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.2019 Mar 1;28(5):818-827.
doi: 10.1093/hmg/ddy393.

A neuronal enhancer network upstream of MEF2C is compromised in patients with Rett-like characteristics

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A neuronal enhancer network upstream of MEF2C is compromised in patients with Rett-like characteristics

Eva D'haene et al. Hum Mol Genet..

Erratum in

Abstract

Mutations in myocyte enhancer factor 2C (MEF2C), an important transcription factor in neurodevelopment, are associated with a Rett-like syndrome. Structural variants (SVs) upstream of MEF2C, which do not disrupt the gene itself, have also been found in patients with a similar phenotype, suggesting that disruption of MEF2C regulatory elements can also cause a Rett-like phenotype. To characterize those elements that regulate MEF2C during neural development and that are affected by these SVs, we used genomic tools coupled with both in vitro and in vivo functional assays. Through circularized chromosome conformation capture sequencing (4C-seq) and the assay for transposase-accessible chromatin using sequencing (ATAC-seq), we revealed a complex interaction network in which the MEF2C promoter physically contacts several distal enhancers that are deleted or translocated by disease-associated SVs. A total of 16 selected candidate regulatory sequences were tested for enhancer activity in vitro, with 14 found to be functional enhancers. Further analyses of their in vivo activity in zebrafish showed that each of these enhancers has a distinct activity pattern during development, with eight enhancers displaying neuronal activity. In summary, our results disentangle a complex regulatory network governing neuronal MEF2C expression that involves multiple distal enhancers. In addition, the characterized neuronal enhancers pose as novel candidates to screen for mutations in neurodevelopmental disorders, such as Rett-like syndrome.

© The Author(s) 2018. Published by Oxford University Press.

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Figures

Figure 1
Figure 1
MEF2C interacts with multiple enhancer elements in its regulatory region.(A) The MEF2C locus is disrupted in patients with a Rett-like phenotype. Black boxes represent the local TAD structure, as found in the 3D Genome Browser (GM12878, 1 kb resolution) and delineate theMEF2C regulatory domain (51,52). Chromosomal abnormalities, including 11 deletions (red bars) and 9 translocations (red arrows) in patients with a Rett-like phenotype, disrupt theMEF2C regulatory region without affecting theMEF2C protein-coding sequence.(B) Chromatin interactions at the MEF2C locus determined by 4C-seq. The 4C-seq profile (RPM normalized and smoothed) from SH-SY5Y (blue) showsMEF2C promoter interactions with multiple regions in theMEF2C TAD (triangle means viewpoint location). These interactions are notably absent from the 4C interaction profile in HEK293 cells (green). 4C peaks called by the peak C algorithm are indicated below the profiles (dark blue/green is based on two biological replicates; light blue/green, based on one of two biological replicates). Shown below are publicly available ChIP-seq data for histone marks H3K27Ac and H3K4me1 in SH-SY5Y (tag count, normalized to 107 reads) (31), publicly available DNaseI-seq data for SK-N-SH (parental cell line of SH-SY5Y, read-depth normalized signal) (30) and ATAC-seq data for SH-SY5Y (RPKM normalized signal). Putative enhancer loci selected for further analyses (e1–e16) are highlighted in green.(C) MEF2C interaction network. All called 4C interactions (in SH-SY5Y) for theMEF2C promoter and all reciprocal viewpoints are plotted as transparent blue arches. Three heatmaps reflect the distance between every region in the interaction network and the nearest DNaseI, H3K27Ac and H3K4me1 mark found in multiple human neuronal cell types and brain tissues as determined through zipper plot analysis (32).
Figure 2
Figure 2
MEF2C enhancers display distinct activity patterns.(A)In vitro enhancer activity of candidate elements. Log2 luciferase activity relative to a negative control (NC) vector, in HEK293 (left) and SH-SY5Y (right), for 16 putative enhancer elements (linear mixed effects model, log2 enhancer effect fold change (FC) ± standard error). Green means significant positive effect (P < 0.01); blue, significant negative effect (P < 0.01); grey, no significant (NS) effect.(B) Enhancer activity in HEK 293 versus SH-SY5Y cells. Log2 of the relative luciferase activity in HEK293 versus SH-SY5Y cells.(C) Tissue-specific enhancers in zebrafish embryos at 24 and 48 hpf. Eight enhancers induce neuro-specific GFP expression: e1 and e2 in the forebrain and specific peripheral neurons; e3 in the middle of the notochord at 24 hpf; e4 in the forebrain, specific neurons above the eye, somitic muscles and heart; e7 in the forebrain and notochord at 24 hpf; e9 in neurons with vertical projections in the midbrain/hindbrain and spinal cord at 24 hpf e12 drove general GFP expression in the central nerve system, including the head, tail and trunk at 24 hpf; and e15 in the forebrain and notochord at 48 hpf. The color code reflects the observed activity of the 16 tested candidate enhancer elements: green means active in neuronal tissues; blue, active in other than neuronal tissues; white, not active.
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