Sexually Dimorphic Alterations in the Transcriptome and Behavior with Loss of Histone Demethylase KDM5C.

Chromatin dysregulation has emerged as a major hallmark of neurodevelopmental disorders such as intellectual disability (ID) and autism spectrum disorders (ASD). The prevalence of ID and ASD is higher in males compared to females, with unknown mechanisms. Intellectual developmental disorder, X-linked syndromic, Claes-Jensen type (MRXSCJ), is caused by loss-of-function mutations of lysine demethylase 5C (KDM5C), a histone H3K4 demethylase gene. KDM5C escapes X-inactivation, thereby presenting at a higher level in females. Initially, MRXSCJ was exclusively reported in males, while it is increasingly evident that females with heterozygous KDM5C mutations can show cognitive deficits. The mouse model of MRXSCJ, male Kdm5c-hemizygous knockout animals, recapitulates key features of human male patients. However, the behavioral and molecular traits of Kdm5c-heterozygous female mice remain incompletely characterized. Here, we report that gene expression and behavioral abnormalities are readily detectable in Kdm5c-heterozygous female mice, demonstrating the requirement for a higher KDM5C dose in females. Furthermore, we found both shared and sex-specific consequences of a reduced KDM5C dose in social behavior, gene expression, and genetic interaction with the counteracting enzyme KMT2A. These observations provide an essential insight into the sex-biased manifestation of neurodevelopmental disorders and sex chromosome evolution.

Small-Molecule-Mediated Stabilization of PP2A Modulates the Homologous Recombination Pathway and Potentiates DNA Damage-Induced Cell Death.

High-grade serous carcinoma (HGSC) is the most common and lethal ovarian cancer subtype. PARP inhibitors (PARPi) have become the mainstay of HGSC-targeted therapy, given that these tumors are driven by a high degree of genomic instability (GI) and homologous recombination (HR) defects. Nonetheless, approximately 30% of patients initially respond to treatment, ultimately relapsing with resistant disease. Thus, despite recent advances in drug development and an increased understanding of genetic alterations driving HGSC progression, mortality has not declined, highlighting the need for novel therapies. Using a small-molecule activator of protein phosphatase 2A (PP2A; SMAP-061), we investigated the mechanism by which PP2A stabilization induces apoptosis in patient-derived HGSC cells and xenograft (PDX) models alone or in combination with PARPi. We uncovered that PP2A genes essential for cellular transformation (B56α, B56γ, and PR72) and basal phosphatase activity (PP2A-A and -C) are heterozygously lost in the majority of HGSC. Moreover, loss of these PP2A genes correlates with worse overall patient survival. We show that SMAP-061-induced stabilization of PP2A inhibits the HR output by targeting RAD51, leading to chronic accumulation of DNA damage and ultimately apoptosis. Furthermore, combination of SMAP-061 and PARPi leads to enhanced apoptosis in both HR-proficient and HR-deficient HGSC cells and PDX models. Our studies identify PP2A as a novel regulator of HR and indicate PP2A modulators as a therapeutic therapy for HGSC. In summary, our findings further emphasize the potential of PP2A modulators to overcome PARPi insensitivity, given that targeting RAD51 presents benefits in overcoming PARPi resistance driven by BRCA1/2 mutation reversions.

Mutually suppressive roles of KMT2A and KDM5C in behaviour, neuronal structure, and histone H3K4 methylation.

Histone H3 lysine 4 methylation (H3K4me) is extensively regulated by numerous writer and eraser enzymes in mammals. Nine H3K4me enzymes are associated with neurodevelopmental disorders to date, indicating their important roles in the brain. However, interplay among H3K4me enzymes during brain development remains largely unknown. Here, we show functional interactions of a writer-eraser duo, KMT2A and KDM5C, which are responsible for Wiedemann-Steiner Syndrome (WDSTS), and mental retardation X-linked syndromic Claes-Jensen type (MRXSCJ), respectively. Despite opposite enzymatic activities, the two mouse models deficient for either Kmt2a or Kdm5c shared reduced dendritic spines and increased aggression. Double mutation of Kmt2a and Kdm5c clearly reversed dendritic morphology, key behavioral traits including aggression, and partially corrected altered transcriptomes and H3K4me landscapes. Thus, our study uncovers common yet mutually suppressive aspects of the WDSTS and MRXSCJ models and provides a proof of principle for balancing a single writer-eraser pair to ameliorate their associated disorders.

Author Correction: Mutually suppressive roles of KMT2A and KDM5C in behaviour, neuronal structure, and histone H3K4 methylation.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.