Chromatin establishes an immature version of neuronal protocadherin selection during the naive-to-primed conversion of pluripotent stem cells

Almenar-Queralt, Angels; Merkurjev, Daria; Kim, Hong Sook; Navarro, Michael; Ma, Qi; Chaves, Rodrigo S.; Allegue, Catarina; Driscoll, Shawn P.; Chen, Andrew G.; Kohlnhofer, Bridget M.; Fong, Lauren; Woodruff, Grace; Mackintosh, Carlos; Bohačiaková, Dáša; Hruška-Plocháň, Marián; Tadokoro, Takahiro; Young, Jessica E.; Hajj, Nady El; Dittrich, Marcus; Maršala, Martin; Goldstein, Lawrence S.B.; García-Bassets, Ivan

doi:10.1038/s41588-019-0526-4

Cited by 29 publications

(29 citation statements)

References 78 publications

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“…Furthermore, epigenetic age acceleration was shown to be associated with AD neuropathological markers such as neuritic plaques, diffuse plaques, and amyloid load in the dorsolateral prefrontal cortex (Levine et al, 2015b). Down's syndrome patients, predisposed to early onset AD, also display DNAm age acceleration in blood and brain tissue starting early during in utero development El Hajj et al, 2016) in addition to epigenetic dysregulation at the clustered protocadherin locus (Almenar-Queralt et al, 2019).…”

Section: Alzheimer's Diseasementioning

confidence: 99%

DNA Methylation Biomarkers in Aging and Age-Related Diseases

2020

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Recent research efforts provided compelling evidence of genome-wide DNA methylation alterations in aging and age-related disease. It is currently well established that DNA methylation biomarkers can determine biological age of any tissue across the entire human lifespan, even during development. There is growing evidence suggesting epigenetic age acceleration to be strongly linked to common diseases or occurring in response to various environmental factors. DNA methylation based clocks are proposed as biomarkers of early disease risk as well as predictors of life expectancy and mortality. In this review, we will summarize key advances in epigenetic clocks and their potential application in precision health. We will also provide an overview of progresses in epigenetic biomarker discovery in Alzheimer's, type 2 diabetes, and cardiovascular disease. Furthermore, we will highlight the importance of prospective study designs to identify and confirm epigenetic biomarkers of disease.

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Section: Alzheimer's Diseasementioning

confidence: 99%

DNA Methylation Biomarkers in Aging and Age-Related Diseases

2020

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“…PCDHGA genes encode protocadherins involved in cell-cell adhesion, boundary formation and maintenance as well as morphogenesis in the developing brain (Halbleib and Nelson, 2006). It has been shown that certain clusters of protocadherins : alfa ( PCDHA ) and gamma ( PCDHG ) are regulated in the stochastic manner in the developing human neurons (Almenar-Queralt et al 2019). The stochastic protocadherin selection occurs at the level of neuronal progenitors and protocadherin expression is reduced or silenced in adult brain neurons.…”

Section: Discussionmentioning

confidence: 99%

Epigenetic regulation of differentially expressed genes between various glioma types

Grabowicz

Wilczyński

Kamińska³

et al. 2020

Preprint

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Gliomas are the most frequent primary tumors of the central nervous system (CNS) and encompass two major subgroups: diffuse, malignant gliomas and benign, well differentiated gliomas showing a more circumscribed growth. Genome-wide next generation sequencing studies have uncovered specific genetic alterations, transcriptomic patterns and epigenetic profiles associated with different types of gliomas improving tumor diagnosis and having important implications for future clinical trials and patient management. We have recently created a unique resource encompassing genome-wide profiles of open chromatin, histone H3K27ac and H3Kme3 modifications, DNA methylation and transcriptomes of 33 glioma samples of different grades. Here, we took advantage of a wealth of data from those high-throughput experiments, intersected those data with topologically associating domains (TADs) and demonstrated that the chromatin organization and epigenetic landscape of enhancers have a strong impact on genes differentially expressed in low grade versus high grade gliomas. We identified TADs enriched in glioma grade-specific genes and/or epigenetic marks. We found a set of transcription factors, including REST, E2F1 and NFKB1, that are most likely to regulate gene expression in multiple TADs, containing glioma-related genes. Moreover, many genes associated with the cell-matrix adhesion Gene Ontology group, in particular 14 PROTOCADHERINs, were found to be regulated by the long range contacts with enhancers. Overall, the results presented here demonstrate the existence of epigenetic differences associated with chromatin organization driving differential gene expression in gliomas of different malignancy. We demonstrated that integration of whole genome epigenetic data with Hi-C data and transcriptomic profiles described in this work, can segregate low and high grade gliomas and reveal new regulatory networks that could explain some of the functional differences between gliomas of different malignancies.HighlightsIntegration of ATAC-seq, ChIP-seq and RNA-seq reveals glioma malignancy-related gene regulatory networks.TADs segmentation contributes to gene-epigenetically modified enhancer relationships.Contacts of active enhancers in gliomas of different malignancies might affect expression of genes involved in cancerogenesis, such as PROTOCADHERINs or EGFR.

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“…A remarkable property of the clustered Pcdh genes is that their promoter choice is inherited and stably maintained by daughter cells as seen in the SK-N-SH cell line and differentiated neurons [ 44 , 86 ]. This suggests that, once chosen, the expression patterns of clustered Pcdh genes are epigenetically inheritable.…”

Section: Mechanisms For Generating Clustered Pcdh Codes Of Neuronal Imentioning

confidence: 99%

“…This suggests that, once chosen, the expression patterns of clustered Pcdh genes are epigenetically inheritable. In addition, Pcdh promoter choice occurs early during the naive-to-primed conversion of ESCs (embryonic stem cells) [ 86 ]. The Pcdh promoters are modified with both active (H3K4me3) and repressive (H3K27me3) chromatin marks, so called bivalent promoters, in the primed ESCs before being activated.…”

Section: Mechanisms For Generating Clustered Pcdh Codes Of Neuronal Imentioning

confidence: 99%

Wiring the Brain by Clustered Protocadherin Neural Codes

Jia

2020

Neurosci. Bull.

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There are more than a thousand trillion specific synaptic connections in the human brain and over a million new specific connections are formed every second during the early years of life. The assembly of these staggeringly complex neuronal circuits requires specific cell-surface molecular tags to endow each neuron with a unique identity code to discriminate self from non-self. The clustered protocadherin (Pcdh) genes, which encode a tremendous diversity of cell-surface assemblies, are candidates for neuronal identity tags. We describe the adaptive evolution, genomic structure, and regulation of expression of the clustered Pcdhs. We specifically focus on the emerging 3-D architectural and biophysical mechanisms that generate an enormous number of diverse cell-surface Pcdhs as neural codes in the brain.

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Chromatin establishes an immature version of neuronal protocadherin selection during the naive-to-primed conversion of pluripotent stem cells

Cited by 29 publications

References 78 publications

DNA Methylation Biomarkers in Aging and Age-Related Diseases

DNA Methylation Biomarkers in Aging and Age-Related Diseases

Epigenetic regulation of differentially expressed genes between various glioma types

Wiring the Brain by Clustered Protocadherin Neural Codes

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