Researchers at the Stowers Institute for Medical Research reveal that a specific DNA locus plays a crucial role in protecting hematopoietic, or blood-forming, stem cells. This particular location in DNA is called the Dlk1-Gtl2 locus. The study highlights the significance of metabolic control in adult stem cells, providing insight for potentially diagnosing and treating conditions like cancer. The study was published in the journal Cell Stem Cell.
The researchers and the collaborators at the institute reveal that the mammals have imprinted Gtl2 which is located on the mouse chromosome 12qF1. It protects adult hematopoietic stem cells by restricting metabolic activity in the mitochondria of the cell.
The study focused on imprinted genes. These genes are stamped according to whether they are inherited from the mother or father. With imprinted genes, one allele or working copy is inherited instead of two. Either the copy from the mother or father is silenced or inactivated. Normally, the alleles inherited paternally express or promote growth. On the other hand, the maternally inherited allele’s expression suppresses it.
The findings of the study suggest that the Gtl2 locus, expressed from the maternally inherited allele, produces non-coding RNAs. These RNAs work to curb the metabolic activity. The mega cluster of microRNA by Gtl2 locus is the largest cluster of microRNA in the mammalian genome.
Mechanistically, it suppresses the mTOR signaling pathway and downstream mitochondrial biogenesis and metabolism. Consequently, it blocks the byproducts associated with mitochondria. These byproducts are called reactive oxygen species (ROS) that are inevitable derivatives of the mitochondrial metabolic process. They can potentially damage the cells and thus should be managed strictly.
What do the findings suggest?
Hematopoietic stems cells renew themselves and differentiate into white blood cells, red blood cells, and platelets. They constantly renew the body’s blood supply in a process called hematopoiesis. The transplantation or transfusion of isolated human hematopoietic stem cells have been used in the treatment of,
- Immune deficiencies
The findings of the study highlight the sensitive metabolic control required to balance hematopoietic stem cell maintenance, health, and action. An upset in the balance can cause cells to grow abnormally and lead to diseases.
Abnormal allelic expressions on the Gtl2 locus, on human chromosome 14q32.2, are associated with uniparental disomy. It arises when an individual receives two copies of a chromosome from one parent and no copy from the other parent. The condition may promote medical problems like delayed development and mental retardation. The abnormalities in the expression have also been linked to fetal alcohol exposure disorder.
Note that when working properly, the Gtl2 locus acts as a great protector of cells. It functions to suppress tumors and maintain normal cell function. In subsequent experiments, deletion of the locus from the maternally inherited allele in hematopoietic stem cells increased mitochondrial biogenesis and subsequent metabolic activity. This led to increased levels of corporal ROS which can cause cell death.
The research scientists are looking for using the Gtl2 locus as a biomarker because it could help label dormant or reserve stem cells in normal or cancerous stem cell populations. Adding a fluorescent tag to the locus could allow marking other adult stem cells in the gut, hair follicle, muscle, and neural systems.