The role of the Prader-Willi syndrome critical interval for epigenetic regulation, transcription and phenotype

Prader-Willi Syndrome (PWS) is a neurodevelopmental disorder caused by loss of expression of the paternally inherited genes on chromosome 15q11.2-q13. However, the core features of PWS have been attributed to a critical interval (PWS-cr) within the 15q11.2-q13 imprinted gene cluster, containing the small nucleolar RNA (snoRNA) SNORD116 and non-coding RNA IPW (Imprinted in Prader-Willi) exons. SNORD116 affects the transcription profile of hundreds of genes, possibly via DNA methylation or post-transcriptional modification, although the exact mechanism is not completely clear. IPW on the other hand has been shown to specifically modulate histone methylation of a separate imprinted locus, the DLK1-DIO3 cluster, which itself is associated with several neurodevelopmental disorders with similarities to PWS. Here we review what is currently known of the molecular targets of SNORD116 and IPW and begin to disentangle their roles in contributing to the Prader-Willi Syndrome phenotype

EHMT1/GLP; biochemical function and association with brain disorders

The gene EHMT1 that encodes the Euchromatic Histone Methyltransferase-1, also known as GLP (G9a-like protein), has been associated with a number of neurodevelopmental and neurodegenerative disorders. GLP is a member of the euchromatic lysine histone methyltransferase family, along with EHMT2 or G9A. As its name implies, Ehmt1/GLP is involved in the addition of methyl groups to histone H3 lysine 9, a generally repressive mark linked to classical epigenetic process such as genomic imprinting, X-inactivation, and heterochromatin formation. However, GLP also plays both a direct and indirect role in regulating DNA-methylation. Here, we discuss what is currently known about the biochemical function of Ehmt1/GLP and its association, via various genetic studies, with brain disorders

Methods of epigenome editing for probing the function of genomic imprinting

The curious patterns of imprinted gene expression draw interest from several scientific disciplines to the functional consequences of genomic imprinting. Methods of probing the function of imprinting itself have largely been indirect and correlational, relying heavily on conventional transgenics. Recently, the burgeoning field of epigenome editing has provided new tools and suggested strategies for asking causal questions with site specificity. This perspective article aims to outline how these new methods may be applied to questions of functional imprinting and, with this aim in mind, to suggest new dimensions for the expansion of these epigenome-editing tools

The contribution of imprinted genes to neurodevelopmental and neuropsychiatric disorders

Imprinted genes are a subset of mammalian genes that are subject to germline parent-specific epigenetic modifications leading monoallelic expression. Imprinted gene expression is particularly prevalent in the brain and it is unsurprising that mutations affecting their expression can lead to neurodevelopmental and/or neuropsychiatric disorders in humans. Here I review the evidence for this, detailing key neurodevelopmental disorders linked to imprinted gene clusters on human chromosomes 15q11-q13 and 14q32, highlighting genes and possible regulatory links between these different syndromes. Similarly, rare copy number variant mutations at imprinted clusters also provide strong links between abnormal imprinted gene expression and the predisposition to severe psychiatric illness. In addition to direct links between brain-expressed imprinted genes and neurodevelopmental and/or neuropsychiatric disorders, I outline how imprinted genes that are expressed in another tissue hotspot, the placenta, contribute indirectly to abnormal brain and behaviour. Specifically, altered nutrient provisioning or endocrine signalling by the placenta caused by abnormal expression of imprinted genes may lead to increased prevalence of neurodevelopmental and/or neuropsychiatric problems in both the offspring and the mother

Genomic imprinting and disorders of the social brain; shades of grey rather than black and white

Crespi & Badcock (C&B) provide a novel hypothesis outlining a role for imprinted genes in mediating brain functions underlying social behaviours. The basic premise is that maternally expressed genes are predicted to promote hypermentalistic behaviours, and paternally expressed genes hypomentalistic behaviours. The authors provide a detailed overview of data supporting their ideas, but as we discuss, caution should be applied in interpreting these data

Genomic imprinting and neurobehavioral programming by adverse early life environments: evidence from studying Cdkn1c

Imprinted genes are subject to epigenetic regulation that leads to monoallelic expression from one parental allele only. Brain expression of the imprinted gene Cdkn1c is sensitive to early life adversity, including exposure to maternal low protein diet (LPD) where increased expression of Cdkn1c is due to de-repression of the normally silent paternal allele. Maternal LPD also leads to changes in the dopamine system and reward related behaviours in offspring. We have recently demonstrated that these brain and behavioural phenotypes are recapitulated in a transgenic model in which Cdkn1c expressi alone is increased. Here we summarise these findings and suggest that the loss of imprinting of Cdkn1c in the offspring following maternal low protein diet is a key contributor to the associated changes in the dopamine system and behavior reported after early life adversity

Lifting the lid on impact and peer review.

