New research at Stowers Institute for Medical Research states that epigenetic regulation of Hoxb genes promotes healthy blood-forming stem cells and inhibits leukemia. The hox family comprises of transcription factors that regulate the formation of blood cells and the development of leukemia. It is a large family of genes, distributed in four separate chromosomal clusters named A through D. Their regulation, however, is less clear.
This innovative research from the Stowers Institute reveals that the Hoxb cluster has a DNA regulatory element which mediates signals to the majority of Hoxb genes. It controls the gene expression in the production of blood-forming stem cells.
The mammalian blood system consists of a number of mature cell types like,
- White blood cells or WBCs
- Red blood cells or RBCs
All of these cells originate from blood-forming, or hematopoietic, stem cells (HSCs). HSCs rejuvenate and differentiate into other cells. In this way, they replenish the blood supply to a body via a process called hematopoiesis. Hox genes are already well known for their roles in establishing the body plan of developing organisms. Moreover, they are also important for HSCs to maintain their critical balancing act in the adult blood system. Furthermore, hox genes have been associated with the development of leukemia.
The research was issued in an article, published in the journal Cell Stem Cell. It details out how hox genes are regulated in HSCs.
How does the study explain gene regulation?
The researchers report that a single cis-long-range-regulatory element, DERARE, controls the majority of hoxb genes in HSCs. It works in a coordinated manner such that the loss of the DERARE decreased the expression of hoxb. Consequently, the types of blood cells arising from HSCs were altered. On the other hand, turning on DERARE promoted the gene expression of the hoxb cluster in progenitor cells and enhanced the progression of leukemia.
Cis-regulatory sequences are non-coding DNA sequences that potentially regulate genes. These sequences get input from multiple types of molecules including,
- Transcription factors
- Histone modifiers
DERARE is the abbreviation of the distal element retinoic acid response element. It is a cis-regulatory element that responds to the signals from retinoic acid and determines the fate of HSCs. Retinoic acid is a derivative of vitamin-A.
The Stowers researchers used human leukemia cell lines and mouse models for the study. They investigated and recognized a method for how the retinoid-sensitive DERARE maintains normal hematopoiesis and prevents acute myeloid leukemia (AML). It works so by regulating Hoxb cluster genes in a methylation-dependent manner.
Methylation accounts for the addition of methyl groups in the DNA molecule. It significantly changes the activity of the DNA segment. DNA methyltransferases are the enzyme behind the process. They mediate DNA methylation on DERARE and cause a reduced Hoxb cluster expression. AML patients have mutated DNA methyltransferase DNMT3A. They exhibit reduced DERARE methylation and have an elevated Hoxb expression as a consequence. Thus, they observe adverse outcomes.
The researchers used an adaptation of genome editing technology in two human AML cell lines carrying a DNMT3A mutation. The technology is called dCas9-DNMT3A and it specifically increases the DNA methylation on DERARE. This targeted methylation technique reduced the expression of hoxb cluster and alleviated the progression of leukemia.
Hoxb cluster genes showed a dramatic increase in expression within the patients with DNMT3A-mutated AML. This research provides a mechanistic insight into the use of DNA methylation on the DERARE as a potential screening tool for therapeutic drugs, targeting DNMT3A-mutated AML. It leads to the development of new drugs for treating AML with abnormal DNA methylation.