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Breaking Down the Science: Wistar’s New Genome Regulation and Cell Signaling Program in the Ellen and Ronald Caplan Cancer Center

Written by The Wistar Institute on . Posted in Featured News.

Upon the launch of The Wistar Institute’s new Genome Regulation and Cell Signaling Program, we sat down with the Program’s leader — Hilary Koprowski, M.D., Endowed Professor Paul M. Lieberman, Ph.D. — and co-leader, professor Bin Tian, Ph.D., to learn more about their vision for the Program and what it means for the future of cancer research at Wistar.

Tell us about the importance and excitement in this new Caplan Cancer Center Program.

PL: Wistar has been at the forefront of cancer research and discovery for decades. Recent advances in genomic technology and computational biology have inspired us to establish the new Genome Regulation and Cell Signaling (GRCS) Program. This new Program brings together a diverse group of investigators to solve complicated problems underlying cancer causation, including persistent viral infection, immune response to cancer, and cell signaling changes in cancer.

The GRCS Program combines multi-disciplinary expertise to solve these complicated problems from many different angles: from specialists in genome architecture and integrity like Drs. Tempera, Gardini, and Sarma, who focus on the physical structure of our genome, which has very critical ramifications for genetic diseases & cancers; to investigators interested in virus’ infection and cancer causation, like myself, Dr. Tempera, and Dr. Price; to researchers of inflammatory signals in cancer cells and metastasis with Drs. Chen and Altieri; to specialists in computational and informatic techniques like Drs. Madzo, Kossenkov, and Srivastava, who are essential for effective analysis and interpretation of the vast datasets our Program generates.

How does the combination of genome regulation and cell signaling synergize in this new Program?

BT: We want to better understand cancer, so we study how genes are regulated or dysregulated at the genomic level; cell signaling provides the biological context for understanding how genome regulation plays out in response to internal & external cues. Because of recent technological advances, gene regulation can now be studied across the entire genome — not just individual genes or small groups of genes with similar functions, but all the genes throughout the genome. The synergy between genome regulation and cell signaling is holistic.

PL: Genome regulation does not occur in a vacuum. Metabolic and environmental changes trigger signaling between cells, which, in turn, affect how the genome is regulated. How the genome responds to these types of signals is central to the problems in cancer biology and part of the new focus areas of the GCSR Program.

Why is genomics so critical to cancer research?

BT: All aspects of a cancer cell’s growth — from tumor formation, to tumor survival, to interactions with other cells in the tumor microenvironment — involve rewiring of our cells’ gene expression programs. And that is a fundamentally genome-based process — whether it is a physical change of some genome sequences; alternation of how the genome is structured in 3-dimentional space; transcription of DNA into RNA; or post-transcriptional regulations.

PL: Cancer is a disease of the genome: tumors start when the genome is changed in ways that give cancer a foot in the door. Genomics and informatics analyses allow us to understand the specific genetic changes — which, in cancer, are more like genetic injuries — that drive a particular individual’s cancer. Ideally, once you understand the underlying genetic nature of an individual cancer, you can design precision medicines targeted more accurately to a specific disease diagnosis.

What advances has sequencing technology unlocked in this area of cancer research?

BT: In essence, cancer is a genetic disease. And advanced sequencing technologies have enabled us to examine the genome with the resolution of a single nucleotide — the fundamental building block of DNA. Sequencing technologies have evolved to a point where we can even use these tools to understand the dynamics of genome regulation within individual cells or tiny regions in the body. Essentially, we see cancer’s real-time changes far more clearly, which is key to understanding and combatting the disease.

PL: Advances in genomics and sequencing technologies allow us to understand cancer as a personal disease. Each tumor is different, but we can use precision sequencing as a springboard for researching precision medicine. Armed with the latest advances like next-generation and ultra-high-throughput sequencing — methods that allow scientists to accurately assess entire genomic samples and in minute detail — the new Program’s scientists have the tools they need to move the field even further.

In state-of-the-science Wistar labs, our researchers can easily sample an entire genomic state with tools to improve and expand into new areas of application and translation. Our Program members combine these advances with technologies like CRISPR to identify, target, modify, and correct the genetic aberrations that drive cancer and other genetic diseases.

How do cancer researchers deal with the complexity of the different variables at play in cancer? And how will your Program’s approach account for that interconnectivity?

