Editorial: Protein post-translational modifications in the nervous system: from development to disease and ageing.

PTMs are crucial for biological processes contributing to healthy organ function. Protein post-translational modifications (PTMs), such as phosphorylation (P), acetylation (Ac), SUMOylation (SUMO), S-nitrosylation (Nitro), ubiquitination (Ub) and glycosylation (Glyco), affect a wide range of cellular and biological functions as depicted in this cartoon. Perturbations lead to severe consequences for the normal function of the brain and other organs, such as muscle.

Differential methylation of OPRK1 in borderline personality disorder is associated with childhood trauma.

According to a growing body of neurobiological evidence, the core symptoms of borderline personality disorder (BPD) may be linked to an opioidergic imbalance between the hedonic and stimulatory activity of mu opioid receptors (MOR) and the reward system inhibiting effects of kappa opioid receptors (KOR). Childhood trauma (CT), which is etiologically relevant to BPD, is also likely to lead to epigenetic and neurobiological adaptations by extensive activation of the stress and endogenous opioid systems. In this study, we investigated the methylation differences in the promoter of the KOR gene (OPRK1) in subjects with BPD (N = 47) and healthy controls (N = 48).

A revised conceptual framework for mouse vomeronasal pumping and stimulus sampling.

The physiological performance of any sensory organ is determined by its anatomy and physical properties. Consequently, complex sensory structures with elaborate features have evolved to optimize stimulus detection. Understanding these structures and their physical nature forms the basis for mechanistic insights into sensory function.

EphrinA5 regulates cell motility by modulating Snhg15/DNA triplex-dependent targeting of DNMT1 to the Ncam1 promoter.

Cell-cell communication is mediated by membrane receptors and their ligands, such as the Eph/ephrin system, orchestrating cell migration during development and in diverse cancer types. Epigenetic mechanisms are key for integrating external "signals", e.g.

Role of DNMTs in the Brain.

DNA methyltransferases (DNMTs) are widely expressed in the brain, dictating the transcriptional activity of genes through various epigenetic mechanisms. Functional irregularities, alterations in the activity, and aberrant expression levels of DNMTs have been linked to various neurodevelopmental abnormalities, neuropsychiatric disorders, neurodegenerative diseases, and brain cancer. A continuously increasing number of studies address the roles DNMTs have in the brain, to reach a better understanding of their involvement in disease-related pathophysiologies, which in turn is required to dissect their applicability as potential therapeutic targets.

lncRNA-mediated synovitis in rheumatoid arthritis: A perspective for biomarker development.

Long noncoding RNAs (lncRNAs) are a regulatory class of noncoding RNAs with a wide range of activities such as transcriptional and post-transcriptional regulations. Emerging evidence has demonstrated that various lncRNAs contribute to the initiation and progression of Rheumatoid Arthritis (RA) through distinctive mechanisms. The present study reviews the recent findings on lncRNA role in RA development.

DNA Methylation in Genetic and Sporadic Forms of Neurodegeneration: Lessons from Alzheimer's, Related Tauopathies and Genetic Tauopathies.

Genetic and sporadic forms of tauopathies, the most prevalent of which is Alzheimer's Disease, are a scourge of the aging society, and in the case of genetic forms, can also affect children and young adults. All tauopathies share ectopic expression, mislocalization, or aggregation of the microtubule associated protein TAU, encoded by the gene. As TAU is a neuronal protein widely expressed in the CNS, the overwhelming majority of tauopathies are neurological disorders.

The Epigenome in Neurodevelopmental Disorders.

Neurodevelopmental diseases (NDDs), such as autism spectrum disorders, epilepsy, and schizophrenia, are characterized by diverse facets of neurological and psychiatric symptoms, differing in etiology, onset and severity. Such symptoms include mental delay, cognitive and language impairments, or restrictions to adaptive and social behavior. Nevertheless, all have in common that critical milestones of brain development are disrupted, leading to functional deficits of the central nervous system and clinical manifestation in child- or adulthood.

The difficulty to model Huntington's disease in vitro using striatal medium spiny neurons differentiated from human induced pluripotent stem cells.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by an expanded polyglutamine repeat in the huntingtin gene. The neuropathology of HD is characterized by the decline of a specific neuronal population within the brain, the striatal medium spiny neurons (MSNs). The origins of this extreme vulnerability remain unknown.

DNA Methyltransferase 1 (DNMT1) Shapes Neuronal Activity of Human iPSC-Derived Glutamatergic Cortical Neurons.

Epigenetic mechanisms are emerging key players for the regulation of brain function, synaptic activity, and the formation of neuronal engrams in health and disease. As one important epigenetic mechanism of transcriptional control, DNA methylation was reported to distinctively modulate synaptic activity in excitatory and inhibitory cortical neurons in mice. Since DNA methylation signatures are responsive to neuronal activity, DNA methylation seems to contribute to the neuron's capacity to adapt to and integrate changing activity patterns, being crucial for the plasticity and functionality of neuronal circuits.

The Expression of the Cancer-Associated lncRNA Is Modulated by EphrinA5-Induced Signaling.

The Eph receptor tyrosine kinases and their respective ephrin-ligands are an important family of membrane receptors, being involved in developmental processes such as proliferation, migration, and in the formation of brain cancer such as glioma. Intracellular signaling pathways, which are activated by Eph receptor signaling, are well characterized. In contrast, it is unknown so far whether ephrins modulate the expression of lncRNAs, which would enable the transduction of environmental stimuli into our genome through a great gene regulatory spectrum.

Mechanical Forces Orchestrate Brain Development.

