ZMYND11 Restrains KMT2A to Enable a Neuronal Developmental Program

Greben, A. W.; Wu, X. S.; Robb, J. E.; Vogel, I. R.; Traunmüller, L.; Krüttner, S.; Fulton, K. A.; Darcera, M. V. L.; Griffith, E. C.; Greenberg, M. E.

doi:10.1101/2025.10.31.685692

bioRxiv · 10.1101/2025.10.31.685692

ZMYND11 Restrains KMT2A to Enable a Neuronal Developmental Program

Greben, A. W.·Wu, X. S.·Robb, J. E.·Vogel, I. R.·Traunmüller, L.·Krüttner, S.·Fulton, K. A.·Darcera, M. V. L.·Griffith, E. C.·Greenberg, M. E.

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Abstract

Mutations in the chromatin reader and tumor suppressor ZMYND11 are the cause of ZMYND11-related syndromic intellectual disability (ZRSID), a disorder characterized by symptoms such as language and motor delay, behavioral disruptions, and seizures. We find that neuronal deletion of ZMYND11 in mice causes aberrant upregulation of non-neuronal gene programs, leading to reduced dendritic branching and spine density, as well as hyperactivity and abnormal motor behavior. We investigated the mechanism by which ZMYND11 regulates gene expression and discovered that ZMYND11 interacts with and inhibits the histone methyltransferase KMT2A (MLL1), a transcriptional co-activator which contributes to oncogenic and developmental gene programs. We find that a ZRSID-associated ZMYND11 point mutation abrogates ZMYND11 interaction with KMT2A, suggesting that this interaction is critical for the function of ZMYND11 in regulating brain development. Using a degron-tagged ZMYND11 mouse model to enable the rapid degradation of ZMYND11 in primary cortical neurons, we show that gene expression changes induced by ZMYND11 loss are attenuated by treatment with the KMT2A inhibitor revumenib, a drug which has recently been approved for the treatment of KMT2A-rearranged leukemia. Our findings shed light on the convergence of chromatin mechanisms regulating neuronal gene expression and raise the possibility that modulation of KMT2A activity may be a useful therapeutic avenue for ZRSID.

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Greben, A. W., Wu, X. S., Robb, J. E., Vogel, I. R., Traunmüller, L., Krüttner, S., Fulton, K. A., Darcera, M. V. L., Griffith, E. C., Greenberg, M. E.. 2025-10-31. ZMYND11 Restrains KMT2A to Enable a Neuronal Developmental Program. https://doi.org/10.1101/2025.10.31.685692

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