PL: Due to the complexity of biological systems — and cancer being among the most complicated biological problem because of the rapid, chaotic evolution of tumors and their surroundings — it’s quite unlikely that any single person or brain will solve this challenge. New artificial intelligence applications are welcome tools for investigators; by leveraging AI, we can sort through the massive amounts of biological information and identify potential vulnerabilities within cancer’s framework.

We do work in a reductionist mindset — where the entire complex network of information is reduced to one simple example — to identify new targets and pharmacological agents that can impact the whole system. While that might seem at odds with cancer’s enormous complexity, we still need to simplify the complex science of cancer. It’s a give and take: we zoom in to find a specific mechanism at play in cancer, and then we zoom out to see whether targeting that mechanism can work its way through the vast, interconnected complexity of the disease system to produce a therapeutic effect. We cut through the jungle one molecule at a time.

What is your plan for translating your Program’s discoveries into testable therapy strategies?

BT: We have several promising thematic areas for therapeutic intervention, including the emerging areas of mRNA vaccines and gene therapies, as well as continued progress in small molecules as drug candidates. So as we make progress on potential therapeutics, we seek to take full advantage of several technologies and investigate how they work together — similar to the multi-pronged approaches the HIV folks are using for disease containment and cure.

We believe in basic science, which pays off in the long run: any discovery and innovation moves the needle in cancer research and future therapeutics.

Five years from now, what do you hope to have achieved through the Program?

BT: We hope to achieve breakthroughs in both basic science research and cancer therapeutics; we can reach these goals because the GCRS Program has faculty with expertise in many cutting-edge and interdisciplinary technologies and is highly collaborative.

PL: The GRCS program has two main goals: advance our knowledge and understanding of the complex mechanisms of genome regulation and cell signaling in cancer; and second, identify new therapeutic targets and strategies to treat cancer and other complex diseases.

We anticipate publications in high-impact journals to highlight breakthroughs in genome regulation and cell signaling, and we also expect to see some of our findings advanced into new therapeutics — small molecules, gene therapies, and vaccines to treat cancer and other diseases — that will reach clinical trials thanks to our continued collaboration between the public and private sectors.

These are broad and ambitious goals, but they are achievable. With an excellent diversity of scientific expertise and supported by the most advanced technologies available from Wistar’s Shared Resources facilities, the GCRS Program is positioned to find answers to some of the most pressing questions in cancer biology.

Learning How to Read the Book of Life

Written by The Wistar Institute on . Posted in Featured News.

Research in the Gene Expression & Regulation Program at Wistar continues to reveal new knowledge on RNA and its functions to regulate how our genes are expressed and how that can go awry.

The advent of mRNA vaccines for COVID-19 — touted as the next-generation tool in vaccinology — brought RNA to the fore, giving popularity to this once less-publicized cousin of DNA.

In high school biology, we learned that our genes are the repositories of the blueprint to make all of our proteins. Our genes carry out most of the functions in our cells. RNA is the carrier of information from DNA to ribosomes — the machines that manufacture proteins.

The process of reading and executing the instruction book of life involves strict oversight and multiple levels of regulation to allow a relatively small number of genes to orchestrate all the functions of our body. Control of gene expression plays a critical role in determining what proteins are present in a cell and in what amounts at any given time.

It is becoming abundantly clear that this control process happens both during and after RNA transcription.

Wistar scientists have pioneered the study of RNA biology, discovering new RNA types and unraveling some of the mechanisms that modify RNA to regulate its functions for gene expression. Following along that path, labs in the Gene Expression and Regulation Program continue to delve deep into the RNA world and make exciting discoveries related to RNA structure and functions.

R-LOOPS: Friend-Foes

Dr. Kavitha Sarma, assistant professor, focuses on particular nucleic acid structures called R-loops that contain both DNA and RNA and form during transcription, the first step of gene expression.

In our DNA book, consider genes as the individual words and nucleotides as the letters that make up those words. When a DNA template is “transcribed” into messenger RNA (mRNA), the sequence of letters that form each gene gets “read” and copied into an RNA molecule that will leave the nucleus and travel to the cytoplasm, where words will be read by ribosomes to provide instructions for making proteins.

Sometimes during transcription, the newly synthesized RNA molecule sticks to its template DNA strand, forming a stable DNA/RNA hybrid that appears like a loop when visualized by electron microscopy, hence the name R-loop.

This is a normal occurrence — R-loops are constantly formed and removed throughout the genome and their presence can be beneficial for transcriptional regulation. However, accumulation of R-loops can cause DNA damage, chromosome rearrangements and genomic instability and underlie a host of diseases from cancer to neurodegenerative disorders and possibly autism.

