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New Insights on How the Reprogramming Factor LIN28 Regulates its Targets

LIN28 Selectively Modulates Subclass Let-7 miRNAs
The proposed model of selective Let-7 microRNA suppression modulated by the bipartite LIN28 binding.(Image courtesy of Zhang Lab)

A new study led by Chaolin Zhang, PhD , assistant professor of systems biology , published today as the cover story of  Molecular Cell , sheds light on a critical RNA-binding protein that is widely researched for its role in stem cell biology and its ties to cancer progression in multiple tissues.

The LIN28 RNA-binding protein, initially found in worms about 15 years ago, is specifically expressed in stem cells.  It became well known because the protein is one of the four factors that were used to “reprogram” skin cells to induced pluripotent stem cells, or iPSCs, a breakthrough that was awarded the Nobel Prize in 2012. More recently, it was determined that the LIN28 RNA-binding protein can also be reactivated in cancer to drive tumor growth and progression. Due to its critical importance in developmental and cancer biology, scientists want to understand the role LIN28 plays at the molecular level. This new study provides some understanding of how the LIN28 protein suppresses a specific family of microRNAs, called Let-7, which are selectively lost in cancer.

“Let-7 microRNAs are the major downstream targets controlled by LIN28 identified so far. While LIN28 is mostly found in stem cells, Let-7 is only detected in differentiated cells because of stem cell-specific suppression by LIN28. However, the interplay between the two is still not well understood,” says Dr. Zhang, who is also a member of Columbia University’s Center for Motor Neuron Biology and Disease . “This study contributes to our understanding of how LIN28 suppresses Let-7, as well as provides a refined model for this important, rather complex molecular pathway.”

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Columbia Awarded NCI Center for Cancer Systems Biology

Master regulators of tumor homeostasis

In this rendering, master regulators of tumor homeostasis (white) integrate upstream genetic and epigenetic events (yellow) and regulate downstream genes (purple) responsible for implementing cancer programs such as proliferation and migration. CaST aims to develop systematic methods for identifying drugs capable of disrupting master regulator activity.

The Columbia University Department of Systems Biology has been named one of four inaugural centers in the National Cancer Institute’s (NCI) new Cancer Systems Biology Consortium. This five-year grant will support the creation of the Center for Cancer Systems Therapeutics (CaST), a collaborative research center that will investigate the general principles and functional mechanisms that enable malignant tumors to grow, evade treatment, induce disease progression, and develop drug resistance. Using this knowledge, the Center aims to identify new cancer treatments that target master regulators of tumor homeostasis.

CaST will build on previous accomplishments in the Department of Systems Biology and its Center for Multiscale Analysis of Genomic and Cellular Networks (MAGNet), which developed several key systems biology methods for characterizing the complex molecular machinery underlying cancer. At the same time, however, the new center constitutes a step forward, as it aims to move beyond a static understanding of cancer biology toward a time-dependent framework that can account for the dynamic, ever-changing nature of the disease. This more nuanced understanding could eventually enable scientists to better predict how individual tumors will change over time and in response to treatment.

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Oliver Hobert Named Javits Neuroscience Investigator

Oliver Hobert
Oliver Hobert

Oliver Hobert, an interdisciplinary faculty member of the Department of Systems Biology, has received a Javits Neuroscience Investigator Award from the National Institute of Neurological Disorders and Stroke (NINDS). This prestigious grant provides long-term support for investigators who have demonstrated exceptional achievement throughout their careers. The award will enable the Hobert Lab to pursue a new project investigating sex-based differences in the regulation of neuronal identity.

Also a Professor of Biochemistry and Molecular Biophysics and an Investigator of the Howard Hughes Medical Institute, Dr. Hobert is known for his research using C. elegans to understand the molecular programs that control cell-type differentiation within the nervous system. C. elegans has become an invaluable model organism for studying the nervous system because it contains just over 300 neurons whose development has been studied in great detail.

Recently, electron microscopy was used to compare nervous systems in male and hermaphrodite worms, and showed that some of these neurons are present in both sexes. Interestingly, the researchers discovered that even when these neurons had the same lineage history, position, morphology, and molecular features, there was a striking divergence in the patterns of synapse formation between the sexes. Under the new grant, the Hobert Lab will attempt to identify the mechanisms that control this divergence. The project should produce not only a much deeper understanding of sex-based differences in neuronal identity, but also new resources that will support future investigation of this phenomenon.

Winners of the Javits Neuroscience Investigator Awards are nominated by NINDS staff members and members of the National Advisory Neurological Disorders and Stoke Council (NANDS). The grant acknowledges grant recipients as being leaders in neuroscience who have been highly productive or have contributed paradigm-shifting ideas. By supporting investigators for 4-7 years, the grant also anticipates high productivity in the years to come. 

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Hynek Wichterle Appointed to Columbia Genome Center

Hynek WichterleThe JP Sulzberger Columbia Genome Center is pleased to announce that Hynek Wichterle has been appointed as associate director. In this role he will advise on stem cell related projects and coordinate interactions between Columbia Stem Cell Facility and the Columbia Genome Center's High-Throughput Screening Facility.

In addition to his position at the Columbia Genome Center, Dr. Wichterle is also an associate professor holding a joint appointment in the Departments of Pathology & Cell Biology and Neuroscience (in Neurology) at Columbia University Medical Center. He received his MS degree from Charles University in Prague and his PhD degree from The Rockefeller University. He trained at Columbia University, where he became assistant professor in 2004 and associate professor in 2012. He serves as a co-director of the Columbia Stem Cell Initiative and as a Vice-Chief of the Division of Regenerative Medicine in the Department of Rehabilitation & Regenerative Medicine.

