Jiou Wang Lab
Discovering how the birth and death of proteins is controlled and how the shape of DNA and RNA controls their function
About the Wang Lab
The Wang Lab is interested in the biological basis for protein and RNA homeostasis in neurodegeneration. Neurodegeneration is a poorly understood biomedical phenomenon and a major public health challenge in our increasingly aging society. We hope to solve problems that not only have biological significance but also have important implications for understanding and treating disease.
Research Overview
Our goal is to describe at the molecular and cellular levels how cells defend against internal and external stress, how protective systems fail under disease conditions, and how the defense systems could be harnessed to develop innovative therapies.
Discovering key regulators of protein homeostasis
Protein misfolding plays a central role in the pathogenesis of many neurodegenerative diseases, including Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD). Elucidating the mechanisms that connect the misfolded proteins to neurodegeneration, and the quality control pathways that normally protect cells from that damage, are critical steps to understanding these diseases and to developing novel and effective therapies.
Uncovering novel players in the regulation of RNA homeostasis
Perturbation of RNA homeostasis in the central nervous system represents another major theme in neurodegeneration, and we are interested in studying new pathways of RNA processing underlying health and disease. We have uncovered novel functions of RNA-binding proteins linked to neurodegeneration, identifying their roles in regulating protein quality control, gene expression, and formation of membraneless organelles.
Revealing the mechanisms of repeat expansion diseases
We are interested in understanding the biology of a hexanucleotide repeat expansion in the C9orf72 gene that is the most common cause of ALS and FTD, and may serve as a model for understanding other neurodegenerative diseases with similar repeat expansions.
DAXX at the C9orf72 gene
A neurodegeneration-linked mutation can trigger cellular changes directly from its DNA, independent of downstream effects on RNA and protein. Normal C9orf72 genes have two to 10 “GGGGCC” repeats, but repeat expansion mutants have hundreds to thousands. Led by postdoctoral fellow Yang Liu, the Lab found the DNA-binding protein DAXX preferentially binds the longer repeats, accumulating in the cell.
DAXX accumulation starts a cascade of effects, triggering a liquid-liquid phase separation that drives chromatin structure and epigenetic modifications, suppressing the normal stress-dependent induction of C9orf72, and influencing global gene expression. These findings may open up new prevention or treatment strategies: The researchers found that reducing DAXX or rebalancing the epigenetic modifications reduced the sensitivity of patient neurons to stress.
DNA-initiated epigenetic cascades driven by C9orf72 hexanucleotide repeat, Liu Y, Huang Z, Liu H, Ji Z, Arora A, Cai D, Wang H, Liu M, Simko EAJ, Zhang Y, Periz G, Liu Z, Wang J, Neuron, 2023.
Selected Publications
Liu Y, Huang Z, Liu H, Ji Z, Arora A, Cai D, Wang H, Liu M, Simko EAJ, Zhang Y, Periz G, Liu Z, Wang J. DNA-initiated epigenetic cascades driven by C9orf72 hexanucleotide repeat. Neuron, 2023.
Lu YN, Kavianpour S, Zhang T, Zhang X, Nguyen D, Thombre R, He L, Wang J. MARK2 phosphorylates eIF2α in response to proteotoxic stress. PLOS Biology, 2021.
Lu J, Periz G, Lu Y, Tang Q, Liu Y, Zhang T, Shah Y, Thombre R, Aljumaah R, Li W, Mojsilovic-Petrovic J, Ji Y, Johnson K, Kalb R, Wang J. L3MBTL1 Regulates ALS/FTD-associated Proteotoxicity and Quality Control. Nature Neuroscience, 2019.
Alexander EJ, Ghanbari Niaki A, Zhang T, Sarkar J, Liu Y, Nirujogi RS, Pandey A, Myong S, Wang J. Ubiquilin 2 modulates ALS/FTD-linked FUS-RNA complex dynamics and stress granule formation. PNAS, 2018.
Haeusler AR, Donnelly CJ, Periz G, Simko EA, Shaw PG, Kim MS, Maragakis NJ, Troncoso JC, Pandey A, Sattler R, Rothstein JD, Wang J. C9orf72 nucleotide repeat structures initiate molecular cascades of disease. Nature, 2014.
How to Join the Wang Lab
Wang Lab members join us from many pathways. Common ways to join the Lab are below.
PhD Students
The Wang Lab is part of the following PhD training programs at Johns Hopkins University. Visit the websites below to learn more about each program and how to apply. All programs provide full tuition and stipend support.
Master's Students
The Wang Lab takes students from the Department of Biochemistry and Molecular Biology Master of Health Science and Master of Science programs.
Postdoctoral Fellows
To apply to be a postdoctoral fellow in the Wang Lab, please send a copy of your CV to Jiou Wang by email. In addition to training within our lab, the Biochemistry and Molecular Biology Department has an active postdoctoral training program.