The Sarma lab is interested in R-loops for their potential in causing disease and in serving as new therapeutic targets. They have been busy developing new, improved techniques to detect R-loops to study the contributions of these structures in gene regulation and the consequences of their accumulation in the cell1.

Thanks to these technological advances, Dr. Sarma and her colleagues were able to identify new factors that regulate R-loops and are now closing in on their function in glioblastoma and colon cancer.

The lab received funding from the W.W. Smith Charitable Trust to study the role of R-loops in brain cancer and with support from the Basser Center for BRCA and the Margaret Q. Landenberger Research Foundation they are dissecting the correlation between R-loop formation and BRCA1/2 gene mutations in breast and ovarian cancer to eventually use R-loops for novel diagnostic and therapeutic applications. The Simons Foundation supports the lab’s work elucidating the consequences of unregulated R-loops in autism spectrum disorders.

EDITING RNA TO RESOLVE R-LOOPS

Dr. Kazuko Nishikura, professor, has published a new function of R-loops2 in preserving the integrity of our chromosome ends — the telomeres.

Dr. Nishikura has been a pillar of Wistar science for almost four decades with a career overlapping with the rise and expansion of the RNA biology field. She was one of the first to characterize a process called RNA editing and its multiple functions in the cell, and to discover the enzyme ADAR1 that is responsible for it.

RNA editing changes one or more letters in RNA “words,” allowing cells to make discrete modifications to an RNA molecule. RNA editing is a good example of how our cells make the most of their genes and create different protein products from a single gene by slightly modifying the RNA sequence.

With support from grants from the National Institutes of Health and Emerson Collective, the Nishikura lab recently showed that ADAR1 helps the cells resolve R-loops formed at the chromosome ends and prevents their accumulation by facilitating degradation of the RNA strand.

Nishikura and colleagues found that depletion of a particular form of the ADAR1 protein leads to extensive telomeric DNA damage and arrested proliferation specifically in cancer cells, indicating this process as a new target for cancer therapy.

ALTERNATIVE POLYADENYLATION: Tell Me What Your APA Is and I Will Tell You Where to Go

An important level of mRNA regulation involves modifying its structure, especially at the tail end of the sequence, termed 3’ end. A process called polyadenylation adds a stretch of specific nucleotides to protein-coding mRNAs to regulate their stability, transportation from nucleus to cytoplasm and translation into proteins.

Dr. Bin Tian, professor, and his lab study this process to understand regulatory mechanisms and to identify new drug targets. They have contributed important knowledge on polyadenylation in normal and diseased conditions, including the discovery that alternative polyadenylation (APA) is widespread across genes.

This is a dynamic mechanism of gene regulation that generates different 3′ ends in mRNA molecules, resulting in multiple mRNAs from the same gene, which scientists call isoforms.

The lab’s latest research is uncovering the role APA plays in facilitating protein production in certain sites within the cell where those proteins are most needed.

When mRNAs leave the nucleus and move to the cytoplasm, they need to be properly directed to reach the ribosomes and be translated into proteins. Although too small to be seen with the naked eye, a cell is a huge space for something as tiny as an mRNA molecule that has to find its way. Imagine finding yourself in a baseball stadium and not knowing how to get to your seat.

The Tian lab discovered that some mRNAs possess specific properties in their sequence and structure that enable them to associate with the endoplasmic reticulum (ER), a network of tubes that build, package and transport proteins and where a large fraction of ribosomes in the cell are located3.

These mRNAs tend to encode for proteins involved in cell signaling, the process that allows the cells to communicate with neighboring cells by sending, receiving and processing signals to respond to changes in their environment.

Dr. Tian and his team hypothesize that association with the ER anchors certain mRNA isoforms in specific cellular locations where important signaling events happen, making the whole process more efficient. According to this model, the ER would serve a new function as a scaffold to keep proteins at hand where they are needed, representing a platform that provides venues for signaling events to happen quickly and effectively.

The lab also creates computer-based data mining tools to analyze APA using large data sets, such as those from The Cancer Genome Atlas (TCGA) program.

The extraordinary biological complexity of human life is a reflection of the many sophisticated ways in which gene expression can be fine-tuned.

The cutting-edge science underway at Wistar pushes the limits of RNA research to advance our understanding of how the human genome is decoded, how the messengers of genetic information are guided, and how accidental mistakes that happen while reading and interpreting the DNA book can be fixed, all of which may enable researchers to develop novel and more precise ways to treat diseases.

