Genetic regions, like the Arctic’s frozen wastes, may be all but inaccessible, posing a challenge to explorers, who live to map the unknown. Such explorers include researchers at the University of Pennsylvania led by Golnaz Vahedi, Ph.D., an assistant professor of genetics. Dr. Vahedi and her team decided to venture into “locked in” chromatin, where DNA is so tightly coiled that it remains outside the flow, beyond the reach of transcription factors.
Well, not all transcription factors. There is transcription factor called TCF-1 that, according to Dr. Vahedi’s team, opens up tightly packed chromatin like an icebreaker plowing through sea ice. Not only that, TCF-1 creates a passage that other transcription factors may follow, enabling the expression of previously silent genomic regions. The regions of interest to the Vahedi expedition make up the regulatory landscape of T-cell development.
The new connection between TCF-1 and chromatin will improve our understanding of how T-cell lineages arise. It may also aid the development of therapies that use epigenetic drugs to alter T-cell fate in cancer, autoimmune disorders, and infectious diseases.
Details of the new work appeared February 20 in the journal Immunity, in an article entitled “Lineage-Determining Transcription Factor TCF-1 Initiates the Epigenetic Identity of T Cells.” This article describes how Dr. Vahedi and colleagues profiled chromatin accessibility at eight stages of T-cell development, and how the earliest stages of development depended on selective enrichment of TCF-1.
Essentially, TCF-1 opens chromatin so that DNA can be read to make proteins, and it also keeps chromatin open so that subsequent factors can access DNA to make protein that guides a maturing T cell to its final identity. This mechanism helps explain the functional importance of TCF-1 in T cells, which has been appreciated for more than 25 years.
The team generated a profile of open and closed areas in eight stages of T-cell development and found an abundance of the transcription factor TCF-1 at regions along the genome that were open at the earliest stages of development.
“TCF-1 was further required for the accessibility of these regulatory elements and at the single-cell level, it dictated a coordinate opening of chromatin in T cells,” the article’s authors explained. “TCF-1 expression in fibroblasts generated de novo chromatin accessibility even at chromatin regions with repressive marks, inducing the expression of T cell-restricted genes.”
“Our lab is interested in understanding how T-cell identity is established,” Dr. Vahedi noted. “We chose to study T cells because of their all-important role in patrolling the body to clear it of germs and such other dangers as cancer cells.”
Dr. Vahedi’s team established the identity-making role for TCF-1 by deleting it in a mouse model. They found that most open sites closed, becoming inaccessible in tightly wound chromatin. On the other hand, when they added TCF-1 to a type of common skin cell, it “broke the ice” and opened closed regions by removing chemical groups that tighten chromatin. The elongated fibroblasts reprogrammed to become more T-cell-like in shape, and hundreds of T-cell genes were also expressed in these skin cells.
Using computational and epigenomic methods, the team found that TCF-1 behaved in a similar manner on the chromatin of individual T cells. Because of the consistency among many cells, they concluded that TCF-1 control of T-cell fate is fundamentally important in determining what a cell will become.
“We showed how TCF-1 controls T-cell fate through its ability to target closed chromatin and establish the identity of developing T cells,” Dr. Vahedi asserted. “TCF-1 is the focus of many immunology and oncology studies, especially those dealing with checkpoint inhibitors and sick immune cells. We think that the 'ice-breaking' ability of TCF-1 can be selectively harnessed to reset 'old' T cells to a 'younger' state so they can fight invaders again.”