A research study led by the Miller School of Medicine’s Lluis Morey, Ph.D., reveals how rare mutations in key epigenetic regulators can derail early brain development to drive cognitive impairment, anxiety and social deficits.
Dr. Morey and Miller School colleagues joined an international contingent of researchers to offer one of the clearest explanations to date for how disruptions in the Polycomb system — a set of proteins that epigenetically regulate gene expression — contribute to neurodevelopmental disorders.
Using advanced stem‑cell models, chromatin‑mapping technologies (to understand DNA organization) and genetically engineered preclinical models, the research team uncovered how a single mutation in the RNF2 gene reshapes the brain’s developmental trajectory long before birth.
“Our findings reveal a novel, epigenetic mechanism essential for neurodevelopmental integrity and brain function and demonstrate how mutations in Polycomb genes contribute to neurodevelopmental disorders,” said Dr. Morey, an associate professor in the Dr. John T. Macdonald Foundation Department of Human Genetics at the Miller School and the study’s senior author. “This study highlights the critical role of RNF2 mutations in advancing our understanding of intellectual disabilities.”
The Miller School team of researchers included:
Ramiro Verdun, Ph.D., research professor in the Division of Hematology
Ramin Shiekhattar, Ph.D., professor and co-leader of the Cancer Epigenetics Research Program at Sylvester Comprehensive Cancer Center and chief of the Division of Cancer Genomics and Epigenetics
Katherina Walz, Ph.D., research associate professor in the Dr. John T. Macdonald Foundation Department of Human Genetics and director of the Division of Human Disease Modeling in the John P. Hussman Institute for Human Genomics
This study builds on Dr. Morey’s years of foundational work on how gene regulation goes awry in cancer. Using experimental and computational approaches, he examines how cell signaling pathways and gene-regulating proteins impact cancer-causing processes. These include transcription factors, which switch individual genes on and off, and chromatin regulators, which control access to regions of DNA. He also studies mutations in genes that encode Polycomb proteins — key regulators of gene expression that are essential for proper human development.
The Consequences of Gene Mutations
Neurodevelopmental disabilities now affect roughly one in six children in the United States. Yet, information about what a specific mutation actually does in the developing brain is scarce, even with genetic testing. This study helps close that gap by dissecting the molecular and cellular consequences of mutations in RING1 and RNF2, two genes that encode core components of a group of Polycomb proteins known as Polycomb Repressive Complex 1 (PRC1). PRC1 helps keep certain developmental genes switched off at the right time.
The team found several previously unknown mutations in the proteins RING1 and RNF2 in individuals with severe intellectual disabilities. By analyzing large genetics databases, they identified rare variants in the genes encoding these proteins that would be likely to disrupt PRC1 functions. Many of these variants occur in important, evolutionarily conserved regions of these PRC1 proteins — sequences that are identical or similar across species. This suggests that those variants may interfere with PRC1’s structure or activity across species and lead to abnormal gene regulation, impaired brain development and related cognitive and behavioral symptoms.
Honing in on RNF2 Mutations
For the study, Dr. Morey’s research team created preclinical models to study RNF2-R70H, a protein mutation they predicted (and later confirmed) would interfere with PRC1’s function. The models featured embryonic stem cells carrying one mutant copy of RNF2. These stem cells allowed researchers to follow the earliest moments of a cell’s neural development.
The researchers found that the RNF2-R70H mutation disrupts the balance between PRC1 complexes, causing the mutant protein to associate with certain PRC1 complexes while displacing others. This shift alters the placement of key chemical tags that are normally required to regulate when neurodevelopmental genes turn on. Without the proper balance of these repressive marks, the genetic program that drives neural differentiation becomes scrambled.
“This study highlights the critical role of RNF2 mutations in advancing our understanding of intellectual disabilities.”
Neural Development Derailed
When the mutant stem cells were guided to form self-renewing neural progenitor cells (NPCs) that are critical to brain development, the NPCs didn’t produce healthy neurons. Instead, they catalyzed changes that prevented healthy brain cell development. Even when researchers restarted an important system that guides early brain development — the Wnt cell-signaling pathway — the cells still failed to develop into healthy neurons. This suggests the problem occurs early and becomes irreversible.
“These findings suggest that a single-point mutation in a Polycomb gene is sufficient to rewire the transcriptional circuits necessary for the generation of functional neurons,” Dr. Morey said. “[It may] pave the way to develop strategies to restore the epigenetic program to improve brain function and to reduce anxiety and sociability deficits driven by genetic mutations.”
Polycomb Mutations Can Drive Behavior
The team also found that preclinical models carrying the two copies of the RNF2-R70H mutation did not survive, highlighting the essential role of RNF2 in development. But those with just one mutant copy, mirroring the situation in patients, provided a deeper look at brain structure and behavior.
These models showed:
- Changes in the circuits that support memory and emotional regulation
- Reduced neuronal density in key regions of the medial prefrontal cortex, which is involved in many higher-order cognitive functions
- Abnormal social behavior, including reduced sociability and impaired recognition of social novelty
- Increased anxiety
A single‑cell analysis of adult brains revealed many neural cells remained in immature states, while glial and inflammatory cell types were over‑represented. Additionally, chromatin in these mutant cells was more compact than normal, restricting access to genes needed for proper brain cell maturation.
Given those findings, the study sheds new light on how Polycomb mutations can drive anxiety‑related behaviors and social difficulties. The disrupted PRC1 function led to altered neuronal architecture and weakened communication in key brain regions such as the prefrontal cortex and hippocampus. These molecular and structural changes translated into reduced sociability, poor recognition of social novelty and heightened anxiety‑like behaviors.
Potential Therapeutic Strategies
By showing exactly how Polycomb mutations disrupt the sequence of events that produces healthy neurons and functional brains, Dr. Morey’s work provides a framework to interpret rare variants uncovered through genetic testing. It also identifies potential therapeutic strategies centered on restoring proper Polycomb balance before critical developmental windows close.
