Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
, 6

Epigenetic Regulation of Lateralized Fetal Spinal Gene Expression Underlies Hemispheric Asymmetries

Affiliations

Epigenetic Regulation of Lateralized Fetal Spinal Gene Expression Underlies Hemispheric Asymmetries

Sebastian Ocklenburg et al. Elife.

Abstract

Lateralization is a fundamental principle of nervous system organization but its molecular determinants are mostly unknown. In humans, asymmetric gene expression in the fetal cortex has been suggested as the molecular basis of handedness. However, human fetuses already show considerable asymmetries in arm movements before the motor cortex is functionally linked to the spinal cord, making it more likely that spinal gene expression asymmetries form the molecular basis of handedness. We analyzed genome-wide mRNA expression and DNA methylation in cervical and anterior thoracal spinal cord segments of five human fetuses and show development-dependent gene expression asymmetries. These gene expression asymmetries were epigenetically regulated by miRNA expression asymmetries in the TGF-β signaling pathway and lateralized methylation of CpG islands. Our findings suggest that molecular mechanisms for epigenetic regulation within the spinal cord constitute the starting point for handedness, implying a fundamental shift in our understanding of the ontogenesis of hemispheric asymmetries in humans.

Keywords: epigenetics; human; lateralization; neuroscience; spinal cord.

Conflict of interest statement

The authors declare that no competing interests exist.

Figures

Figure 1.
Figure 1.. Gene expression asymmetries in human fetal spinal cord at 8, 10 and 12 weeks PC.
X-axis shows the extent of asymmetry measured in log2(fold change) between right and left spinal cord samples. Blue bars show leftward asymmetrically expressed genes, red bars show rightward asymmetrically expressed genes. For 8 weeks PC, the top 25 genes with highest rightward/leftward gene expression asymmetries are depicted. For 10 and 12 weeks PC, all genes with a log2(fold change) > 1.5 are shown. The source files of asymmetrically expressed genes per developmental stage with corresponding fold change values are available in Figure 1—source data 1. DOI: http://dx.doi.org/10.7554/eLife.22784.002
Figure 2.
Figure 2.. Functional genes and gene groups.
(A) Gene expression asymmetries for previously published candidate genes for handedness and functional lateralization. Asterisks indicate biologically relevant gene expression asymmetry with a log2(fold change) > 1.5. (B) Number of significant Gene Ontology (GO) groups for the three main categories ‘biological processes’, 'molecular function' and 'cellular component' for weeks 8, 10 and 12 PC. (C) Main GO groups for 8 and 10 weeks PC with p-value and number of involved genes for the left and right spinal cord. The source files of all enriched GO groups are available in Figure 2—source data 1. DOI: http://dx.doi.org/10.7554/eLife.22784.004
Figure 3.
Figure 3.. Epigenetic regulation of gene expression asymmetries in human fetal spinal cord.
(A) Asymmetrically expressed miRNA transcripts at 8, 10 and 12 weeks PC. The extent of expression asymmetries is measured in log2(fold change). Red bars show rightward asymmetrically expressed microRNA transcripts, blue bars show leftward asymmetrically expressed miRNA transcripts. (B) Number of CpG sites showing differential DNA methylation per chromosome, compared between the left and right spinal cord for 8 and 10 weeks PC. Depicted are only CpG sites with methylation asymmetries in both samples. Red bars represent the number of CpG sites that showed significantly higher DNA methylation on the right side, blue bars show the number of CpG sites that showed significantly more DNA methylation on the left side. (C) Percentage of differential DNA methylation in leftward (blue) and rightward (red) asymmetrically methylated CpG sites as a function of p-value. (D) Percentage of gene expression asymmetries on each chromosome at 8 weeks PC that can be explained by regulation via asymmetrically expressed miRNAs or asymmetric DNA methylation of CpG sites within and 1500 nucleotides upstream of the expressed genes. The source files of asymmetrically expressed miRNAs, asymmetrically expressed targets of miRNAs, enriched KEGG pathways and differentially methylated CpG sites are available in Figure 3—source data 1, Figure 3—source data 2, Figure 3—source data 3, and Figure 3—source data 4 respectively. DOI: http://dx.doi.org/10.7554/eLife.22784.006

Similar articles

See all similar articles

Cited by 12 PubMed Central articles

See all "Cited by" articles

References

    1. Abu-Khalil A, Fu L, Grove EA, Zecevic N, Geschwind DH. Wnt genes define distinct boundaries in the developing human brain: implications for human forebrain patterning. The Journal of Comparative Neurology. 2004;474:276–288. doi: 10.1002/cne.20112. - DOI - PubMed
    1. Akalin A, Kormaksson M, Li S, Garrett-Bakelman FE, Figueroa ME, Melnick A, Mason CE. methylKit: a comprehensive R package for the analysis of genome-wide DNA methylation profiles. Genome Biology. 2012;13:R87 doi: 10.1186/gb-2012-13-10-r87. - DOI - PMC - PubMed
    1. Alqadah A, Hsieh YW, Chuang CF. microRNA function in left-right neuronal asymmetry: perspectives from C. elegans. Frontiers in Cellular Neuroscience. 2013;7:158 doi: 10.3389/fncel.2013.00158. - DOI - PMC - PubMed
    1. Annett M. Handedness and cerebral dominance: the right shift theory. The Journal of Neuropsychiatry and Clinical Neurosciences. 1998;10:459–469. doi: 10.1176/jnp.10.4.459. - DOI - PubMed
    1. Armour JA, Davison A, McManus IC. Genome-wide association study of handedness excludes simple genetic models. Heredity. 2014;112:221–225. doi: 10.1038/hdy.2013.93. - DOI - PMC - PubMed

Publication types

Grant support

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Feedback