Dr. Wichterle developed groundbreaking methods for producing spinal cord neurons from pluripotent embryonic stem cells in a culture dish. The process faithfully recapitulates normal embryonic development, providing a unique opportunity to study and experimentally probe nerve cells in a controlled environment outside of the embryo. He is using the system to decode transcriptional programs that control genes important for neuronal differentiation and function. His lab also capitalizes on the unlimited source of spinal neurons to study motor neuron degenerative diseases, such as amyotrophic lateral sclerosis (ALS or Lou Gehrig’s disease), with the goal of discovering new drugs for these currently untreatable, devastating conditions.

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Prestigious NIH Director's Awards Go to Two Department of Systems Biology Researchers

Dana Pe'er and Kyle Allison

Dana Pe'er has received the Pioneer Award for high-risk, high-reward research, and postdoctoral scientist Kyle Allison has won an Early Independence Award.

Two members of the Columbia University Department of Systems Biology have been named recipients of NIH Director’s Awards from the National Institutes of Health Common Fund.

Associate Professor Dana Pe’er is one of 10 winners of the 2014 NIH Director’s Pioneer Awards. The Pioneer Awards provide up to $2.5 million over 5 years to support exceptionally creative investigators who are pursuing “high risk, high reward” science that holds great potential to transform biomedical or behavioral research. The award will support an ambitious new project to develop the technological and computational methods necessary to create a comprehensive, high-resolution atlas of development for all cell types in the human body.

In addition, Kyle Allison, a postdoctoral scientist in the laboratory of Professor Saeed Tavazoie, has received the NIH Director’s Early Independence Award. (Dr. Tavazoie is also a past winner of the Pioneer Award.) This program enables outstanding young investigators who have recently completed their PhD’s to move rapidly into independent research positions. Dr. Allison is one of just 17 scientists to receive this award this year. In combination with the Department of Systems Biology Fellows program, this five-year, $1.25 million grant will allow him to open his own laboratory at Columbia and pursue independent research to investigate the problem of bacterial persistence. He is the second Department of Systems Biology investigator to receive the Early Independence Award, joining Assistant Professor Harris Wang in being recognized with this honor.

“Having four recipients of NIH Director’s Awards within the Department of Systems Biology — and particularly two in one year — is quite remarkable,” said Department Chair Andrea Califano. “I think it’s a testimony to the timeliness of the perspectives and tools that systems biology offers and to the high quality of research being conducted at Columbia. I look forward to the discoveries that will undoubtedly come from Dana’s and Kyle’s extremely exciting efforts.”

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Three CUMC Faculty Members Receive Interdisciplinary Appointments

We are pleased to announce that Columbia University Medical Center professors Oliver Hobert, Richard Mann, and Rodney Rothstein have been named to interdisciplinary appointments in the Department of Systems Biology. The addition of this new expertise will expand the breadth of science currently being explored in the Department, enhance educational opportunities for students, facilitate new collaborations, and promote the integration of systems biology perspectives and methods into research being conducted elsewhere in the university.

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Using New Single-Cell Technologies, Researchers Create Comprehensive Map of Human B Cell Development

Distribution of marker expression across development

A new algorithm called Wanderlust uses single-cell measurements to detect how marker expression changes across development.

In a new paper published in the journal Cell, a team of researchers led by Dana Pe’er at Columbia University and Garry Nolan at Stanford University describes a powerful new method for mapping cellular development at the single cell level. By combining emerging technologies for studying single cells with a new, advanced computational algorithm, they have designed a novel approach for mapping development and created the most comprehensive map ever made of human B cell development. Their approach will greatly improve researchers’ ability to investigate development in cells of all types, make it possible to identify rare aberrations in development that lead to disease, and ultimately help to guide the next generation of research in regenerative medicine.

Pointing out why being able to generate these maps is an important advance, Dr. Pe’er, an associate professor in the Columbia University Department of Systems Biology and Department of Biological Sciences, explains, “There are so many diseases that result from malfunctions in the molecular programs that control the development of our cell repertoire and so many rare, yet important, regulatory cell types that we have yet to discover. We can only truly understand what goes wrong in these diseases if we have a complete map of the progression in normal development. Such maps will also act as a compass for regenerative medicine, because it’s very difficult to grow something if you don’t know how it develops in nature. For the first time, our method makes it possible to build a high-resolution map, at the single cell level, that can guide these kinds of research.”

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Study Supports Cell-of-Origin Model of Prostate Cancer Heterogeneity

The cell-of-origin model in cancer biology suggests that some tumors are more aggressive than others because of differences in the cell lineages from which they arise. In the prostate gland, there are three types of epithelial stem cell — luminal cells, basal cells, and rare neuroendocrine cells. There has been some discrepancy in the scientific literature, however, about whether luminal cells, basal cells, or both can act as a cell of tumor origin.

In a paper published online in the journal Nature Cell Biology, researchers in the laboratories of Columbia University Department of Systems Biology members Michael Shen, Andrea Califano, and Cory Abate-Shen undertook a comprehensive analysis of prostate basal cell properties in mouse models. They used a technique called genetic linkage marking to study an identical cell population in multiple assays of stem cell function.

The studies showed that discrepancies in the published literature arise because basal stem cell properties can change when studied outside their endogenous tissue microenvironment; that is, in ex vivo cell culture and tissue grafting assays. To avoid this problem, they suggest, genetic lineage tracing in vivo should be considered the gold standard for identifying physiologically relevant stem cells.

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