Penn Medicine Awarded $6 Million to Advance Understanding of Human Genome Function in Health and Disease

The National Institutes of Health (NIH) has selected Penn Medicine as one of 25 award recipients across 30 sites in the United States to serve as Impact of Genomic Variation on Function (IGVF) investigators, with the goal of better understanding how genetic differences impact how human genes function, and how these variations influence human health and disease. Funded by the NIH’s National Human Genome Research Institute (NHGRI), Penn Medicine will be awarded more than $1.2 million per year, with a contract that is expected to be supported for five years, totaling more than $6 million in funding for this research.

While genome sequences among people are more than 99.9 percent identical, it’s the 0.1 percent of differences, alternate orders of the As, Cs, Gs and Ts that make up DNA, combined with environment and lifestyle, that shape a person’s overall physical features and disease risk. Researchers have identified millions of human genomic variants that differ across the world, including thousands associated with disease. With results from this new research and advanced computer modeling, Penn and other IGVF consortium investigators aim to identify which variants in the genome are relevant for health and disease, with major implications for physicians and their patients.

“A fundamental question in biology is to understand how genetic variation affects genome function to influence human health and diseases,” said Hao Wu, PhD, an assistant professor of Genetics in the Perelman School of Medicine at the University of Pennsylvania, who will serve as the Penn site’s principal investigator. “With the IGVF award, we can leverage the brain power of Penn’s experts in human genetics, single cell sequencing and functional genomics to decode how genetic variants may contribute to how genes are regulated, how cells function, and ultimately, human diseases. This is a terrific opportunity for collaboration with researchers across departments and institutions.”

Read more about Penn’s IGVF award in Penn Medicine News.

Distinct first responder cells lead the skin’s wound healing response

Under normal conditions, a menagerie of separate cell populations work to maintain skin health. However, injury prompts these isolated pools of cells to exit their individual niches and re-epithelialize the epidermis (the surface skin layer). This raises important questions about which cells react first and how the body primes them for rapid injury response.

A study by the Rompolas lab published this week in Cell Stem Cell provides a closer look at how mice maintain these pools of cells and how the cells respond after injury. Led by postdoctoral researcher Sixia Huang, the team used live cell imaging to confirm that that cells expressing Lgr6 serve as first responders that proliferate and initiate epithelial repair following injury. Moreover, the researchers show that targeted destruction of Lgr6+ cells slows the injury response by requiring other stem cells to respond.

So what makes Lgr6+ cells step up first? Consistent with previous data showing that Lgr6 expression by keratinocytes depends on skin innervation, the researchers find that sensory nerves contact the pool of Lgr6+ stem cells and are required for normal cellular dynamics post-injury. This nerve interaction regulates Lgr6+ cell identity and fate by regulating the expression of other genes within the cells, something that is drastically altered if nerves are lost.

Altogether, these results shed light on how the nervous system crosstalks with stem cells in the body. Rather than simply serve as pain receptors, cutaneous nerves prime Lgr6+ cells to function as first responders to injury. These observations may shed light on why patients suffering medical conditions associated with neuropathies, like diabetes, may also suffer from diminished wound healing.

Photo courtesy of Sixia Huang

The immune link between a leaky blood-brain barrier and schizophrenia

Like a stern bodyguard for the central nervous sytem, the blood-brain barrier keeps out anything that could lead to disease and dangerous inflammation—at least when all is functioning normally.

That may not be the case in people with schizophrenia and other mental disorders, suggest new findings from a team led by researchers from the School of Veterinary Medicine, Perelman School of Medicine, and Children’s Hospital of Philadelphia (CHOP). In these individuals, a more permissive barrier appears to allow the immune system to get improperly involved in the central nervous system, the researchers showed. The inflammation that arises likely contributes to the clinical manifestations of neuropsychiatric conditions.

Read more about how Jorge Alvarez, Stewart Anderson and their team used patient-derived stem cells and mouse models to examine the role of immune cells in schizophrenia in Penn Today.

Arcuate organoids to study development and disease of the hypothalamus

Human brain organoids are remarkable platforms for modeling features of human brain development and diseases. Building on methods to generate organoids to model different brain regions such as the cortex and the midbrain, researchers at the Perelman School of Medicine at the University of Pennsylvania have generated the first organoids of the arcuate nucleus (ARC), an essential structure in the hypothalamus that sends signals of hunger and feeling full. This part of the hypothalamus exhibits a tremendous amount of cell diversity, and is far more complex than previously modeled parts of the brain.

In a recent paper in Cell Stem Cell, researchers at Penn report generating arcuate organoids (ARCOs) that model the ARC of the hypothalamus. Previous studies have generated 2D hypothalamic-like neurons and 3D hypothalamic organoids from human induced pluripotent stem cells (iPSCs). However, no protocols previously existed to generate hypothalamus nucleus-specific organoids.

Read more about this work from Guo-li Ming‘s lab in Penn Medicine News.