Paraspeckle Protein NONO Regulates Active Chromatin by Allosterically Stimulating NSD1
Dissertation Defense: Paraspeckle Protein NONO Regulates Active Chromatin by Allosterically Stimulating NSD1
Chen-I Hsu
Graduate Student, Biomedical and Veterinary Sciences
Graduate Research Assistant, Yu Lab, Fralin Biomedical Research Institute at VTC
Nov. 7, 2025, at 10 a.m.
Children's National Research and Innovation Campus, Conference Room 6203
More About the Candidate and Project
Mentor
Jia-Ray Yu, Ph.D., Assistant Professor, Fralin Biomedical Research Institute at VTC
Committee Members
- Hehuang “David” Xie, Ph.D., Professor, Department of Biomedical Sciences and Pathobiology
- Kathleen Mulvaney, Ph.D., Assistant Professor, Fralin Biomedical Research Institute at VTC
- Pedro P. Rocha, Ph.D., Stadtman Investigator, Center for Cancer Research, National Cancer Institute
Hsu C-I, Mei S, Demmerle J, Prakash A, Ruttenberg S, Sahn M, Yu J. Paraspeckle protein NONO regulates active chromatin by allosterically stimulating NSD1. Cell Reports. 2025; 41(11): 116247. doi:10.1016/j.celrep.2025.116247.
Hsu C-I, Yeh E., Chen C.C.L., Sahn M., Yu J.R. (2025). Protocol for reconstituting enzymatic activities for ultra-large histone methyltransferases NSD1 and SETD2 using a baculovirus expression system. STAR Protocols, 6(3): 103963. doi:10.1016/j.xpro.2025.103963
Selected Participant, 2023 Cold Spring Harbor Course in Expression, Purification & Analysis of Proteins and Protein Complexes
Selected Participant, 2025 Cold Spring Harbor Course in Synthetic Biology
About this Dissertation
DNA is the blueprint that carries all the genetic information of living organisms. In humans, every cell contains nearly identical copies of this DNA blueprint, yet cells become remarkably different, forming tissues such as muscle, skin, and brain. This diversity arises from a process called epigenetic regulation, which controls how genes are switched on or off without altering the DNA sequence itself. One way this occurs is through small chemical marks that attach to proteins called histones, which help organize DNA into compact structures known as chromatin. These marks determine which parts of the genome remain active and which stay silent.
My dissertation focuses on a large enzyme called NSD1, which helps place one of these chemical marks to keep certain regions of DNA active. NSD1 is essential for normal growth and development, and when its activity is disrupted, it can lead to childhood overgrowth syndromes and several types of cancer. Because NSD1 is unusually large and flexible, it has been very challenging for scientists to purify and study.
In the first part of my research, I developed a reliable method to produce the complete NSD1 protein in the laboratory. This method made it possible to examine its biochemical behavior in detail. In the second part, I discovered that NSD1 does not function alone. It must first be activated by another protein called NONO, which helps form small structures inside the nucleus known as paraspeckles. When NONO interacts with NSD1, it activates the enzyme, enabling it to place the necessary chemical marks on DNA-associated histones. Disrupting this interaction affects how stem cells develop into neurons, offering new clues about why certain genetic disorders impact brain development.
The third part of my dissertation reviews recent research suggesting that NSD1 and paraspeckles work together to control how active regions of DNA are maintained and passed on when cells divide. This cooperation may also contribute to diseases caused by disruptions in chromatin regulation.
Overall, this research establishes a framework for studying the full-length NSD1 protein, reveals how it is activated by NONO, and proposes a new model connecting paraspeckles to the regulation of active DNA. These findings deepen our understanding of how cells manage their genetic information and open potential directions for treating diseases related to errors in epigenetic control.