Elucidating the RBFOX1 transcription regulation network in human neurons and its role in epileptic encephalopathy

The human cortex plays critical roles in cognition, motor function and emotion. It is comprised of complex neuronal networks that are produced by two major cell types: excitatory projection neurons and inhibitory interneurons. Interneurons are produced outside the cortex in the ventral forebrain and migrate into the cortex during development. Failure in neuronal differentiation and migration process, or excitation-inhibition imbalance are linked with neurodevelopmental disorders and epileptic encephalopathy (EE).

The RNA binding fox-1 homolog-1 (RBFOX1) protein is expressed in the cortex and plays a pivotal role in alternative splicing of genes that are critical for neuronal development. Mutations in RBFOX1 and in structural variants in the non-coding sequences proximal to RBFOX1 are both linked to EE. The latter could indicate the disruption of RBFOX1 regulatory elements that are yet to be discovered. In my study, the aim is to elucidate that alteration of RBFOX1 regulatory elements effect on transcription and post-transcription splicing. Indeed, we found a large deletion proximal to RBFOX1 in a patient diagnosed with epilepsy. The genetic diagnosis suggests that not the RBFOX1 coding sequence is affected but rather the transcription regulation that is essential to control the RBFOX1 expression. To test this, I reprogrammed fibroblasts and generated iPS cells that will be differentiated into neurons and used to determine the chromatin interactions at the RBFOX1 locus. Taken together, elucidation of the RBFOX1 regulatory network in human neurons will open new venues towards understanding the pathogenesis of neurodevelopmental disorders that are caused by mutations in non-coding regulatory elements.