Emerging Insights into the Distinctive Neuronal Methylome

Clemens, Adam; Gabel, Harrison W.

doi:10.1016/j.tig.2020.07.009

Cited by 26 publications

(18 citation statements)

References 104 publications

(303 reference statements)

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“…Genome-wide rearrangements of DNA methylome is crucial for the normal development of mammalian brains. The disruption of the de novo “writer” of DNA methylation DNMT3A ( 38, 39 ), or the “reader” of DNA methylation MECP2, cause molecular to behavioral alterations in animal models ( 39 ) and lead to human neuropsychiatric conditions such as the DNMT3A-associated Tatton Brown Rahman Syndrome, or the MECP2-associated Rett Syndrome ( 40, 41 ). Using single-cell multi-omic profiling, our study found the remodeling of neuronal methylome predominantly occurs during late-gestational and early-post-natal development, suggesting the human brain is particularly vulnerable to genetic and environmental perturbations that impact DNA methylation functions in these developmental stages.…”

Section: Main Textmentioning

confidence: 99%

Epigenomic and chromosomal architectural reconfiguration in developing human frontal cortex and hippocampus

Heffel

Zhou

Zhang

et al. 2022

Preprint

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The human frontal cortex and hippocampus play critical roles in learning and cognition. We investigated the epigenomic and 3D chromatin conformational reorganization during the development of the frontal cortex and hippocampus, using more than 53,000 joint single-nucleus profiles of chromatin conformation and DNA methylation (sn-m3C-seq). The remodeling of DNA methylation predominantly occurs during late-gestational to early-infant development and is temporally separated from chromatin conformation dynamics. Neurons have a unique Domain-Dominant chromatin conformation that is different from the Compartment-Dominant conformation of glial cells and non-brain tissues. We reconstructed the regulatory programs of cell-type differentiation and found putatively causal common variants for schizophrenia strongly overlap with chromatin loop-connected, cell-type-specific regulatory regions. Our data demonstrate that single-cell 3D-regulome is an effective approach for dissecting neuropsychiatric risk loci.

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Section: Main Textmentioning

confidence: 99%

Epigenomic and chromosomal architectural reconfiguration in developing human frontal cortex and hippocampus

Heffel

Zhou

Zhang

et al. 2022

Preprint

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“…Besides this consensual repressive role, some studies have suggested an activating role in the expression of certain genes 27 . Interpretations about the repressive or activating role of MeCP2 have also been challenged because of the ability of MeCP2 to recognize methylated base‐pair couples guanine–cytosine and cytosine–adenine, hydroxymethylated cytosines, and because these modifications are associated with either repression (methylated cytosine–adenine/methylated guanine–cytosine) or activation (hydroxymethylated cytosines) of transcription 28 . For years, many efforts were deployed to unambiguously determine the target sequences of MeCP2.…”

Section: Mecp2 Cellular Functions and Mouse Modelsmentioning

confidence: 99%

State‐of‐the‐art therapies for Rett syndrome

Panayotis

Ehinger

Félix

et al. 2022

Develop Med Child Neuro

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Rett syndrome (RTT, Mendelian Inheritance in Man [MIM] 312750) is a rare genetic disorder leading to severe and progressive intellectual disability, almost exclusively affecting female children with an incidence of approximately 1 in 15 000 live births. It was first characterized in 1966 by Andreas Rett, a psychiatrist from Austria who specialized in neurodevelopmental disorders. 1 However, it was not until two decades later that RTT became officially recognized after a Swedish neurologist, Bengt Hagberg, observed patients with similar symptoms and decided, with French and Portuguese colleagues, to publish an article describing the syndrome. 2 RTT alone accounts for 10% of cases of profound intellectual disability of genetic origin in females. 3 RTT is a severe developmental disorder. 4,5 Females with RTT begin life apparently 'healthy'. However, from 6 to 18 months of age they undergo regression of early milestones, with deterioration of motor skills, eye contact, speech, and motor control; they then develop a range of neurological symptoms, including anxiety, respiratory dysrhythmias, and seizures. 5 Since most cases are sporadic, identifying a causative locus has been fraught with difficulties. Initially RTT was considered a purely nervous system pathology including neurons and astrocytes but in recent years it has emerged that RTT is also a neurometabolic pathology involving cholesterol abnormalities. 6,7

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“…However, 5-hmC itself is fairly stable and is likely the main product of TET1 enzyme activity in neurons. 17 As reviewed by Clemens and Gabel, 18 DNA cytosines in brain neurons are methylated and hydroxmethylated at levels that are very different than in most tissues of the body. Neurons have about 11 million 5-mCpG sites and about 6 million 5-hmCpG sites in their DNA.…”

Section: Alteration Of Expression By 5-hydroxymethylcytosine In Neuronsmentioning

confidence: 99%

DNA Methylation and Establishing Memory

Bernstein

2022

Genet Epigenet

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A single event can cause a life-long memory. Memories physically reside in neurons, and changes in neuronal gene expression are considered to be central to memory. Early models proposed that specific DNA methylations of cytosines in neuronal DNA encode memories in a stable biochemical form. This review describes recent research that elucidates the molecular mechanisms used by the mammalian brain to form DNA methylcytosine encoded memories. For example, neuron activation initiates cytosine demethylation by stimulating DNA topoisomerase II beta (TOP2B) protein to make a temporary DNA double-strand break (repaired within about 2 hours) at a promoter of an immediate early gene, EGR1, allowing expression of this gene. The EGR1 proteins then recruit methylcytosine dioxygenase TET1 proteins to initiate demethylation at several hundred genes, facilitating expression of those genes. Initiation of demethylation of cytosine also occurs when OGG1 localizes at oxidized guanine in a methylated CpG site and recruits TET1 for initiation of demethylation at that site. DNMT3A2 is another immediate early gene upregulated by synaptic activity. DNMT3A2 protein catalyzes de novo DNA methylations. These several mechanisms convert external experiences into DNA methylations and initiated demethylations of neuronal DNA cytosines, causing changes in gene expression that are the basis of long-term memories.

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Emerging Insights into the Distinctive Neuronal Methylome

Cited by 26 publications

References 104 publications

Epigenomic and chromosomal architectural reconfiguration in developing human frontal cortex and hippocampus

Epigenomic and chromosomal architectural reconfiguration in developing human frontal cortex and hippocampus

State‐of‐the‐art therapies for Rett syndrome

DNA Methylation and Establishing Memory

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