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The histone H3-lysine 4-methyltransferase Mll4 governs the development of growth hormone-releasing hormone-producing neurons

ABSTRACT: In humans, inactivating mutations in MLL4, which encodes a histone H3-lysine 4-methyltrasferase, lead to Kabuki syndrome (KS). While dwarfism is a cardinal feature of KS, the underlying etiology remains unclear. Here we report that Mll4 is a critical regulator of the development of growth hormone-releasing hormone (GHRH)-producing neurons in the hypothalamus. The two distinct Mll4 mutant mouse models exhibited dwarfism, accompanied by impairment of developmental programs for GHRH-neurons. Our genome-wide studies revealed that, in the developing hypothalamus, Mll4 collaborates mainly with the transcription factor Nrf1 to trigger the expression of GHRH-neuronal genes. Interestingly, the deficiency of Mll4 resulted in a marked reduction of transcriptionally active histone marks in the embryonic hypothalamus, which was rescued by treatment with the histone deacetylase inhibitor AR-42. Further, AR-42 treatment restored GHRH-neuronal production in Mll4 mutant mice. Together, our results suggest that the dysregulation of MLL4-directed epigenetic control of GHRH-neuronal genes is a substantial contributing factor to dwarfism in human KS.

ORGANISM(S): Mus musculus

PROVIDER: GSE149439 | GEO | 2020/11/07

REPOSITORIES: GEO

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