Abstract
Neurogenesis is an elegantly coordinated developmental process that must maintain a careful balance of proliferation and differentiation programs to be compatible with life. Due to the fine-tuning required for these processes, epigenetic mechanisms (e.g., DNA methylation and histone modifications) are employed, in addition to changes in mRNA transcription, to regulate gene expression. The purpose of this review is to highlight what we currently know about histone 4 lysine 20 (H4K20) methylation and its role in the developing brain. Utilizing publicly-available RNA-Sequencing data and published literature, we highlight the versatility of H4K20 methyl modifications in mediating diverse cellular events from gene silencing/chromatin compaction to DNA double-stranded break repair. From large-scale human DNA sequencing studies, we further propose that the lysine methyltransferase gene, KMT5B (OMIM: 610881), may fit into a category of epigenetic modifier genes that are critical for typical neurodevelopment, such as EHMT1 and ARID1B, which are associated with Kleefstra syndrome (OMIM: 610253) and Coffin-Siris syndrome (OMIM: 135900), respectively. Based on our current knowledge of the H4K20 methyl modification, we discuss emerging themes and interesting questions on how this histone modification, and particularly KMT5B expression, might impact neurodevelopment along with current challenges and potential avenues for future research.
Highlights
Neurogenesis is an elegantly coordinated developmental process that must maintain a careful balance of proliferation and differentiation programs to be compatible with life
From large-scale human DNA sequencing studies, we further propose that the lysine methyltransferase gene, KMT5B (OMIM: 610881), may fit into a category of epigenetic modifier genes that are critical for typical neurodevelopment, such as EHMT1 and ARID1B, which are associated with Kleefstra syndrome (OMIM: 610253) and Coffin-Siris syndrome (OMIM: 135900), respectively
These N-terminal tails are permissive to modifications, such as acetylation, methylation, phosphorylation, and ubiquitination, which can translate into more relaxed DNA that is permissive to transcriptional machinery or more condensed DNA—where transcriptional machinery has limited access [2] (Figure 1A)
Summary
Hereditary information is encoded in long strands of DNA that must be compacted and organized in the cell nucleus This process is accomplished by the wrapping of DNA around histone proteins forming dense nucleosome complexes, collectively termed chromatin (Figure 1A). The major players that act on the H4K20 modification are recognize the methylated site/state (readers) [10]. H4K20me1/me and other histone modifications that occur in response to DNA damage to facilitate DSB protein that binds H4K20me1/me and other histone modifications that occur in response to DNA repair via non-homologous end joining (NHEJ). DNA DSBs (red bolt) are (MRE11/RAD50/NBS1) binding, which leads to autophosphorylation of ATM kinase and phosphorylation recognized by the MRN complex (MRE11/RAD50/NBS1) binding, which leads to autophosphorylation of histone H2AX on S 139 (γ-H2AX) This creates a biding site for mediator of DNA damage checkpoint ofprotein. Signaling NHEJ factors, including p53, to either repair the DNA or execute apoptosis/autophagy [13]
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