Thousands of genes affected by DNA loop changes caused by the cancer-causing HTLV-1 virus

New research exposes that the human leukemia virus (HTLV-1) disrupts the regulation processes of thousands of genes and changes intracellular DNA loops, raising the risk of a rare type of leukemia.

The virus affects many sections of the human genome

The research, published by the eLife Journal, exposes that the human leukemia virus (HTLV-1) acts on an extensive number of locations of the human genome. With such a behavior it manages to disrupt the regulation processes of thousands of genes and hence changes intracellular DNA loops. With such a mechanism, the virus raises the risk of a rare type of leukemia.

The team from the Imperial College London and European Bioinformatics Institute (EMBL-EBI), exposed how the HTLV-1 virus changes the folding pattern of human DNA in affected cells. The risk of leukemia is increased, according to the researchers, because of the gene function disruption triggered by the virus.

Humans can be asymptomatic carriers of the virus for decades, while up to 90% of carriers may be unaware of their diagnosis. Some 5 to 10 percent of those infected may develop an aggressive form of leukemia or even a progressive paralytic disease. Forms of viral transmission include unprotected sex, blood transfusions, and mother-to-infant transmission via breastfeeding. HTLV-1 is estimated to have infected some 10 million people worldwide at present. 

The researchers analyzed the interactions of HTLV-1 with human DNA as the virus focuses on attacking the specialized white blood cells (T cells) in an infected host. A human cell contains at its nucleus some two meters of DNA, packed in a dense coiled structure, the chromatin. In itself, the chromatin is folded in loops that protrude from the main structural strand. It is here where the problem lies. With these loops, DNA sections are exposed and vulnerable to a cell’s process able to copy DNA sections, allowing for the genome to be read and transcribed, with the possibility that any disruption or replacement with new loops can affect (and more specifically, displace) a gene’s expression, a risk that may be associated with disease incidence. 

Researchers isolated the T-cells of HTLV-1-infected patients and analyzed their altered DNA regions. This enabled them to find how the virus binds to the CTCF protein, a crucial element in the formation of the genome’s normal loops. The virus is able therefore to change the loop structure, and furthermore, a gene’s internal activity. Imperial College London’ Chair of Immunology at the Department of Medicine, Professor Charles Bangham, and the study’s leading author explained that with a binding process done in the genome, the HTLV-1 retrovirus “can alter chromatin loops and disrupt how a number of important genes are regulated. This can lead to the abnormalities and disease, such as leukemia associated with HTLV-1." And the vulnerability to this alteration is extensive, as the human genome possesses a large number of CTCF sites that gives the HTLV-1 virus the opportunity to affect tens of thousands of genes. 

The research team argues that their findings not only expands our understanding of how viruses like HTLV-1 alter the human genome structure. Moreso, they believe that in understanding how the human T-cell leukemia virus works and integrating complex genomic data, scientists will be able to determine why some patients suffer the virus’ harsh symptoms and others stay asymptomatic.

Anat Melamed, Hiroko Yaguchi, Michi Miura, Aviva Witkover, Tomas W Fitzgerald, Ewan Birney, Charles R. M. Bangham, "The human leukemia virus HTLV-1 alters the structure and transcription of host chromatin in cis". 
bioRxiv 277335;