The rockefeller university

RNA is the driving force of biological complexity, determining when and where genes are expressed, shaping cellular identity and function. Darnell pioneered crosslinking immunoprecipitation (CLIP) to map RNA-protein interactions in living tissues, revealing how neuron-specific RNA-binding proteins regulate splicing, translation, and disease. His work connects RNA regulation to intellectual function autoimmunity, and brain evolution.

Darnell’s lab has pioneered the study of RNA regulation in the brain, leading to foundational discoveries in neurobiology, developmental disease, and RNA-based diagnostics. He was initially inspired by studies of paraneoplastic neurologic disorders (PNDs), which develop when tumors make proteins normally unique to the brain, triggering an anti-tumor immune response that then causes collateral damage to the nervous system. This led to the discovery of neuron RNA binding proteins (RBPs) in mammals, which act as immune targets in PNDs, and spared the concept of neuronspecific RNA regulation.

To define the functions of RBPs in vivo, Darnell developed CLIP, a transformative method able to map RBP-RNA interactions at single-nucleotide resolution in living tissue. The lab is advancing CLIP to enable cell-type-specific and subcellular analyses, including in the human brain, yielding mechanistic insights into how individual neurons regulate gene expression via alternative splicing, mRNA stabilization, localization, and translational control.

Darnell’s studies of NOVA and FMRP, two key neuronal RBPs, have uncovered how posttranscriptional RNA regulation shapes synaptic function, plasticity, and congition. His lab showed that FMRP inhibitors ribosomal translocation on specific neuronal mRNAs, revealing a direct molecular mechanism for how translation control underlies Fragile X syndrome and autism. Recent optogenetic CLIP studies now detail how FMRP differentially controls translation of chromatin modifiers versus synaptic regulators within single CA1 hippocampal neurons, depending on location and activation state.

Parallel studies on NOVA1, which Darnell first cloned from a paraneoplastic patient, have culminated in the discovery of a modern human-specific amino acid variant (I197V) that subtly alters splicing of vocalization-related genes. Humanized mouse models reveal NOVA1’s role in communication circuits, and clinical genetics has uncovered multiple patients with NOVA1 mutations exhibiting speech delay. Together, these findings suggest NOVA1 may function as a core language gene linking evolution, autism, and splicing regulation.

The lab has recently extended its interests in neurodegenerative disease and systemic inflammation. By leveraging RNA-seq and machine learning, Darnell’s team has identified blood-based RNA signatures that correlate with brain molecular states and clinical outcomes in Parkinson’s disease, rheumatoid arthritis, and viral infections such as COVID-19. These studies suggest that longitudinal RNA monitoring may become a powerful tool to predict disease course and therapeutic response.

Spanning molecular tools, neurobiology, human evolution, and clinical translation, Darnell’s work offers a cohesive model of how RNA regulation underlies both the complexity of human cognition and the pathophysiology of human disease.

Darnell is a faculty member in the David Rockefeller Graduate Program, and the Tri-Institutional M.D.-Ph.D. Program.