Regulating BETs at central station
Authors: Mark A. Dawson
Journal: The Journal of Experimental Medicine (2015)

The Journal of Experimental MedicineThe establishment of complex behaviors, memory, and language has long fascinated humanity.It is, after all, what makes us human.Understanding this complexity presents one of the most significant challenges in biomedical research.Autism spectrum disorders (ASDs) are a group of neurodevelopmental disorders often characterized by repetitive and stereotyped behavior, impaired social development, and diminished language skills.ASDs are estimated to affect up to 1:100 children, many of whom require lifelong social support.The advent of the genomic era has provided unprecedented insight into the molecular architecture of ASDs, and genes controlling transcription and chromatin remodeling appear central to pathogenesis of ASDs.In this issue, Sullivan et al.demonstrate that pharmacological suppression of the critical BET bromodomain transcriptional regulators induces an ASD-like syndrome in mice.The BET proteins contain tandem bromodomains that mediate their interaction with chromatin by binding acetylated lysines on histone tails.They function as part of multisubunit chromatin complexes to nuance and facilitate transcription.BET inhibitors disrupt this protein-protein interaction by displacing the BET proteins from chromatin, leading to transcriptional repression.These drugs have shown promise in a range of human pathologies, including inflammation and cancer, and clinical trials in a variety of malignancies are underway.Sullivan et al. report on their development of a novel BET bromodomain inhibitor (I-BET858) with excellent central nervous system (CNS) penetration.Although the BET proteins are not known to be mutated in ASDs, treating mice with I-BET858 resulted in the selective down-regulation of genes associated with synaptic transmission and neuronal development, several of which have previously been implicated in pathogenesis of ASDs.BET inhibition did not affect the expression of housekeeping genes or the immediate early response genes that are activated by brainderived neutrophic factor (BDNF); instead, I-BET858 preferentially reduced the transcriptional output from longer genes (>100 kb), many of which mediate the secondary response to BDNF stimulation.The functional consequence of these transcriptional changes was the manifestation of an ASD-like syndrome.Interestingly, the behavioral changes induced by BET inhibition appeared to be independent of effects on memory formation, and, crucially, these features were only partially reversed after cessation of the drug.This study offers some intriguing insights into the functional interplay between transcription regulation and complex behaviors.It also provides the impetus to understand at the molecular level why certain extra-long genes, associated with ASDs, appear to be preferentially regulated by BET proteins.Importantly, the clinical consequences of these findings need further exploration.On the one hand, the novel CNSpermeable inhibitor offers a therapeutic opportunity to patients with primary or metastatic CNS tumors.But it also emphasizes the importance of vigilant monitoring of patients currently on these therapies for subtle behavioral and cognitive deficits.