AUTHOR=Roth Charlotte , Kilpinen Helena , Kurian Manju A. , Barral Serena 

TITLE=Histone lysine methyltransferase-related neurodevelopmental disorders: current knowledge and saRNA future therapies

JOURNAL=Frontiers in Cell and Developmental Biology

VOLUME=Volume 11 - 2023

YEAR=2023

URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2023.1090046

DOI=10.3389/fcell.2023.1090046

ISSN=2296-634X

ABSTRACT=Neurodevelopmental disorders (NDDs) encompass a group of debilitating diseases presenting with motor and cognitive dysfunction with variable age of onset and disease severity. Advances in genetic diagnostic tools have facilitated the identification of several monogenic chromatin remodelers as underlying genetic cause of NDDs. Such genes play a key role in the neuro-epigenetic landscape and regulation of brain development; it is therefore not surprising that loss-of-function mutations in these genes result in aberrant neurodevelopment. NDD patients have been described with heterozygous, usually de novo mutations in histone lysine methyltransferases (HKMTs) leading to haploinsufficiency, dysregulated protein levels and impaired function. Studies in animal models and patient-derived cell lines, have highlighted roles of HKMTs in the regulation of cell self-renewal, cell fate specification, and apoptosis. The role of HKMTs has been analyzed in-depth in oncology, providing strong evidence of HKMT dysregulation as a determinant of cancer progression and therapeutic resistance. As a result, HKMTs have become a therapeutic target for the treatment of different cancer forms.
Despite recent advances, we still lack knowledge about the role of HKMTs in neuronal development. This has hampered both the study and development of precision therapies for HKMT-related NDDs mutations. In this review, we will discuss the current knowledge of the role of HKMT in neural development and disease in NDDs. We will also discuss how RNA-based technologies using small-activating RNA could provide a novel therapeutic approach for the treatment of HKMT haploinsufficiency in NDDs, and how they could be tested in state-of-the-art patient-derived neuronal models.