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Mutations of the transcriptional regulator PHF6 cause the X-linked intellectual disability disorder Börjeson-Forssman-Lehmann syndrome (BFLS), but the pathogenesis of BFLS remains poorly understood. Here, we report a mouse model of BFLS, generated using a CRISPR-Cas9 approach, in which cysteine 99 within the PHD domain of PHF6 is replaced with phenylalanine (C99F). Mice harboring the patient-specific C99F mutation display deficits in cognitive functions, emotionality, and social behavior, as well as reduced threshold to seizures. Electrophysiological studies reveal that the intrinsic excitability of entorhinal cortical stellate neurons is increased in PHF6 C99F mice. Transcriptomic analysis of the cerebral cortex in C99F knockin mice and PHF6 knockout mice show that PHF6 promotes the expression of neurogenic genes and represses synaptic genes. PHF6-regulated genes are also overrepresented in gene signatures and modules that are deregulated in neurodevelopmental disorders of cognition. Our findings advance our understanding of the mechanisms underlying BFLS pathogenesis.
Understanding the mechanisms of activity-dependent gene transcription underlying adaptive behaviors is challenging at neuronal-subtype resolution. Using cell-type specific molecular analysis in agouti-related peptide (AgRP) neurons, we reveal that the profound hunger-induced transcriptional changes greatly depend on plant homeodomain finger protein 6 (PHF6), a transcriptional repressor enriched in AgRP neurons. Loss of PHF6 in the satiated mice results in a hunger-state-shifting transcriptional profile, while hunger fails to further induce a rapid and robust activity-dependent gene transcription in PHF6-deficient AgRP neurons. We reveal that PHF6 binds to the promoters of a subset of immediate-early genes (IEGs) and that this chromatin binding is dynamically regulated by hunger state. Depletion of PHF6 decreases hunger-driven feeding motivation and makes the mice resistant to body weight gain under repetitive fasting-refeeding conditions. Our work identifies a neuronal subtype-specific transcriptional repressor that modulates transcriptional profiles in different nutritional states and enables adaptive eating behavior.
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