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Chaolin Zhang
Chaolin Zhang, PhD, associate professor of systems biology

A new study by researchers in Dr. Chaolin Zhang’s lab at Columbia’s Department of Systems Biology details a novel computational method that models how RNA-binding proteins (RBPs) recognize specific sites in the target RNA transcripts, precisely and accurately. The researchers’ findings include identification of entirely new motifs (RNA sequence patterns), and their research in complex RNA regulation contributes to our understanding of the molecular basis of disease and conditions, and down the road, could aid in the development of targeted therapies. 

The study, led by Dr. Zhang, associate professor of systems biology, with senior co-authors Suying Bao, PhD, and Huijuan Feng, PhD, appears today in Molecular Cell

RNA has traditionally been considered mere “messengers” that transfer genetic information from DNA to proteins that ultimately carry out cellular functions. However, it is now increasingly appreciated that RNA can be tightly regulated to control gene expression and diversity protein products. RNA-binding proteins (RBPs) are at the center of such regulation, with important roles in many cellular processes, including cell function, transport, and location. Gaining mechanistic insights of the binding specificity of RBPs in a genome-wide scale helps advance our knowledge of gene regulation.

“RNA-binding proteins are crucial for gene expression,” says Dr. Feng, coauthor of the study and post-doctoral research scientist in the Zhang lab. “RNA is heavily regulated, and when this regulation goes wrong, instabilities or disease could occur.”  

 

In neurons lacking Rbfox, the AIS is disrupted, impairing neuron’s ability to fire action potentials.
The Rbfox protein is a master regulator of neuronal RNA splicing that is demonstrated to be pivotal to establish the mature RNA splicing program in neurons. In neurons lacking this protein, an axonal cytoskeletal structure called “axon initial segment” is disrupted, impairing neuron’s ability to fire action potentials. (Image courtesy of Zhang Lab).

Neurons, or nerve cells, in the brain communicate with each other by transmitting electric signals, or firing action potentials, through long processes named axons (which send out signals) and dendrites (which receive signals). The capability of firing action potentials, among other functions of mature neurons, has to be acquired during development and neuronal maturation. However, the molecular mechanisms governing this complex process are so far poorly understood.

To peel away at the intricate layers that govern the development of neurons, a research team led by Chaolin Zhang, PhD, Assistant Professor in Systems Biology and Biochemistry and Molecular Biophysics and Hynek Wichterle, PhD, Associate Professor in Pathology & Cell Biology, Neuroscience, and Neurology , at the Center for Motor Neuron Biology and Disease , Columbia University Medical Center, focuses on a level of molecular regulation called alternative splicing. Alternative splicing is a process of generating multiple transcripts and protein variants by joining different combinations of coding segments. This process is highly dynamic during neural development with dramatic switches of splicing patterns in thousands of genes, which produce a repertoire of protein products required at specific developmental stages.

A key regulator of alternative splicing is the Rbfox family of proteins, which are enriched in neurons and previously were linked to neurodevelopmental disorders, including autism, schizophrenia, and epilepsy.

Faculty

Chaolin Zhang

Associate Professor, Department of Systems Biology
Associate Professor, Department of Systems Biology

Faculty

Brent Stockwell

Professor, Departments of Biological Sciences and Chemistry
Co-director, High-Throughput Screening