Research Suggests New Paradigm for Global Genome Programming

“Our research shows how a single growth factor receptor protein moves directly to the nucleus in order to program the entire genome,” says senior author Michal K. Stachowiak, PhD, professor of pathology and anatomical sciences.

“The finding provides a new level of understanding of the fundamental aspects of how organisms develop,” he explains.

“This seminal discovery lends new perspectives to the origin, nature and treatment of a variety of human diseases,” says Stachowiak, who directs UB's stem cell engraftment and in vivo analysis core facility as well as the stem cell culture and training facility.

A more advanced understanding of how organisms form, based on this work, has the potential to significantly enhance the understanding and treatment of cancers, which result from uncontrolled development as well as congenital diseases, the researchers say.

The research challenges a long-held supposition in biology that specific types of growth factors only function at a cell’s surface. For two decades, Stachowiak’s team has been intrigued by the possibility that growth factors function from within the nucleus, a point, he says, this current paper finally proves.

“We’ve known that the human body has almost 30,000 genes that must be controlled by thousands of transcription factors that bind to those genes,” Stachowiak says, “yet we didn’t understand how the activities of genes were coordinated so that they properly develop into an organism.”

“Now we think we have discovered what may be the most important player, which organizes this cacophony of genes into a symphony of biological development with logical pathways and circuits,” he says.

At the center of the discovery is a single protein called nuclear Fibroblast Growth Factor Receptor 1 (nFGFR1). “FGFR1 occupies a position at the top of the gene hierarchy that directs the development of multicellular animals,” explains Stachowiak.

The FGFR1 gene is known to govern gastrulation, occurring in early development, where the three-layered embryonic structure forms. It also plays a major role in the development of the central and peripheral nervous systems and the development of the body’s major systems, including muscles and bones.

To study how nuclear FGFR1 works, the UB team used genome-wide sequencing of mouse embryonic stem cells programmed to develop cells of the nervous system. They performed additional experiments in which nuclear FGFR1 was either introduced or blocked. 

The researchers found that the protein was responsible, either alone or with partner nuclear receptors, for ensuring that embryonic stem cells develop into differentiated cells. By targeting thousands of genes, it controls the development of the major points of growth in the body as well as neuronal and muscle development.

The research shows that nuclear FGFR1 binds to promoters of genes that encode transcription factors, the proteins that control which genes are turned on or off in the genome.

“We found that this protein works as a kind of ‘orchestration factor,’ preferably targeting certain gene promoters and enhancers. The idea that a single protein could bind thousands of genes and then organize them into a hierarchy, that was unknown,” Stachowiak says. “Nobody predicted it.”

The discovery that a single protein can exert such a global genomic function stems from recent advances in DNA sequencing technologies, which allow for the sequencing of a complex genome in just hours.

“NextGen DNA sequencing allows us to analyze millions of DNA sequences selected by the interacting protein,” Stachowiak said.  

In the UB research, the DNA sequencing data were processed by UB's genomics and bioinformatics core facility. Stachowiak and his colleagues then spent weeks aligning these data to the genome and conducting further analyses.

“We imposed nuclear FGFR1 on every little corner of genome,” he said. “The computer spit out which genes are affected by nuclear FGFR1: it was an enormously complex network of genome activity.”

They found that the protein binds to genes that make neurons and muscles as well as to an important oncogene, TP53, which is involved in a number of common cancers.

Other studies in Stachowiak’s laboratory demonstrate that these interactions also take place in the human genome, controlling function and possibly underlying diseases like schizophrenia. 

Targeting of the nuclear FGFR1 allows for the reactivation of neural development in the adult brain in preclinical studies and may offer unprecedented opportunity for regenerative medicine, says Stachowiak.

Nuclear accumulation of nuclear FGFR1 may be altered in some cancer cells, and could become a focus in cancer therapy, he adds.  

Faculty co-authors from the UB Department of Pathology and Anatomical Sciences are Ewa K. Stachowiak, PhD, assistant professor, and Barbara Birkaya, PhD, research assistant professor.

Other co-authors from the department are current and former doctoral students: 

• Sridhar Narla
• Christopher Terranova, PhD, now at the University of Texas
• Yu-Wei Lee, PhD, now a post-doctoral researcher at Yale University
• Abhirath Parikh, PhD

Michael Buck, PhD, associate professor in the UB Department of Biochemistry, and Emmanuel Tzanakakis, PhD, an associate professor at Tufts University also authored the paper.

The study was supported by grants from New York State Stem Cell Science of the New York State Department of Health and the Patrick P. Lee Foundation.