MODULATION OF NEURONAL IDENTITY THROUGH THE CUT HOMEOBOX FAMILY OF TRANSCRIPTION FACTORS

The nervous system’s complexity arises from the diversity of its fundamental units, neurons. Neuronal identity is established during development by specific transcriptional programs and is actively maintained throughout life. Defining the molecular identity of fully differentiated neurons is essential for understanding nervous system function. Neuron type–specific genes, whose expression is restricted to particular neuronal subtypes, contribute to this identity by distinguishing one neuron type from another. However, neuronal identity also relies on shared neuronal genes that underlie fundamental neuronal properties.
In C. elegans, the expression of shared synaptic genes is regulated by the combined action of broadly expressed CUT homeobox transcription factors and neuron type–specific master regulators known as terminal selector (TS) transcription factors. Previous studies have shown that CUT homeodomain binding motifs are strongly associated with differential chromatin accessibility between induced neurons and fibroblasts, suggesting a potential pioneer factor role for CUT proteins. We hypothesize that CUT factors modulate chromatin accessibility to facilitate the binding of additional transcription factors.
To investigate how CUT factors influence the neuronal chromatin landscape, we developed a method to isolate nuclei from all C. elegans neurons by FACS and profile chromatin accessibility in CUT homeobox mutants. Previous bulk transcriptional analyses reveal downregulation of both shared neuronal and neuron type–specific genes, suggesting a broader role for CUT factors in neuronal identity. Ongoing single-cell transcriptional profiling of FACS-sorted neuronal nuclei from wild-type and CUT mutant animals will directly test the contribution of CUT factors to neuron-type specificity.