Mutations in more than 450 different genes have been associated with intellectual disability (ID) and related cognitive disorders (CDs), such as autism. It is to be expected that this number will ...increase three to fourfold in the next years due to the rapid implementation of innovative high-throughput sequencing technology in genetics labs. Numerous functional relationships have been identified between the products of individual ID genes, and common molecular and cellular pathways onto which these networks converge are beginning to emerge. Prominent examples are genes involved in synaptic plasticity, Ras and Rho GTPase signaling, and epigenetic genes that encode modifiers of the chromatin structure. It thus seems that there might be common pathological patterns in ID, despite its bewildering genetic heterogeneity. These common pathways provide attractive opportunities for knowledge-based therapeutic interventions.
Abstract
Disruption of chromatin structure due to epimutations is a leading genetic etiology of neurodevelopmental disorders, collectively known as chromatinopathies. We show that there is an ...increasing level of convergence from the high diversity of genes that are affected by mutations to the molecular networks and pathways involving the respective proteins, the disrupted cellular and subcellular processes, and their consequence for higher order cellular network function. This convergence is ultimately reflected by specific phenotypic features shared across the various chromatinopathies. Based on these observations, we propose that the commonly disrupted molecular and cellular anomalies might provide a rational target for the development of symptomatic interventions for defined groups of genetically distinct neurodevelopmental disorders.
The transcription factor p63 plays a pivotal role in keratinocyte proliferation and differentiation in the epidermis. However, how p63 regulates epidermal genes during differentiation is not yet ...clear. Using epigenome profiling of differentiating human primary epidermal keratinocytes, we characterized a catalog of dynamically regulated genes and p63‐bound regulatory elements that are relevant for epithelial development and related diseases. p63‐bound regulatory elements occur as single or clustered enhancers, and remarkably, only a subset is active as defined by the co‐presence of the active enhancer mark histone modification H3K27ac in epidermal keratinocytes. We show that the dynamics of gene expression correlates with the activity of p63‐bound enhancers rather than with p63 binding itself. The activity of p63‐bound enhancers is likely determined by other transcription factors that cooperate with p63. Our data show that inactive p63‐bound enhancers in epidermal keratinocytes may be active during the development of other epithelial‐related structures such as limbs and suggest that p63 bookmarks genomic loci during the commitment of the epithelial lineage and regulates genes through temporal‐ and spatial‐specific active enhancers.
Synopsis
The key epithelial transcription factor p63 functions as a placeholder to bookmark genomic loci for gene regulation in epithelial development. The data suggest that different sets of co‐regulators are required to activate proliferation and differentiation genes during epidermal differentiation and developmental genes in other epithelial tissues.
We report p63‐regulated gene expression dynamics during epidermal differentiation.
Gene expression correlates with the activity of p63‐dependent enhancers rather than p63 binding itself.
Co‐regulators of p63 are required during epidermal differentiation and the development of other epithelial tissues.
The key epithelial transcription factor p63 functions as a placeholder to bookmark genomic loci for gene regulation in epithelial development. The data suggest that different sets of co‐regulators are required to activate proliferation and differentiation genes during epidermal differentiation and developmental genes in other epithelial tissues.
The epigenetic modification of chromatin structure and its effect on complex neuronal processes like learning and memory is an emerging field in neuroscience. However, little is known about the ..."writers" of the neuronal epigenome and how they lay down the basis for proper cognition. Here, we have dissected the neuronal function of the Drosophila euchromatin histone methyltransferase (EHMT), a member of a conserved protein family that methylates histone 3 at lysine 9 (H3K9). EHMT is widely expressed in the nervous system and other tissues, yet EHMT mutant flies are viable. Neurodevelopmental and behavioral analyses identified EHMT as a regulator of peripheral dendrite development, larval locomotor behavior, non-associative learning, and courtship memory. The requirement for EHMT in memory was mapped to 7B-Gal4 positive cells, which are, in adult brains, predominantly mushroom body neurons. Moreover, memory was restored by EHMT re-expression during adulthood, indicating that cognitive defects are reversible in EHMT mutants. To uncover the underlying molecular mechanisms, we generated genome-wide H3K9 dimethylation profiles by ChIP-seq. Loss of H3K9 dimethylation in EHMT mutants occurs at 5% of the euchromatic genome and is enriched at the 5' and 3' ends of distinct classes of genes that control neuronal and behavioral processes that are corrupted in EHMT mutants. Our study identifies Drosophila EHMT as a key regulator of cognition that orchestrates an epigenetic program featuring classic learning and memory genes. Our findings are relevant to the pathophysiological mechanisms underlying Kleefstra Syndrome, a severe form of intellectual disability caused by mutations in human EHMT1, and have potential therapeutic implications. Our work thus provides novel insights into the epigenetic control of cognition in health and disease.