1 A nuclease- and bisulfite-based strategy captures strand-specific R-loops genome-wide, Elife 2021
2 ADAR1 RNA editing enzyme regulates R-loop formation and genome stability at telomeres in cancer cells, Nature Communications 2021
3 Alternative 3’UTRs play a widespread role in translation-independent mRNA association with endoplasmic reticulum, Cell Reports 2021

Wistar Scientists Described Fundamental Gene Expression Mechanism With Implications in Immunity and Cancer

Written by The Wistar Institute on . Posted in Featured News.

In a recent Cell Reports paper, Dr. Bin Tian and team revealed a mechanism that has far-reaching implications in development and diseases, including immunity and cancers.

The lab studies RNA biology to understand just how gene expression is regulated at the RNA level.

The genetic code of DNA to RNA and proteins is fine-tuned at different stages. Most control mechanisms take place after RNA is made.

Tian and colleagues focus on a mechanism called alternative polyadenylation (APA) that modifies the tail end of RNA sequences to generate multiple messenger RNAs from the same gene, which scientists call isoforms. This dramatically increases the complexity of our genome, so that fewer genes are needed to encode all the proteins a cell needs.

Though this mechanism affects more than half of human genes, its significance was poorly understood.

However, the lab uncovered the role APA plays in facilitating protein production in certain sites within the cell where those proteins are most needed.

“When mRNAs leave the nucleus and move to the cytoplasm, they need to be properly directed to reach the appropriate site of protein translation,” said Dr. Tian. “The cytoplasm is a huge space for an RNA molecule: For comparison, imagine entering a baseball stadium and needing directions to reach your seat.”

Researchers discovered that APA directs certain messenger RNAs to the endoplasmic reticulum (ER), a network of tubes that build, package and transport proteins. They also found that specific sequences and structures within the messenger RNAs determine their potential to undergo APA and ultimately associate with the ER.

These mRNAs tend to encode for signaling proteins, which help cells communicate with each other by sending, receiving, and processing signals in response to changes in the environment.

Dr. Tian and his team hypothesize that association with the ER anchors certain mRNA isoforms in specific cellular locations where important signaling events happen, making the whole process more efficient.

“According to our model, the ER would serve as a scaffold to keep proteins ‘on hand’ where they are most needed,” said Tian. “This would provide a platform for signaling events to happen effectively at the right place in the cell.”

This study has far-reaching implications in development and disease, including immunity and cancer. The Tian lab is exploring approaches to regulate APA as a new therapeutic modality.

To learn more about the study, read our press release.

Dr. Bin Tian

Wistar Scientists Discovered Fundamental and Widespread Gene Expression Control Mechanism that Potentially Creates Proteins at Distinct Locations in the Cell, with Implications in Immunity and Cancers

Written by The Wistar Institute on . Posted in Press Releases.

PHILADELPHIA — (July 20, 2021) — Alternative polyadenylation (APA) is an RNA processing mechanism that regulates gene expression by generating different ends on RNA transcripts of the same gene. Though it affects more than half of human genes, the significance of APA was poorly understood. Now a new study by The Wistar Institute describes an important function of APA in allowing certain mRNAs to reach specific sites of protein synthesis and reveals that length, sequence and structural properties can determine the destination (and fate) of mRNAs within the cell. These findings, published online in the journal Cell Reports, shed light on the consequences of APA that may represent a paradigm shift in the mRNA metabolism field.

The laboratory of Bin Tian, Ph.D., professor and co-leader of the Gene Expression & Regulation Program at The Wistar Institute Cancer Center and senior author on the study, was among the first to discover the widespread occurence of APA using genomic and bioinformatic approaches.

Following gene transcription, messenger RNAs are chemically modified to become mature RNA molecules that can leave the nucleus and perform their functions. One of these modifications is polyadenylation, which prevents RNA degradation and favors its translation into protein.

Through APA, a gene can be polyadenylated at multiple sites, resulting in mRNAs with different coding sequences and/or regulatory regions (3’untranslated regions or 3’UTRs), called isoforms. Transcripts encoding the same protein can have different fates in the cell because of distinct 3’UTRs, which harbor regulatory elements for mRNA metabolism. This dramatically increases the complexity of our genome, so that fewer genes are needed to encode all the proteins a cell needs.

Tian and colleagues employed functional genomics methods to analyze the distribution of the APA isoforms in mouse cells. Bioinformatic analysis and machine learning approaches revealed that APA, via modulation of mRNA 3’UTRs, impacts the connection between mRNAs and the endoplasmic reticulum (ER), a network of tubes that build, package and transport proteins.