During brain development, progenitors generate successive waves of neurons that populate distinct cerebral regions, where they settle and differentiate within layers or nuclei. While migrating and differentiating, neurons are subjected to mechanical forces arising from the extracellular matrix, and their interaction with neighboring cells. Changes in brain biomechanical properties, during its formation or aging, are converted in neural cells by mechanotransduction into intracellular signals that control key neurobiological processes.

DNA Methylation-Dependent Dysregulation of GABAergic Interneuron Functionality in Neuropsychiatric Diseases.

Neuropsychiatric diseases, such as mood disorders, schizophrenia, and autism, represent multifactorial disorders, differing in causes, disease onset, severity, and symptoms. A common feature of numerous neuropsychiatric conditions are defects in the cortical inhibitory GABAergic system. The balance of excitation and inhibition is fundamental for proper and efficient information processing in the cerebral cortex.

Methods for Single-Cell Isolation and Preparation.

Within the last decade, single-cell analysis has revolutionized our understanding of cellular processes and heterogeneity across all disciplines of life science. As the transcriptome, genome, or epigenome of individual cells can nowadays be analyzed at low cost and in high-throughput within a few days by modern techniques, tremendous improvements in disease diagnosis on the one hand and the investigation of disease-relevant mechanisms on the other were achieved so far. This relies on the parallel development of reliable cell capturing and single-cell sequencing approaches that have paved the way for comprehensive single-cell studies.

DNA Methyltransferase 1 (DNMT1) Function Is Implicated in the Age-Related Loss of Cortical Interneurons.

Increased life expectancy in modern society comes at the cost of age-associated disabilities and diseases. Aged brains not only show reduced excitability and plasticity, but also a decline in inhibition. Age-associated defects in inhibitory circuits likely contribute to cognitive decline and age-related disorders.

DNA Methyltransferase 1 (DNMT1) Acts on Neurodegeneration by Modulating Proteostasis-Relevant Intracellular Processes.

The limited regenerative capacity of neurons requires a tightly orchestrated cell death and survival regulation in the context of longevity, as well as age-associated and neurodegenerative diseases. Subordinate to genetic networks, epigenetic mechanisms, such as DNA methylation and histone modifications, are involved in the regulation of neuronal functionality and emerge as key contributors to the pathophysiology of neurodegenerative diseases. DNA methylation, a dynamic and reversible process, is executed by DNA methyltransferases (DNMTs).

Epigenomic Remodeling in Huntington's Disease-Master or Servant?

In light of our aging population, neurodegenerative disorders are becoming a tremendous challenge, that modern societies have to face. They represent incurable, progressive conditions with diverse and complex pathological features, followed by catastrophic occurrences of massive neuronal loss at the later stages of the diseases. Some of these disorders, like Huntington's disease (HD), rely on defined genetic factors.

Neuronal expression is regulated by DNMT1-dependent modulation of histone marks.

Apart from the conventional view of repressive promoter methylation, the DNA methyltransferase 1 (DNMT1) was recently described to modulate gene expression through a variety of interactions with diverse epigenetic key players. We here investigated the DNMT1-dependent transcriptional control of the homeobox transcription factor LHX1, which we previously identified as an important regulator in cortical interneuron development. We found that LHX1 expression in embryonic interneurons originating in the embryonic pre-optic area (POA) is regulated by non-canonic DNMT1 function.

DNA Methylation-Mediated Modulation of Endocytosis as Potential Mechanism for Synaptic Function Regulation in Murine Inhibitory Cortical Interneurons.

The balance of excitation and inhibition is essential for cortical information processing, relying on the tight orchestration of the underlying subcellular processes. Dynamic transcriptional control by DNA methylation, catalyzed by DNA methyltransferases (DNMTs), and DNA demethylation, achieved by ten-eleven translocation (TET)-dependent mechanisms, is proposed to regulate synaptic function in the adult brain with implications for learning and memory. However, focus so far is laid on excitatory neurons.

Emerging Roles of Long Non-Coding RNAs as Drivers of Brain Evolution.

Mammalian genomes encode tens of thousands of long-noncoding RNAs (lncRNAs), which are capable of interactions with DNA, RNA and protein molecules, thereby enabling a variety of transcriptional and post-transcriptional regulatory activities. Strikingly, about 40% of lncRNAs are expressed specifically in the brain with precisely regulated temporal and spatial expression patterns. In stark contrast to the highly conserved repertoire of protein-coding genes, thousands of lncRNAs have newly appeared during primate nervous system evolution with hundreds of human-specific lncRNAs.

Diverse facets of cortical interneuron migration regulation - Implications of neuronal activity and epigenetics.

The proper function of the cerebral cortex relies on the delicate balance of excitation and inhibition determined by the accurate number and subtype composition of the diverse group of inhibitory gamma-aminobutyric (GABA)-expressing interneurons. Developmental defects can lead to impaired cortical inhibition and seem implicated in neuropsychiatric disorders like schizophrenia. The multifaceted development of cortical interneurons, of which the long-range migration from the basal telencephalon to cortical targets represents a critical step, is orchestrated by various intrinsic and extrinsic factors.

DNMT1 modulates interneuron morphology by regulating Pak6 expression through crosstalk with histone modifications.

Epigenetic mechanisms of gene regulation, including DNA methylation and histone modifications, call increasing attention in the context of development and human health. Thereby, interactions between DNA methylating enzymes and histone modifications tremendously multiply the spectrum of potential regulatory functions. Epigenetic networks are critically involved in the establishment and functionality of neuronal circuits that are composed of gamma-aminobutyric acid (GABA)-positive inhibitory interneurons and excitatory principal neurons in the cerebral cortex.