Menin deficiency induces autism-like behaviors by regulating Foxg1 transcription and participates in Foxg1-related encephalopathy

FOXG1 syndrome is a developmental encephalopathy with a high phenotypic variability, which results from FOXG1 mutations. However, the upstream transcriptional regulation of Foxg1 expression remains unclear. Here we report that both deficiency and overexpression of Men1 (protein: menin, a pathogenic gene of MEN1 syndrome) result in autism-like behaviors, including social defects, increased repetitive behaviors and cognition impairments. We employed multifaceted transcriptome analyses and found that Foxg1 signaling is mostly altered in Men1 deficiency mice, through its regulation over Alpha Thalassemia/Mental Retardation Syndrome X-Linked (Atrx) factor. Atrx recruits menin to bind to the transcriptional start region of Foxg1 and mediates the regulation of Foxg1 expression by H3K4me3 modification. Notably, the described changes in menin deficient mice were rescued by over-expression of Foxg1, leading to normalized spine growth and hippocampal synaptic plasticity. Collectively, these results indicate a putative role of menin in maintaining Foxg1 expression, and menin signaling may serve as Foxg1-related encephalopathy therapeutic targets. Overall design: CUT&Tag was performed with Hyperactive In-Situ ChIp Library Prep Kit forlllumina (pG-Tn5) (TD901, Vazyme Biotech) according to the manufacturer'sinstructions. In brief, primary neurons were collected and bounded to Concanavalin A-coated beads. Subsequently, cells were resuspended in antibodybuffer and incubated with primary antibodies against menin antibody (A300-105A; Bethyl) and secondary antibodies in order. The samples were incubated with pA-Tn5 transposase. Aftertransposon activation and tagmentation, DNA was isolated, amplified, and purified to construct library, The library for sequencing was constructed and VAHTS DNAClean Beads (N411, Vazyme Biotech) were used for purification steps. The librarywas quantified with VAHTS Library Quantification Kit for lllumina (VazymeBiotech) and sequenced on an lllumina novaseq 150PE. The sequencing was carried out by Novogene (Novogene, Beijing, China).