Yin-yang actions of histone methylation regulatory complexes in the brain

Abstract

Dysregulation of histone methylation has emerged as a major driver of neurodevelopmental disorders including intellectual disabilities and autism spectrum disorders. Histone methyl writer and eraser enzymes generally act within multisubunit complexes rather than in isolation. However, it remains largely elusive how such complexes cooperate to achieve the precise spatiotemporal gene expression in the developing brain. Histone H3K4 methylation (H3K4me) is a chromatin signature associated with active gene-regulatory elements. We review a body of literature that supports a model in which the RAI1-containing H3K4me writer complex counterbalances the LSD1-containing H3K4me eraser complex to ensure normal brain development. This model predicts H3K4me as the nexus of previously unrelated neurodevelopmental disorders.

Keywords: LSD1; PHF21A; RAI1; activity-dependent gene expression; autism spectrum disorders; chromatin regulatory complex; circadian gene expression; histone methylation; intellectual disability; neurodevelopmental disorders.

Figure 1.. Structural features of LSD1–CoREST complex and RAI1 complex components.

LSD1–CoREST complex (A) and RAI1 complex (B) components and associated neurodevelopmental disorders. ^†Known missense mutations associated with neurodevelopmental disorders. aa: Amino acids; AOD-N: Amine oxidase domain (N-terminal); CC: Coiled-coil domain; ELM2: Egl27 and MtA1 homology domain; ePHD: Extended plant homeodomain; HMG: High mobility group domain; NBD: Nucleosome binding domain; PHD: Plant homeodomain; SANT: Swi3-Ada2-N-cor-Transcription factor domain; TOW: TOWER domain.

Figure 2.. A model of opposing roles of LSD1–CoREST complex and RAI1 complex on histone H3K4 methylation.

The LSD1–CoREST complex facilitates demethylation of H3K4me1/2, repressing expression of neuron-specific genes in neuroprogenitors. Through iBRAF, the RAI1 complex recruits MLL1 to methylate H3K4, which in turn leads to activation of neuronal genes. Note that iBRAF can substitute for BRAF35 in the LSD1–CoREST complex, suggesting multiple modes of regulation between the RAI1 and LSD1–CoREST complex.

Figure 3.. Spatiotemporal expression of LSD1–CoREST and RAI1 complex components in developing mouse brain.

(A) Expression of three of the six LSD1–CoREST complex components: Rcor2 (CoREST2), Hdac2 and Braf35 (Hmg20b). (B) Expression of three of the four RAI1 complex components Rai1, Tcf20 and iBraf (Hmg20a). Braf35 and iBraf are reciprocally expressed during development, whereas the components of the RAI1 complex are generally co-expressed at later developmental stages. Time points extend from embryonic day 11.5 (E11.5) to postnatal day 28 (P28). Different subregions of the developing brain are: RSP: Rostral secondary prosencephalon; Tel: Telencephalon; PHy: Peduncular hypothalamus; p3: Prosomere 3; p2: Prosomere 2; p1: Prosomere 1; M: Midbrain. PPH: Prepontine hindbrain; PH: Pontine hindbrain; PMH: Pontomedullary hindbrain and MH: Medullary hindbrain. Corresponding mature brain areas are Hippo: Hippocampus, and Mid: Midbrain. Images are adapted from Expression Summaries obtained from the Allen Developing Mouse Brain Atlas, which compiles in situ hybridization data. The original Allen Developing Mouse Brain Atlas Expression Summaries were found at the following web links: Rcor2: [102]; Hdac2: [103]; Braf35 (Hmg20b): [104]; Rai1: [105]; Tcf20: [106]; iBraf (Hmg20a): [107]. ^©2015 Allen Institute for Brain Science; Allen Developing Mouse Brain Atlas. Available from [97].

Figure 4.. LSD1–CoREST and RAI1 complex components in activity-dependent gene expression and circadian gene expression.

Evidence suggests both the LSD1 complex and the RAI1 complex are involved in activity-dependent transcription (A & B) and circadian transcription (C & D). P and Ac regulate the actions of the two complexes. Experimental validations are needed to determine if the RAI1 complex and/or the iBRAF-containing LSD1 complex regulate a variety of activity-dependent genes. Ac: Acetylation; P: Phosphorylation.