The genetics of cognitive epigenetics Kleefstra, Tjitske; Schenck, Annette; Kramer, Jamie M. ...
Neuropharmacology,
05/2014, Letnik:
80
Journal Article
Recenzirano
Cognitive disorders (CDs) are a heterogeneous group of disorders for which the genetic foundations are rapidly being uncovered. The large number of CD-associated gene mutations presents an ...opportunity to identify common mechanisms of disease as well as molecular processes that are of key importance to human cognition. Given the disproportionately high number of epigenetic genes associated with CD, epigenetic regulation of gene transcription is emerging as a process of major importance in cognition. The cognate protein products of these genes often co-operate in shared protein complexes or pathways, which is reflected in similarities between the neurodevelopmental phenotypes corresponding to these mutant genes. Here we provide an overview of the genes associated with CDs, and highlight some of the epigenetic regulatory complexes involving multiple CD genes. Such common gene networks may provide a handle for designing therapeutic interventions applicable to a number of cognitive disorders with variable genetic etiology.
This article is part of the Special Issue entitled ‘Neuroepigenetic Disorders’.
•Mutations in genes encoding modulators of chromatin structure are frequent causes of cognitive disorders.•Proteins encoded these epigenetic genes cluster in functional networks.•Disruption of nodes of these epigenetic gene networks often result is similar phenotypes.
Joubert syndrome and related disorders (JSRDs) are genetically heterogeneous and characterized by a distinctive mid-hindbrain malformation. Causative mutations lead to primary cilia dysfunction, ...which often results in variable involvement of other organs such as the liver, retina, and kidney. We identified predicted null mutations in CSPP1 in six individuals affected by classical JSRDs. CSPP1 encodes a protein localized to centrosomes and spindle poles, as well as to the primary cilium. Despite the known interaction between CSPP1 and nephronophthisis-associated proteins, none of the affected individuals in our cohort presented with kidney disease, and further, screening of a large cohort of individuals with nephronophthisis demonstrated no mutations. CSPP1 is broadly expressed in neural tissue, and its encoded protein localizes to the primary cilium in an in vitro model of human neurogenesis. Here, we show abrogated protein levels and ciliogenesis in affected fibroblasts. Our data thus suggest that CSPP1 is involved in neural-specific functions of primary cilia.
Mutations affecting the levels of microRNA miR-137 are associated with intellectual disability and schizophrenia. However, the pathophysiological role of miR-137 remains poorly understood. Here, we ...describe a highly conserved miR-137-binding site within the mRNA encoding the GluA1 subunit of AMPA-type glutamate receptors (AMPARs) and confirm that GluA1 is a direct target of miR-137. Postsynaptic downregulation of miR-137 at the CA3-CA1 hippocampal synapse selectively enhances AMPAR-mediated synaptic transmission and converts silent synapses to active synapses. Conversely, miR-137 overexpression selectively reduces AMPAR-mediated synaptic transmission and silences active synapses. In addition, we find that miR-137 is transiently upregulated in response to metabotropic glutamate receptor 5 (mGluR5), but not mGluR1 activation. Consequently, acute interference with miR-137 function impedes mGluR-LTD expression. Our findings suggest that miR-137 is a key factor in the control of synaptic efficacy and mGluR-dependent synaptic plasticity, supporting the notion that glutamatergic dysfunction contributes to the pathogenesis of miR-137-linked cognitive impairments.
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•AMPA receptor subunit GluA1 is a direct target of miR-137•miR-137 represses AMPA-receptor-mediated synaptic transmission•miR-137 is required for mGluR5-mediated long-term depression
Olde Loohuis et al. reveal that microRNA miR-137, which is associated with intellectual disability and schizophrenia, controls AMPA-receptor-mediated transmission by targeting AMPA receptor subunit GluA1. miR-137 levels are regulated by mGluR5 activation, and, consequently, acute interference with miR-137 function impedes mGluR5-dependent synaptic plasticity.
