell fates. By introducing noncoding RNAs from different cell types, embryonic stem cells or adult cells may be directly reprogrammed into the desired cell type. While these potential application are far in the future, we believe that better knowledge of this new level of gene regulation will one day lead to more facile and efficient manipulation of cell fates for regenerative medicine.

Year 3

The human body is composed of thousands of cell types, which all came originally from embryonic stem cells. Although all these cell types have the same genetic blueprint, different genes are active in different cells in order to give each its distinctiveness. The process by which the genes remember whether they are in liver, brain, or skin cells is called “epigenetics.” A central problem in regenerative medicine is to understand the epigenetic program so that human embryonic stem cells can be efficiently turned into the cell types required for each specific patient. Conversely, by manipulating the epigenetic program, adult cells may be reprogrammed into primitive cells that can turn into other cell types to repair diseased or damaged tissues. The goal of the proposed research is to better understand the epigenetic program in human embryonic stem cells and adult cells. We want to tap into the natural mechanisms by which the body normally “remembers” what kinds of cells reside in each tissue and apply them to regenerative therapies. Specifically, the research will study the roles of a newly discovered type of genes, termed “noncoding RNAs”, in stem cell epigenetics. A better understanding of how cells remember their own fates can improve regenerative medicine in several ways. First, by appreciating the roles of noncoding RNAs in this process, specific noncoding RNAs can be used as markers to track and predict when cells are acquiring or forgetting specific cell fates. For instance, it may be possible to learn from the pattern of noncoding RNAs that an embryonic stem cell is ready to become brain cells, which can be used to treat a patient with stroke. Second, beyond tracking cell fate, noncoding RNAs may be used to directly manipulate stem or adult cell fates. By introducing noncoding RNAs from different cell types, embryonic stem cells or adult cells may be directly reprogrammed into the desired cell type. While these potential application are far in the future, we believe that better knowledge of this new level of gene regulation will one day lead to more facile and efficient manipulation of cell fates for regenerative medicine.

Year 4

The human body is composed of thousands of cell types, which all came originally from embryonic stem cells. Although all these cell types have the same genetic blueprint, different genes are active in different cells in order to give each its distinctiveness. The process by which the genes remember whether they are in liver, brain, or skin cells is called “epigenetics.” A central problem in regenerative medicine is to understand the epigenetic program so that human embryonic stem cells can be efficiently turned into the cell types required for each specific patient. Conversely, by manipulating the epigenetic program, adult cells may be reprogrammed into primitive cells that can turn into other cell types to repair diseased or damaged tissues. The goal of the proposed research is to better understand the epigenetic program in human embryonic stem cells and adult cells. We want to tap into the natural mechanisms by which the body normally “remembers” what kinds of cells reside in each tissue and apply them to regenerative therapies. Specifically, the research will study the roles of a newly discovered type of genes, termed “noncoding RNAs”, in stem cell epigenetics. A better understanding of how cells remember their own fates can improve regenerative medicine in several ways. First, by appreciating the roles of noncoding RNAs in this process, specific noncoding RNAs can be used as markers to track and predict when cells are acquiring or forgetting specific cell fates. For instance, we have started to learn from the pattern of noncoding RNAs that an embryonic stem cell is ready to become a specific cell type, which can be used to tailor stem cell derivative to treat diseases lacking that cell type. Second, beyond tracking cell fate, noncoding RNAs may be used to directly manipulate stem or adult cell fates. By introducing noncoding RNAs from different cell types, embryonic stem cells or adult cells may be directly reprogrammed into the desired cell type. While these potential application are far in the future, we believe that better knowledge of this new level of gene regulation will one day lead to more facile and efficient manipulation of cell fates for regenerative medicine.

© 2013 California Institute for Regenerative Medicine