Brain and Neuroscience Advances has grown in tandem with the British Neuroscience Association's campaign to build Credibility in Neuroscience, which encourages actions and initiatives aimed at improving reproducibility, reliability and openness. This commitment to credibility impacts not only what the Journal publishes, but also how it operates. With that in mind, the Editorial Board sought the views of the neuroscience community on the peer review process, and on how they should respond to the Journal Impact Factor that will be assigned to Brain and Neuroscience Advances. In this editorial, we present the results of a survey of neuroscience researchers conducted in the autumn of 2020 and discuss the broader implications of our findings for the Journal and the neuroscience community

Detailed analysis of paternal knockout <i>Grb10 </i>mice suggests effects on stability of social behavior, rather than social dominance

Imprinted genes are highly expressed in monoaminergic regions of the midbrain and their functions in this area are thought to have an impact on mammalian social behaviors. One such imprinted gene is Grb10, of which the paternal allele is generally recognized as mediating social dominance behavior. However, there has been no detailed study of social dominance in Grb10 +/p mice. Moreover, the original study examined tube‐test behavior in isolated mice 10 months of age. Isolation testing favors more territorial and aggressive behaviors, and does not address social dominance strategies employed in group housing contexts. Furthermore, isolation stress impacts midbrain function and dominance related behavior, often through alterations in monoaminergic signaling. Thus, we undertook a systematic study of Grb10 +/p social rank and dominance behavior within the cage group, using a number of convergent behavioral tests. We examined both male and female mice to account for sex differences and tested cohorts aged 2, 6 and 10 months to examine any developments related to age. We found group‐housed Grb10 +/p mice do not show evidence of enhanced social dominance, but cages containing Grb10 +/p and wild‐type mice lacked the normal correlation between three different measures of social rank. Moreover, a separate study indicated isolation stress induced inconsistent changes in tube test behavior. Taken together, these data suggest future research on Grb10 +/p mice should focus on the stability of social behaviors, rather than dominance per se

Regulation of glutamate transport and neuroinflammation in a term newborn rat model of hypoxic-ischaemic brain injury

In the newborn brain, moderate-severe hypoxia–ischaemia induces glutamate excitotoxicity and inflammation, possibly via dysregulation of candidate astrocytic glutamate transporter (Glt1) and pro-inflammatory cytokines (e.g. Tnfα, Il1β, Il6). Epigenetic mechanisms may mediate dysregulation. Hypotheses: (1) hypoxia–ischaemia dysregulates mRNA expression of these candidate genes; (2) expression changes in Glt1 are mediated by DNA methylation changes; and (3) methylation values in brain and blood are correlated. Seven-day-old rat pups (n = 42) were assigned to nine groups based on treatment (for each timepoint: naïve (n = 3), sham (n = 3), hypoxia–ischaemia (n = 8) and timepoint for tissue collection (6, 12 and 24 h post-hypoxia). Moderate hypoxic–ischemic brain injury was induced via ligation of the left common carotid artery followed by 100 min hypoxia (8% O2, 36°C). mRNA was quantified in cortex and hippocampus for the candidate genes, myelin (Mbp), astrocytic (Gfap) and neuronal (Map2) markers (qPCR). DNA methylation was measured for Glt1 in cortex and blood (bisulphite pyrosequencing). Hypoxia–ischaemia induced pro-inflammatory cytokine upregulation in both brain regions at 6 h. This was accompanied by gene expression changes potentially indicating onset of astrogliosis and myelin injury. There were no significant changes in expression or promoter DNA methylation of Glt1. This pilot study supports accumulating evidence that hypoxia–ischaemia causes neuroinflammation in the newborn brain and prioritises further expression and DNA methylation analyses focusing on this pathway. Epigenetic blood biomarkers may facilitate identification of high-risk newborns at birth, maximising chances of neuroprotective interventions

Impairments in sensory-motor gating and information processing in a mouse model of Ehmt1 haploinsufficiency

Regulators of chromatin dynamics and transcription are increasingly implicated in the aetiology of neurodevelopmental disorders (NDDs). Haploinsufficiency of EHMT1, encoding a histone methyl-transferase, is associated with several NDDs, including Kleefstra syndrome, developmental delay and autism spectrum disorder. Using a mouse model of Ehmt1 haploinsufficiency (Ehmt1D6Cre/+), we examined a number of brain and behavioural endophenotypes of relevance to NDDs. Specifically, we show that Ehmt1D6Cre/+ mice have deficits in information processing, evidenced by abnormal sensory-motor gating, a complete absence of object recognition memory and a reduced magnitude of auditory evoked potentials in both paired-pulse inhibition and mismatch negativity (MMN). The electrophysiological experiments show that differences in magnitude response to auditory stimulus were associated with marked reductions in total and evoked beta- and gamma-band oscillatory activity, as well as significant reductions in phase synchronisation. The pattern of electrophysiological deficits in Ehmt1D6Cre/+ matches those seen in control mice following administration of the selective NMDA-R antagonist, ketamine. This, coupled with reduction of Grin1 mRNA expression in Ehmt1D6Cre/+ hippocampus, suggests that Ehmt1 haploinsufficiency may lead to disruption in NMDA-R. Taken together, these data indicate that reduced Ehmt1 dosage during forebrain development leads to abnormal circuitry formation, which in turn results in profound information processing deficits. Such information processing deficits are likely paramount to our understanding of the cognitive and neurological dysfunctions shared across the NDDs associated with EHMT1 haploinsufficiency