A clinically recognizable 9q subtelomeric deletion syndrome has recently been established. Common features seen in these patients are severe mental retardation, hypotonia, brachycephaly, flat face ...with hypertelorism, synophrys, anteverted nares, cupid bow or tented upper lip, everted lower lip, prognathism, macroglossia, conotruncal heart defects, and behavioral problems. The minimal critical region responsible for this 9q subtelomeric deletion (9q
−) syndrome has been estimated to be <1 Mb and comprises the
euchromatin histone methyl transferase 1 gene (
EHMT1). Previous studies suggested that haploinsufficiency for
EHMT1 is causative for 9q subtelomeric deletion syndrome. We have performed a comprehensive mutation analysis of the
EHMT1 gene in 23 patients with clinical presentations reminiscent of 9q subtelomeric deletion syndrome. This analysis revealed three additional microdeletions that comprise the
EHMT1 gene, including one interstitial deletion that reduces the critical region for this syndrome. Most importantly, we identified two de novo mutations—a nonsense mutation and a frameshift mutation—in the
EHMT1 gene in patients with a typical 9q
− phenotype. These results establish that haploinsufficiency of
EHMT1 is causative for 9q subtelomeric deletion syndrome.
Abstract
Kleefstra syndrome, a disease with intellectual disability, autism spectrum disorders and other developmental defects is caused in humans by haploinsufficiency of EHMT1. Although EHMT1 and ...its paralog EHMT2 were shown to be histone methyltransferases responsible for deposition of the di-methylated H3K9 (H3K9me2), the exact nature of epigenetic dysfunctions in Kleefstra syndrome remains unknown. Here, we found that the epigenome of Ehmt1+/− adult mouse brain displays a marked increase of H3K9me2/3 which correlates with impaired expression of protocadherins, master regulators of neuronal diversity. Increased H3K9me3 was present already at birth, indicating that aberrant methylation patterns are established during embryogenesis. Interestingly, we found that Ehmt2+/− mice do not present neither the marked increase of H3K9me2/3 nor the cognitive deficits found in Ehmt1+/− mice, indicating an evolutionary diversification of functions. Our finding of increased H3K9me3 in Ehmt1+/− mice is the first one supporting the notion that EHMT1 can quench the deposition of tri-methylation by other Histone methyltransferases, ultimately leading to impaired neurocognitive functioning. Our insights into the epigenetic pathophysiology of Kleefstra syndrome may offer guidance for future developments of therapeutic strategies for this disease.
Cleft lip with or without cleft palate (CL/P) is generally viewed as a complex trait with multiple genetic and environmental contributions. In 70% of cases, CL/P presents as an isolated feature ...and/or deemed nonsyndromic. In the remaining 30%, CL/P is associated with multisystem phenotypes or clinically recognizable syndromes, many with a monogenic basis. Here we report the identification, via exome sequencing, of likely pathogenic variants in two genes that encode interacting proteins previously only linked to orofacial clefting in mouse models. A variant in GDF11 (encoding growth differentiation factor 11), predicting a p.(Arg298Gln) substitution at the Furin protease cleavage site, was identified in one family that segregated with CL/P and both rib and vertebral hypersegmentation, mirroring that seen in Gdf11 knockout mice. In the second family in which CL/P was the only phenotype, a mutation in FST (encoding the GDF11 antagonist, Follistatin) was identified that is predicted to result in a p.(Cys56Tyr) substitution in the region that binds GDF11. Functional assays demonstrated a significant impact of the specific mutated amino acids on FST and GDF11 function and, together with embryonic expression data, provide strong evidence for the importance of GDF11 and Follistatin in the regulation of human orofacial development.
The authors report the identification, via exome sequencing, of segregating variants in two genes, GDF11 and FST (encoding the GDF11 antagonist, Follistatin), in families with cleft lip/palate. The GDF11 variant segregated with both cleft lip/palate, as well as rib and vertebral hypersegmentation, mirroring the Gdf11 knockout mouse, and suggesting a new clefting syndrome, whereas the family harboring the segregating FST variant exhibited isolated cleft lip/palate. Functional assays, together with biochemical, genetic, and expression data support the pathogenicity of the variants and highlight a previously unappreciated role for this pathway in human orofacial development.
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