Judith Schmitz

Epigenetic regulation of lateralized fetal spinal gene expression underlies hemispheric asymmetries

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. DOI: http://dx.doi.org/10.7554/eLife.22784.001

The Functional Genetics of Handedness and Language Lateralization: Insights from Gene Ontology, Pathway and Disease Association Analyses

Handedness and language lateralization are partially determined by genetic influences. It has been estimated that at least 40 (and potentially more) possibly interacting genes may influence the ontogenesis of hemispheric asymmetries. Recently, it has been suggested that analyzing the genetics of hemispheric asymmetries on the level of gene ontology sets, rather than at the level of individual genes, might be more informative for understanding the underlying functional cascades. Here, we performed gene ontology, pathway and disease association analyses on genes that have previously been associated with handedness and language lateralization. Significant gene ontology sets for handedness were anatomical structure development, pattern specification (especially asymmetry formation) and biological regulation. Pathway analysis highlighted the importance of the TGF-beta signaling pathway for handedness ontogenesis. Significant gene ontology sets for language lateralization were responses to different stimuli, nervous system development, transport, signaling, and biological regulation. Despite the fact that some authors assume that handedness and language lateralization share a common ontogenetic basis, gene ontology sets barely overlap between phenotypes. Compared to genes involved in handedness, which mostly contribute to structural development, genes involved in language lateralization rather contribute to activity-dependent cognitive processes. Disease association analysis revealed associations of genes involved in handedness with diseases affecting the whole body, while genes involved in language lateralization were specifically engaged in mental and neurological diseases. These findings further support the idea that handedness and language lateralization are ontogenetically independent, complex phenotypes.

Beyond the genome—Towards an epigenetic understanding of handedness ontogenesis

Hemispheric asymmetries represent one of the major organizational principles in vertebrate neurobiology, but their molecular determinants are not well understood. For handedness, the most widely investigated form of hemispheric asymmetries in humans, single gene explanations have been the most popular ontogenetic model in the past. However, molecular genetic studies revealed only few specific genes that explain a small fraction of the phenotypic variance. In contrast, family studies indicated heritability of up to 0.66. It has been suggested that the lack of recognizable genetic heritability is partly accounted for by heritable epigenetic mechanisms. Based on recent neuroscientific findings highlighting the importance of epigenetic mechanisms for brain function and disease, we review recent findings describing non-genetic influences on handedness from conception to childhood. We aim to advance the idea that epigenetic regulation might be the mediating mechanism between environment and phenotype. Recent findings on molecular epigenetic mechanisms indicate that particular asymmetries in DNA methylation might affect asymmetric gene expression in the central nervous system that in turn mediates handedness. We propose that an integration of genes and environment is essential to fully comprehend the ontogenesis of handedness and other hemispheric asymmetries.

DNA methylation in candidate genes for handedness predicts handedness direction

ABSTRACT Handedness is a complex trait influenced by both genetic and non-genetic factors. Asymmetries of DNA methylation and gene expression in the developing foetus are thought to underlie its development. However, its molecular epigenetics are not well understood. We collected buccal cells from adult left- and right-handers (n = 60) to investigate whether epigenetic biomarkers of handedness can be identified in non-neuronal tissue. We associated DNA methylation in promoter regions of candidate genes with handedness direction. Results indicate that DNA methylation of genes asymmetrically expressed in the foetal brain or spinal cord might play a role within such a multifactorial model. Moreover, we provide tentative evidence that birth stress might be a factor that affects DNA methylation in NEUROD6, a gene that is asymmetrically expressed in foetal brains.

Methylation of MORC1: A possible biomarker for depression?

New findings identified the MORC1 gene as a link between early life stress and major depression. In this study, MORC1 methylation was investigated in 60 healthy human adults (30 women, 30 men) between 19 and 33 years of age. For analysis, DNA was isolated from buccal cells. The results show that DNA methylation in the MORC1 promoter region significantly correlates with the Beck Depression Inventory score in the examined non-clinical population. Sum score of birth complications, however, seems to correlate negatively with methylation. These findings further confirm that MORC1 is a stress sensitive gene and a possible biomarker for depression.

