Genome scientist Ana Pombo joins Johns Hopkins faculty

^{© Will Kirk / Johns Hopkins University}

While a strand of human DNA is approximately 6.5 feet long, it is folded into a cell nucleus that is only 10 micrometers in diameter—roughly one tenth of the width of a sheet of paper. This compaction results in a three-dimensional configuration that brings distant regions of the genome into close physical contact.

Genes require regulatory enhancers, control switches located elsewhere along the DNA strand, to control their activity and turn genes on or off. When the genome folds, these distant switches are brought closer to their target genes, allowing genes to interact with regulatory elements. How the DNA is folded determines its function: A liver cell and a skin cell, for example, contain identical DNA, but behave very differently because the DNA strands are folded differently. Incorrect folding can contribute to disease, such as cancer, or developmental disorders.

Ana Pombo, who has joined Johns Hopkins University as the Bloomberg Distinguished Professor of Genome Biology, investigates the complex relationship between genome structure and gene expression. She studies how chromosomes are organized within the nucleus and how this organization influences gene regulation and cellular function, how environmental factors and experiences impact this interplay, and how diseases arise.

"Within the genome, we have not only sequences that encode the building blocks of cells, but we also have many sequences that are instructions for reading the genome itself," Pombo explains. "Learning how this regulation occurs is important across many fields of the life sciences. Regulatory sequences within the genome work through different mechanisms. One way to find out how they work is to map their physical structure and determine the physical position of the regulatory regions relative to their target genes."

Pombo employs a combination of advanced genomics and imaging techniques, computational biology, and statistical analysis to understand how the physical positioning of genes and their regulatory sequences affects their activity. She has pioneered groundbreaking methods that provide unique insights and have transformed our ability to study genome organization.

Pombo notably developed Genome Architecture Mapping, or GAM, an innovative technique that maps the positions of every part of the genome relative to every other part of the genome within a nucleus and allows scientists to determine how different parts of the genome interact with each other in three-dimensional space. Genome Architecture Mapping involves freezing nuclei and cutting them into thin slices. DNA is then extracted from individual nuclear slices and sequenced to identify which genomic regions are present. When this is done many times, patterns emerge showing, for example, which parts of the genome are proximal to each other.

In contrast to previously existing techniques that primarily detected two-way interactions, GAM captures more complex, multi-way interactions between active genes, regulatory regions, and super-enhancers across large genomic distances. This approach has provided unprecedented insights into the intricate ways chromosomes fold and interact, revealing organizational principles and novel genomic interactions that were previously invisible to researchers. Pombo says that because GAM is rooted in electron microscopy, it has several powerful advantages.

"Genome Architecture Mapping preserves the structure of the organization of the genome, allowing for a more holistic understanding of the structure," she explains. "GAM also makes it possible to access specific cell types within complex tissues, such as the brain, which contains several dozens of different cell types. We can select a particular cell type that we are interested in probing in detail, and we're able to do this even with a small sample size, such as a clinical biopsy."

A significant portion of Pombo's work focuses on how genome organization relates to human health and disease. Disruptions in the three-dimensional configuration of the genome can lead to disease. Many neurodevelopmental disorders are caused by mutations in chromatin enzymes that result in neurological symptoms such as memory impairment or intellectual disability. She is also interested in how genome structure may hold epigenetic memory of an external insult, such as exposure to a drug of addiction. Pombo aims to uncover how this happens, with the hope that her research can contribute to novel diagnostics, prognostics, and therapeutics.

Beyond studies of the genome, Pombo's methods can also be applied in other contexts. For instance, she currently develops strategies to map the preferred positions of different bacteria species relative to each other in different microbiota environments, such as the intestine.

At Johns Hopkins, Pombo will be part of the Epigenome Sciences BDP cluster, an interdisciplinary group that unites researchers from across the university who share a commitment to understanding the fundamental principles of genome organization and function in eukaryotic organisms. This collaborative environment provides an ideal setting for Pombo to extend her research while working alongside experts in complementary areas.

"My research interests are rooted in central and basic questions that are important across species, from bacteria to plants to humans," Pombo says. "Through my appointment in the Department of Biology, and through the Epigenome Sciences cluster, I will be able to have a much broader scope of where my research can contribute and be impactful. At the same time, my appointment in the Department of Molecular Biology and Genetics in the School of Medicine brings many opportunities for interdisciplinary collaborations to work on projects immediately relevant to human disease."

According to Christopher Celenza, dean of the Krieger School of Arts and Sciences, Pombo was a prime candidate for a Bloomberg Distinguished Professorship.

"Ana Pombo has made important discoveries about how our genomes function in three-dimensional space, work that has advanced the field of genome cell biology and has significant implications for human disease," he says. "She naturally builds bridges between disciplines, and that collaborative spirit will undoubtedly spark new partnerships and propel important discoveries in the years ahead."

Adds Theodore DeWeese, dean of the medical faculty and CEO of Johns Hopkins Medicine: "Dr. Pombo's ability to merge cutting-edge experimental techniques with systems-level thinking, along with her commitment to building new tools and asking bold questions, makes her an exceptional addition to Johns Hopkins University. Her innovative Genome Architecture Mapping technique has opened entirely new avenues of inquiry for researchers around the world, and we eagerly anticipate the discoveries that will emerge from Dr. Pombo's laboratory at Johns Hopkins."

While embarking on this exciting new chapter at Johns Hopkins University, Ana Pombo will remain a NeuroCure Principal Investigator and continue her research activities at the Max Delbrück Center in Berlin, further strengthening scientific exchange between Berlin and Baltimore.

Source: Press Release John Hopkins University

Contact:

Kontakt:
Prof. Dr. Ana Pombo
Group Leader
NeuroCure PI
Max-Delbrück-Centrum für Molekulare Medizin (MDC)
Hannoversche Straße 28
10115 Berlin, Deutschland

Ana Pombo Lab