Study provides new view of immune cell identity, which can be harnessed to fight cancer, autoimmune disorders, and infectious diseases
Almost all cells in the human body have identical DNA sequences, yet there are 200-plus cell types with different sizes, shapes, and chemical compositions. Determining what parts of the genome are read to make protein and which are silenced is orchestrated by proteins called transcription factors. These regulate the availability of distinct stretches of DNA to be expressed as opposed to others that remain buried in tightly coiled structures called chromatin.
Researchers in the Perelman School of Medicine at the University of Pennsylvania, describe this week in Immunity the role of a transcription factor called TCF-1 in targeting the condensed chromatin and regulating the availability of genome sequences in T-cell development. The new connection between TCF-1 and chromatin will aid in developing new therapies using epigenetic drugs to alter T-cell fate in cancer, autoimmune disorders, and infectious diseases.
Senior author Golnaz Vahedi, PhD, an assistant professor of Genetics, brings her multidisciplinary training in computational biology, epigenetics, and immunology to bear on the question of T-cell identity. She leads a multidisciplinary team integrating computational and experimental approaches to develop an understanding of gene regulation in immune cells. Vahedi is also a member of Penn's Institute for Immunology and Epigenetics Institute.
She likens TCF-1 to an icebreaker ship that initially opens the ice (condensed, closed chromatin) and keeps a path available for other ships (other transcription factors that work in later stages of development) to steam through the now-open water (unwound chromatin). TCF-1 ultimately 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 guide a maturing T cell to its final identity.
Although the functional importance of TCF-1 in T cells has been known for more than 25 years, the mechanism by which this protein controls T-cell identity remained unknown. 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.
"Our lab is interested in understanding how T-cell identity is established," Vahedi said. "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."
They established the identity-making role for TCF-1 by deleting it in a mouse model and 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," Vahedi said. "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."
Coauthors are John Johnson, George Georgakilas, Stanley Cai, all from the Vahedi lab; Jelena Petrovic, Makoto Kurachi, Warren Pear, and John Wherry, all from Penn; and Christelle Harly and Avinash Bhandoola, from the National Cancer Institute.
This study was funded in part by the National Institutes of Health (NIH K22AI112570, R01AI047833, P01CA119070, NIH AI105343, AI082630, AI112521, AI115712, AI117718, AI108545, AI117950), the Sloan Foundation, the National Psoriasis Foundation, and the Parker Institute for Cancer Immunotherapy.
Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $7.8 billion enterprise.
The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 20 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $405 million awarded in the 2017 fiscal year.
The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center -- which are recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report -- Chester County Hospital; Lancaster General Health; Penn Medicine Princeton Health; Penn Wissahickon Hospice; and Pennsylvania Hospital - the nation's first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine, and Princeton House Behavioral Health, a leading provider of highly skilled and compassionate behavioral healthcare.
Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2017, Penn Medicine provided $500 million to benefit our community.
Karen Kreeger | EurekAlert!
Building blocks for new medications: the University of Graz is seeking a technology partner
19.03.2019 | Karl-Franzens-Universität Graz
Scientists find new approach that shows promise for treating cystic fibrosis
14.03.2019 | NIH/National Heart, Lung and Blood Institute
The Potsdam Echelle Polarimetric and Spectroscopic Instrument (PEPSI) at the Large Binocular Telescope (LBT) in Arizona released its first image of the surface magnetic field of another star. In a paper in the European journal Astronomy & Astrophysics, the PEPSI team presents a Zeeman- Doppler-Image of the surface of the magnetically active star II Pegasi.
A special technique allows astronomers to resolve the surfaces of faraway stars. Those are otherwise only seen as point sources, even in the largest telescopes...
Researchers at Chalmers University of Technology and the University of Gothenburg, Sweden, have proposed a way to create a completely new source of radiation. Ultra-intense light pulses consist of the motion of a single wave and can be described as a tsunami of light. The strong wave can be used to study interactions between matter and light in a unique way. Their research is now published in the scientific journal Physical Review Letters.
"This source of radiation lets us look at reality through a new angle - it is like twisting a mirror and discovering something completely different," says...
New research group at the University of Jena combines theory and experiment to demonstrate for the first time certain physical processes in a quantum vacuum
For most people, a vacuum is an empty space. Quantum physics, on the other hand, assumes that even in this lowest-energy state, particles and antiparticles...
Physicists in the EPic Lab at University of Sussex make crucial development in global race to develop a portable atomic clock
Scientists in the Emergent Photonics Lab (EPic Lab) at the University of Sussex have made a breakthrough to a crucial element of an atomic clock - devices...
Every year earthquakes worldwide claim hundreds or even thousands of lives. Forewarning allows people to head for safety and a matter of seconds could spell...
11.03.2019 | Event News
01.03.2019 | Event News
28.02.2019 | Event News
19.03.2019 | Physics and Astronomy
19.03.2019 | Life Sciences
19.03.2019 | Physics and Astronomy