ESPEYB18 1. Pituitary and Neuroendocrinology Development/Ontogeny (6 abstracts)
1.6. The histone H3-lysine 4-methyltransferase Mll4 regulates the development of growth hormone-releasing hormone-producing neurons in the mouse hypothalamus
Huisman C , Kim YA , Jeon S , Shin B , Choi J , Lim SJ , Youn SM , Park Y , K C M , Kim S , Lee SK , Lee S & Lee JW
Nat Commun. 2021 Jan 11;12(1):256. doi: 10.1038/s41467-020-20511-7. PMID: 33431871.
These authors report two Mll4 mutant mouse models that exhibited dwarfism and altered development of GHRH−neurons.
Inactivating mutations in KDM6A (aka UTX) or KMT2D (aka MLL4) genes result in Kabuki syndrome (KS), whose hallmarks include facial features, intellectual disability of variable degree, skeletal abnormalities, and postnatal growth retardation. MLL4 encodes a histone H3−lysine 4−methyltransferase, and together MLL4 and UTX form the MLL4−complex, which controls gene expression. This study identifies the transcription factor Nrf1, that interacts with Mll4, to be mediator of Mll4 actions. By integrating Mll4 and Nrf1 ChIP−seq datasets with single cell RNA−seq analyses of E15 ARC neurons, the authors pinpointed 83 genes most specifically enriched in the developing GHRH neurons relative to other ARC neuronal types. Treatment of the Mll4 mutant mice with the histone deacetylase inhibitor, AR−42, rescued the histone mark signature and restored GHRH−neuronal production.
The authors conclude that developmental dysregulation of Mll4−directed epigenetic control of transcription plays a role in the development of GHRH−neurons and dwarfism phenotype in mice.
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ESPE Yearbook of Paediatric Endocrinology
ISSN 1662-4009 (Online)
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