Regulation of neural circuit formation by protocadherins

Peek, Stacey L.; Mah, Kar Men; Weiner, Joshua A.

doi:10.1007/s00018-017-2572-3

Cited by 114 publications

(103 citation statements)

References 207 publications

(350 reference statements)

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“…The remaining 43 WP-DMRs were pair-specific, of which 27 showed an abnormal methylation level in the MS-affected co-twin. These WP-DMRs have not previously been associated with MS, although two WP-DMRs were related to genes encoding protocadherins that are involved in neuronal development 42 . Hence, a contribution of these WP-DMRs to the discordant phenotype cannot be excluded, but since they are pair-specific, these results should be interpreted very cautiously.…”

Section: Discussionmentioning

confidence: 94%

DNA Methylation Signatures of a Large Cohort Monozygotic Twins Clinically Discordant for Multiple Sclerosis

Souren

Gerdes

Lutsik

et al. 2018

Preprint

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Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system with a modest concordance rate in monozygotic twins that strongly argues for involvement of epigenetic factors. We observe in 45 MS discordant monozygotic twins highly similar peripheral blood mononuclear cell-based methylomes. However, a few MS-associated differentially methylated positions (DMP) were identified and validated, including a region in the TMEM232 promoter and ZBTB16 enhancer. In CD4+ T cells we observed an MS-associated differentially methylated region in FIRRE. In addition, many regions showed large methylation differences in individual pairs, but were not clearly associated with MS. Furthermore, epigenetic biomarkers for current interferon-beta treatment were identified, and extensive validation revealed the ZBTB16 DMP as a signature of prior glucocorticoid treatment. Altogether, our study represents an important reference for epigenomic MS studies. It identifies new candidate epigenetic markers, highlights treatment effects and genetic background as major confounders, and argues against some previously reported MS-associated epigenetic candidates.

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Section: Discussionmentioning

confidence: 94%

DNA Methylation Signatures of a Large Cohort Monozygotic Twins Clinically Discordant for Multiple Sclerosis

Souren

Gerdes

Lutsik

et al. 2018

Preprint

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“…The main objective of the current study was to identify differentially and variably methyl- CDHs/PCDHs are a group of calcium dependent cell-cell adhesion molecules that are abundantly expressed in the nervous system and play a major role in multiple steps essential to neurodevelopment including dendrite arborization, axon outgrowth and targeting, synaptogenesis, and synapse elimination [60][61][62][63][64][65][66] .…”

Section: Discussionmentioning

confidence: 99%

Twin Study of Early-Onset Major Depression Finds DNA Methylation Enrichment for Neurodevelopmental Genes

Roberson‐Nay

Wolen

Lapato

et al. 2018

Preprint

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Major depression (MD) is a debilitating mental health condition with peak prevalence occurring early in life. Genome-wide examination of DNA methylation (DNAm) offers an attractive complement to studies of allelic risk given it can reflect the combined influence of genes and environment.The current study used a co-twin control design to identify differentially and variably methylated regions of the genome that distinguish monozygotic (MZ) twins with and without a lifetime history of early-onset MD. The sample included 150 Caucasian monozygotic twins (73% female;Mage=17.52 SD=1.28) assessed during a developmental stage characterized by relatively distinct neurophysiological changes. All twins were generally healthy and currently free of medications with psychotropic effects. DNAm was measured in peripheral blood cells using the Infinium Human BeadChip 450K Array. MD associations were detected at 760 differentially and variably methylated probes/regions that mapped to 428 genes. Gene enrichment analyses implicated genes related to neuron structures and neurodevelopmental processes including cell-cell adhesion genes (e.g., CDHs, PCDHAs, PCDHA1C/2C). Genes previously implicated in mood and psychiatric disorders as well as chronic stress (e.g., HDAC4, NRG1) also were identified. Results indicated an association between early-onset MD and many genes and genomic regions involved in neural circuitry formation, projection, functioning, and plasticity. DNAm regions associated with MD where found to overlap genetic loci observed in the latest Psychiatric Genomics Consortium meta-analysis of depression. Understanding the time course of epigenetic influences during emerging adulthood may clarify developmental phases where genes modulate individual differences in MD risk.

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“…We have found that the 1.2Mb superTAD, which contains >70 genes at the clustered Protocadherin (cPcdh) locus (Table 1) (106) is also found in srHC (109). The cPcdh exons are expressed combinatorially in neurons and the Protocadherin proteins that arise from this process form multimers that interact homophilically and mediate a variety of developmental processes, including neuronal survival, synaptic maintenance, axonal tiling, and dendritic selfavoidance (194). The Protocadherin superTAD is regulated by the KRAB-ZNP pathway and, notably, ablation of the SETDB1 H3K9HMTase leads to collapse of the entire superTAD (106).…”

Section: Heterochromatin-like Domains/complexes and The Phylotypic Stmentioning

confidence: 99%

On the relation of phase separation and Hi-C maps to epigenetics

Singh

Newman²

2019

Preprint

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The relationship between compartmentalisation of the genome and epigenetics is long and hoary. In 1928 Heitz defined heterochromatin as the largest differentiated chromatin compartment in eukaryotic nuclei. Müller's (1930) discovery of position-effect variegation (PEV) went on to show that heterochromatin is a cytologically-visible state of heritable (epigenetic) gene repression. Current insights into compartmentalisation have come from a high-throughput top-down approach where contact frequency (Hi-C) maps revealed the presence of compartmental domains that segregate the genome into heterochromatin and euchromatin. It has been argued that the compartmentalisation seen in Hi-C maps is due to the physiochemical process of phase separation. Oddly, the insights provided by these experimental and conceptual advances have remained largely silent on how Hi-C maps and phase separation relate to epigenetics. Addressing this issue directly in mammals we have made use of a bottom-up approach starting with the hallmarks of constitutive heterochromatin, heterochromatin protein 1 (HP1) and its binding partner the H3K9me2/3 determinant of the histone code. They are key epigenetic regulators in eukaryotes. Both hallmarks are also found outside mammalian constitutive heterochromatin as constituents of larger (0.1-5Mb) heterochromatin-like domains and smaller (less than 100Kb) complexes. The well-documented ability of HP1 proteins to function as bridges between H3K9me2/3-marked nucleosomes enables cross-linking within and between chromatin fibres that contributes to polymer-polymer phase separation (PPPS) that packages epigenetically-heritable chromatin states during interphase. Contacts mediated by HP1 "bridging" are likely to have been detected in Hi-C maps, as evidenced by the B4 heterochromatic sub-compartment that emerges from contacts between large KRAB-ZNF heterochromatin-like domains. Further, mutational analyses have revealed a finer, innate, compartmentalisation in Hi-C experiments that likely reflect contacts involving smaller domains/complexes. Proteins that bridge (modified) DNA and histones in nucleosomal fibres -where the HP1-H3K9me2/3 interaction represents the most evolutionarilyconserved paradigm -could drive and generate the fundamental compartmentalisation of the interphase nucleus.This has implications for the mechanism(s) that maintains cellular identity, be it a terminally-differentiated fibroblast or a pluripotent embryonic stem cell.

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Regulation of neural circuit formation by protocadherins

Cited by 114 publications

References 207 publications

DNA Methylation Signatures of a Large Cohort Monozygotic Twins Clinically Discordant for Multiple Sclerosis

DNA Methylation Signatures of a Large Cohort Monozygotic Twins Clinically Discordant for Multiple Sclerosis

Twin Study of Early-Onset Major Depression Finds DNA Methylation Enrichment for Neurodevelopmental Genes

On the relation of phase separation and Hi-C maps to epigenetics

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