Abstract
The role of bona fide epigenetic regulators in the process of neuronal transdifferentiation was until recently largely uncharacterized, despite their key role in the physiological processes of neural fate acquisition and maintenance. In this commentary, we describe the main findings of our recent paper “KMT2B is selectively required for neuronal transdifferentiation, and its loss exposes dystonia candidate genes,” where we investigated the role of this histone H3K4 methyltransferase during mouse embryonic fibroblasts (MEFs) to induced neuronal cells (iNs) direct conversion. Indeed, Kmt2b–/– MEFs, transduced with three neuronal-specific transcription factors (TFs), Brn2, Ascl1, and Myt1l, show lower transdifferentiation efficiency, defective iN maturation, and augmented alternative cell fates acquisition, with respect to controls. Here, we went beyond the data, hypothesizing how KMT2B executes its fundamental role. In particular, we supposed that MYT1L, which has been proven to be fundamental for iN maturation and the switch-off of alternative cell fates, directly or indirectly needs KMT2B. Indeed, KMT2B could be important both to make MYT1L-target genes accessible, because MYT1L is not a pioneer TF and preferentially binds to open chromatin, and to activate MYT1L-downstream genes.
Highlights
Wapinski and colleagues demonstrated that efficiency of neuronal transdifferentiation positively correlates with the percentage of trivalent chromatin states, which are specific sites in the transdifferentiating cell type, composed by H3K4me[1], H3K9me[1], and H3K27ac.[3] As KMT2 proteins, beyond catalyzing H3K4 trimethylation, are responsible for the deposition of H3K4me[1], we analyzed whether we were able to identify differentially monomethylated H3K4 sites between Kmt2b–/– and control mouse embryonic fibroblasts (MEFs). As we quite expected, we did not score a dysregulation in H3K4me[1] deposition, because this mark is mainly deposited by KMT2C and KMT2D.8,9 to date, we cannot exclude that the deposition of H3K9me[1] and H3K27ac is not been impaired in the absence of KMT2B
We focused on the chromatin regulation of this process, investigating the role of two histone H3 lysine 4 (H3K4) trimethylases, KMT2A and KMT2B, whose role during neuronal differentiation has been extensively studied, to probe their specific impact on neuronal transdifferentiation
As mentioned above, we demonstrated that a portion of differentially expressed genes during transdifferentiation loses H3K4me[3] already at mouse embryonic fibroblasts (MEFs) stage upon Kmt2b deletion
Summary
Wapinski and colleagues demonstrated that efficiency of neuronal transdifferentiation positively correlates with the percentage of trivalent chromatin states, which are specific sites in the transdifferentiating cell type, composed by H3K4me[1], H3K9me[1], and H3K27ac.[3] As KMT2 proteins, beyond catalyzing H3K4 trimethylation, are responsible for the deposition of H3K4me[1], we analyzed whether we were able to identify differentially monomethylated H3K4 sites between Kmt2b–/– and control MEFs. As we quite expected, we did not score a dysregulation in H3K4me[1] deposition, because this mark is mainly deposited by KMT2C and KMT2D.8,9 to date, we cannot exclude that the deposition of H3K9me[1] and H3K27ac is not been impaired in the absence of KMT2B.
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