The role of histone methyltransferases in neurocognitive disorders associated with brain size abnormalities

Abstract

Brain size is controlled by several factors during neuronal development, including neural progenitor proliferation, neuronal arborization, gliogenesis, cell death, and synaptogenesis. Multiple neurodevelopmental disorders have co-morbid brain size abnormalities, such as microcephaly and macrocephaly. Mutations in histone methyltransferases that modify histone H3 on Lysine 36 and Lysine 4 (H3K36 and H3K4) have been identified in neurodevelopmental disorders involving both microcephaly and macrocephaly. H3K36 and H3K4 methylation are both associated with transcriptional activation and are proposed to sterically hinder the repressive activity of the Polycomb Repressor Complex 2 (PRC2). During neuronal development, tri-methylation of H3K27 (H3K27me3) by PRC2 leads to genome wide transcriptional repression of genes that regulate cell fate transitions and neuronal arborization. Here we provide a review of neurodevelopmental processes and disorders associated with H3K36 and H3K4 histone methyltransferases, with emphasis on processes that contribute to brain size abnormalities. Additionally, we discuss how the counteracting activities of H3K36 and H3K4 modifying enzymes vs. PRC2 could contribute to brain size abnormalities which is an underexplored mechanism in relation to brain size control.

Keywords: autism; brain size; chromatin; histone methyltransferase; macrocephaly; microcephaly; neurodevelopment.

FIGURE 1

Role of H3K36me2/3, H3K4me3, and H3K27me3 in transcriptional activation and repression. (A) Depiction of a nucleosome showing the location of the different lysine histone modifications in the tail of histone H3. (B) Schematic showing histone methyltransferases and their corresponding histone marks associated with transcriptional activation (top panel) and repression (bottom panel). H3K36me2 (light green), H3K36me3 (light blue), and H3K4me3 (dark blue) histone marks are associated with transcriptional activation. Histone methyltransferases associated with deposition of either H3K36me2, H3K36me3, or H3K4me3 are shown. ASH1L is in gray for H3K4me3 as it might indirectly affect the levels of this histone mark. Bold enzyme names are associated with neurodevelopmental disorders or have neuronal phenotypes. H3K27me3 (red) histone mark is associated with transcriptional repression. The PRC2 complex catalyzes H3K27 methylation, its individual core subunits are shown in red. (C) Diagram illustrates the distribution of the different histone marks in different genomic locations including the enhancer, CpG island, promoter, transcription start site (TSS), gene body, and transcription end site (TES). Left panel depicts the histone modification distribution in a transcriptionally active gene. Right panel shows histone modifications in a transcriptionally silent gene (Lim et al., 2010).

FIGURE 2

Neuronal phenotypes associated with brain size abnormalities. Schematic shows brain size abnormalities and potential cellular defects associated with differences in brain size. Microcephaly mechanism are shown in red while macrocephaly mechanisms are shown in light pink. Histone methyltransferases and their corresponding neuronal phenotypes that have been associated with either microcephaly or macrocephaly are shown in black, while enzymes for which there is no conclusive evidence on specific phenotypes are shown in gray.