KIAA0319 promoter DNA methylation predicts dichotic listening performance in forced-attention conditions

HighlightsKIAA0319 is a gene involved in dyslexia, ciliogenesis, and language lateralization.KIAA0319 DNA methylation is an epigenetic marker for language lateralization.We propose an effect of multiple (epi)genetic factors on language lateralization. Abstract Language lateralization is one of the most prominent examples of functional hemispheric asymmetries. Previous studies indicate a significant contribution of factors not related to DNA sequence variation on the development of language lateralization, but the molecular processes underlying this relation are unclear. The Brandler‐Paracchini model of hemispheric asymmetries assumes that genes involved in the establishment of ciliogenesis and bodily asymmetries also affect functional hemispheric asymmetries. Thus, genes implicated in this model represent a key target for epigenetic modulation of language lateralization. Here, we analyzed DNA methylation in the KIAA0319 (a gene involved in dyslexia and ciliogenesis) promoter region to investigate whether epigenetic markers of language lateralization can be identified in non‐neuronal tissue. We found sex‐specific effects of DNA methylation in single CpG sites on language lateralization in the forced‐left (FL) and the forced‐right (FR), but not on language lateralization in the non‐forced (NF) condition of the dichotic listening task. These findings suggest that DNA methylation patterns in the KIAA0319 promoter region might be associated with cognitive control processes that are necessary to perform well in the forced‐attention conditions. Furthermore, the assumption of an association between genes involved in ciliogenesis and the ontogenesis of functional hemispheric asymmetries is supported.

Hugs and kisses – The role of motor preferences and emotional lateralization for hemispheric asymmetries in human social touch

&NA; Social touch is an important aspect of human social interaction ‐ across all cultures, humans engage in kissing, cradling and embracing. These behaviors are necessarily asymmetric, but the factors that determine their lateralization are not well‐understood. Because the hands are often involved in social touch, motor preferences may give rise to asymmetric behavior. However, social touch often occurs in emotional contexts, suggesting that biases might be modulated by asymmetries in emotional processing. Social touch may therefore provide unique insights into lateralized brain networks that link emotion and action. Here, we review the literature on lateralization of cradling, kissing and embracing with respect to motor and emotive bias theories. Lateral biases in all three forms of social touch are influenced, but not fully determined by handedness. Thus, motor bias theory partly explains side biases in social touch. However, emotional context also affects side biases, most strongly for embracing. Taken together, literature analysis reveals that side biases in social touch are most likely determined by a combination of motor and emotive biases.

Links- oder Rechtshänder? – Die molekularen Grundlagen der Händigkeit

AbstractHandedness is one of the most prominent functional hemispheric asymmetries. Initially thought to be determined by a single gene, molecular genetic studies have shown that it is influenced by multiple genes. Recent research indicates that epigenetic regulation induces asymmetrical gene expression in the embryonic spinal cord, potentially leading to motor asymmetries. An integration of multiple genetic, epigenetic, and environmental factors is essential to fully comprehend handedness ontogenesis.

A commentary on Karlebach and Francks, (2015).

Since the beginning of the 20th century, the observation that handedness runs in families led to the development of genetic theories about lateralization (Ramaley, 1912). While some of these theories had immense influence on howwe understand the development of handedness and other forms of functional lateralization (e.g., McManus, 2002), one big problem with all of them is the fact that they are based on the distribution of the phenotype rather than actual molecular genetic data. This phenotype-driven approach is particularly problematic for single-gene theories, since no genetic study has ever successfully identified a gene explaining a sufficient amount of phenotypic variance to qualify as the single determinant of any form of lateralization (Ocklenburg, Beste, Arning, Peterburs, & Güntürkün, 2014). For example, Armour, Davison, and McManus (2014) conducted a genome-wide association study (GWAS) with 3940 twins. Not able to detect an SNP reaching genome-wide significance, they reasoned that these results disprove single-gene theories, and that handedness must be determined by a multifactorial model which includes at least 40 genes. However, it is doubtful that a GWAS represents the best way to investigate genetic determination of lateralization, at least with a sample size in the lower thousands.With samples including less than a 6-digit number of participants this method might not provide enough power to detect small effects of multiple interacting genotypes (Eriksson et al., 2010). Moreover, results might be imprecise due to inflated type two error rates after correction for multiple comparisons (Williams & Haines, 2011). Furthermore, it has to be taken into account that complex phenotypes like handedness or language lateralization are not only influenced