Epigenetic dysregulation in meningiomas.

Background: Meningiomas are the most common primary brain tumor. Though typically benign with a low mutational burden, tumors with benign histology may behave aggressively and there are no proven chemotherapies. Although DNA methylation patterns distinguish subgroups of meningiomas and have higher predictive value for tumor behavior than histologic classification, little is known about differences in DNA methylation between meningiomas and surrounding normal dura tissue. Methods: Whole-exome sequencing and methylation array profiling were performed on 12 dura/meningioma pairs (11 WHO grade I and 1 WHO grade II). Single-nucleotide polymorphism (SNP) genotyping and methylation array profiling were performed on an additional 19 meningiomas (9 WHO grade I, 5 WHO grade II, 4 WHO grade III). Results: Using multimodal studies of meningioma/dura pairs, we identified 4 distinct DNA methylation patterns. Diffuse DNA hypomethylation of malignant meningiomas readily facilitated their identification from lower-grade tumors by unsupervised clustering. All clusters and 12/12 meningioma-dura pairs exhibited hypomethylation of the gene promoters of a module associated with the craniofacial patterning transcription factor FOXC1 and its upstream lncRNA FOXCUT. Furthermore, we identified an epigenetic continuum of increasing hypermethylation of polycomb repressive complex target promoters with increasing histopathologic grade. Conclusion: These findings support future investigations of the role of epigenetic dysregulation of FOXC1 and cranial patterning genes in meningioma formation as well as studies of the utility of polycomb inhibitors for the treatment of malignant meningiomas.

Identification of spatial and temporal cues that regulate postembryonic expression of axon maintenance factors in the C. elegans ventral nerve cord.

Patterns of gene expression are under precise spatial and temporal control. A particularly striking example is represented by several members of the zig gene family, which code for secreted immunoglobulin domain proteins required for maintaining ventral nerve cord organization in Caenorhabditis elegans. These genes are coordinately expressed in a single interneuron in the ventral nerve cord, known as PVT. Their expression is initiated at a precise postembryonic stage, long after PVT has been generated in mid-embryogenesis. We define spatial and temporal cues that are required for the precise regulation of zig gene expression. We find that two LIM homeobox genes, the Lhx3-class gene ceh-14 and the Lmx-class gene lim-6 are coordinately required for zig gene expression in PVT. Temporal control of zig gene expression is conferred by the heterochronic gene lin-14, a nuclear factor previously implicated in developmental timing in various contexts. Loss of the lim-6 and ceh-14 transcription factors and the developmental timer lin-14 cause not only a loss of zig gene expression but also lead to defects in the maintenance of ventral nerve cord architecture. Overriding the normal spatiotemporal control of zig gene expression through expression of one of the zig genes under control of heterologous promoters also causes axon patterning defects in the ventral nerve cord. Our findings illustrate the importance of spatial and temporal control of gene expression in the nervous system and, furthermore, implicate heterochronic genes in postmitotic neural patterning events.

Immunoglobulin-domain proteins required for maintenance of ventral nerve cord organization.

During development, neurons extend axons along defined routes to specific target cells. We show that additional mechanisms ensure that axons maintain their correct positioning in defined axonal tracts. After termination of axonal outgrowth and target recognition, axons in the ventral nerve cord (VNC) of Caenorhabditis elegans require the presence of a specific VNC neuron, PVT, to maintain their correct positioning in the left and right fascicles of the VNC. PVT may exert its stabilizing function by the temporally tightly controlled secretion of 2-immunoglobulin (Ig)-domain proteins encoded by the zig genes. Dedicated axon maintenance mechanisms may be widely used to ensure the preservation of functional neuronal circuitries.