They named this mechanism translation-independent ER association (TiERA) and found that some mRNAs possess specific sequences and structures that determine their potential to undergo APA and ultimately associate with the ER.

“When mRNAs leave the nucleus and move to the cytoplasm, they need to be properly directed to reach the appropriate site of protein translation,” said Tian. “The cytoplasm is a huge space for an RNA molecule: For comparison, imagine entering a baseball stadium and needing directions to reach your seat.”

The team found that mRNAs with higher TiERA tend to encode for signaling proteins,which help cells communicate with each other by sending, receiving and processing signals in response to changes in the environment.

They propose that APA renders this process more efficient by anchoring certain mRNA isoforms with the ER in specific cellular locations where important signaling events happen.

“According to our model, the ER would serve as a scaffold to keep proteins ‘on hand’ where they are most needed,” said Tian. “This would provide a platform for signaling events to happen effectively at the right place in the cell.”

Co-authors: Larry C. Cheng (co-first author) from The Wistar Institute; Dinghai Zheng and Aysegul Guvenek from Rutgers University; Qiang Zhang and Hong Cheng from Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, China.

Work supported by: National Institutes of Health (NIH) grants R01 GM129069 and T32 GM008339, and a Rutgers Presidential Fellowship Award. Additional support was provided by The Pew Charitable Trusts. Support for The Wistar Institute facilities was provided by Cancer Center Support Grant P30 CA010815.

Publication information: Alternative 3’UTRs play a widespread role in translation-independent mRNA association with endoplasmic reticulum, Cell Reports (2021). Online publication.

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The Wistar Institute is an international leader in biomedical research with special expertise in cancer research and vaccine development. Founded in 1892 as the first independent nonprofit biomedical research institute in the United States, Wistar has held the prestigious Cancer Center designation from the National Cancer Institute since 1972. The Institute works actively to ensure that research advances move from the laboratory to the clinic as quickly as possible. wistar.org.

The Wistar Institute Appoints Bin Tian, Ph.D., as Professor in the Cancer Center and Co-director of the Center for Systems & Computational Biology

Written by The Wistar Institute on . Posted in Press Releases.

PHILADELPHIA — (May, 1, 2020) — The Wistar Institute, an international biomedical research leader in cancer, immunology and infectious diseases, announces the appointment of molecular systems biologist Bin Tian, Ph.D., as professor in the Cancer Center.

“I am excited to join the high-caliber faculty and collaborative culture at Wistar, a premier research institution with a long, distinguished history of fundamental achievements,” said Tian. “The wide spectrum of technology support at the Institute will be instrumental to advance my work. I look forward to further expanding my research into cancer and immunity through collaboration with Wistar colleagues.”

A molecular biologist by training, Tian focuses on RNA biology and understanding how gene expression is regulated at the post-transcriptional level. His research involves interdisciplinary approaches, including molecular biology, genomics and computational biology, to study RNA biogenesis and metabolism. His lab was among the first to characterize the functional genomics of alternative polyadenylation and has uncovered its role in many diverse cellular processes.

“Bin’s research has led to groundbreaking advances understanding the role of alternative polyadenylation in development and cell differentiation as well as in the context of cancer and cellular stress,” said Dario C. Altieri, M.D., Wistar president and CEO, director of the Cancer Center, and the Robert and Penny Fox Distinguished Professor. “Bin’s work strengthens our RNA biology research and brings expertise in complex computational and genomic methods that will synergize with the work of our scientists across our research programs.”

Tian joins Wistar from Rutgers New Jersey Medical School where he was a professor. Tian serves on several editorial boards and review panels, and has published more than 150 research articles, reviews, and book chapters. In 2000, he received a Ph.D. degree in molecular biology from Rutgers Biomedical and Health Sciences (formerly UMDNJ). After receiving his Ph.D., Tian was appointed a postdoctoral fellow in bioinformatics and genomics at Johnson & Johnson Pharmaceutical Research & Development in La Jolla, CA. Then in 2003, he established his research group at Rutgers New Jersey Medical School where he became a tenured professor in 2014.

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The Wistar Institute is an international leader in biomedical research with special expertise in cancer, immunology, infectious diseases and vaccine development. Founded in 1892 as the first independent nonprofit biomedical research institute in the United States, Wistar has held the prestigious Cancer Center designation from the National Cancer Institute since 1972. The Institute works actively to ensure that research advances move from the laboratory to the clinic as quickly as possible. wistar.org.