The emerging roles for the chromatin structure regulators CTCF and cohesin in neurodevelopment and behavior

Davis, Liron; Onn, Itay; Elliott, Evan

doi:10.1007/s00018-017-2706-7

Cited by 25 publications

(18 citation statements)

References 69 publications

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“…CTCF is another transcription factor of interest with 17% of the DNMT1-dependent human regions overlapping the CCCTC-binding motif. CTCF is also critical in neurodevelopment and chromatin organization [14,21]. CTCF mediates the formation of chromatin loops and thus can promote widespread changes in gene expression [30,58].…”

Section: Discussionmentioning

confidence: 99%

“…The top transcription factors with binding motifs found in intergenic sites were CTCF, SIN3A, and RAD21. All three transcription factors are crucial in regulating chromatin structure to repress gene transcription and inhibition of these factors is closely associated with human disease [14,78,85]. We searched conserved human genes for known imprinted genes at germline ASMs using the GeneImprint database and found 20 known imprinted genes ( Fig.…”

Section: Dnmt1-dependent Regions In the Mouse And Human Genomementioning

confidence: 99%

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The conserved DNMT1-dependent methylation regions in human cells are vulnerable to neurotoxicant rotenone exposure

Freeman

Lou

et al. 2020

Epigenetics & Chromatin

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Background: Allele-specific DNA methylation (ASM) describes genomic loci that maintain CpG methylation at only one inherited allele rather than having coordinated methylation across both alleles. The most prominent of these regions are germline ASMs (gASMs) that control the expression of imprinted genes in a parent of origin-dependent manner and are associated with disease. However, our recent report reveals numerous ASMs at non-imprinted genes. These non-germline ASMs are dependent on DNA methyltransferase 1 (DNMT1) and strikingly show the feature of random, switchable monoallelic methylation patterns in the mouse genome. The significance of these ASMs to human health has not been explored. Due to their shared allelicity with gASMs, herein, we propose that non-traditional ASMs are sensitive to exposures in association with human disease. Results:We first explore their conservancy in the human genome. Our data show that our putative non-germline ASMs were in conserved regions of the human genome and located adjacent to genes vital for neuronal development and maturation. We next tested the hypothesized vulnerability of these regions by exposing human embryonic kidney cell HEK293 with the neurotoxicant rotenone for 24 h. Indeed,14 genes adjacent to our identified regions were differentially expressed from RNA-sequencing. We analyzed the base-resolution methylation patterns of the predicted non-germline ASMs at two neurological genes, HCN2 and NEFM, with potential to increase the risk of neurodegeneration. Both regions were significantly hypomethylated in response to rotenone. Conclusions:Our data indicate that non-germline ASMs seem conserved between mouse and human genomes, overlap important regulatory factor binding motifs, and regulate the expression of genes vital to neuronal function. These results support the notion that ASMs are sensitive to environmental factors such as rotenone and may alter the risk of neurological disease later in life by disrupting neuronal development.

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Section: Discussionmentioning

confidence: 99%

Section: Dnmt1-dependent Regions In the Mouse And Human Genomementioning

confidence: 99%

The conserved DNMT1-dependent methylation regions in human cells are vulnerable to neurotoxicant rotenone exposure

Freeman

Lou

et al. 2020

Epigenetics & Chromatin

View full text Add to dashboard Cite

show abstract

“…CTCF is another transcription factor of interest with 17% of the DNMT1 dependent human regions overlapping the CCCTC-binding motif. CTCF is also critical in neurodevelopment and chromatin organization (Franco et al 2014, Davis et al 2018. CTCF mediates the formation of chromatin loops and thus can promote widespread changes in gene expression (Hou et al 2008, Phillips andCorces 2009).…”

Section: Discussionmentioning

confidence: 99%

The conserved DNMT1 dependent methylation regions in human cells are vulnerable to environmental rotenone

Freeman

Lou

et al. 2019

Preprint

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Allele-specific DNA methylation (ASM) describes genomic loci that maintain CpG methylation at only one inherited allele rather than having coordinated methylation across both alleles. The most prominent of these regions are germline ASMs (gASMs) that control the expression of imprinted genes in a parent of origindependent manner and are associated with disease. However, our recent report reveals numerous ASMs at non-imprinted genes. These non-germline ASMs are dependent on DNA methyltransferase 1 (DNMT1) and strikingly show the feature of random, switchable monoallelic methylation patterns in the mouse genome. The significance of these ASMs to human health has not been explored. Due to their shared allelicity with gASMs, herein, we propose that non-traditional ASMs are sensitive to exposures in association with human disease. We first explore their conservancy in the human genome. Our data show that our putative non-germline ASMs were in conserved regions of the human genome and located adjacent to genes vital for neuronal development and maturation. We next tested the hypothesized vulnerability of these regions by exposing human embryonic kidney cell HEK293 with the neurotoxicant rotenone for 24h. Indeed,14 genes adjacent to our identified regions were differentially expressed from RNA-sequencing. We analyzed the base-resolution methylation patterns of the predicted non-germline ASMs at two neurological genes, HCN2 and NEFM, with potential to increase the risk of neurodegeneration. Both regions were significantly hypomethylated in response to rotenone. Our data indicate that non-germline ASMs seem conserved between mouse and human genomes, overlap important regulatory factor binding motifs, and regulate the expression of genes vital to neuronal function. These results support the notion that ASMs are sensitive to environmental factors and may alter the risk of neurological disease later in life by disrupting neuronal development.

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“…Although mammalian CTCF is required for viability in all cell types thus far tested, the nervous system may be particularly sensitive to CTCF function. This topic has been reviewed in detail in two recent review articles [47,48], and we focus here on CTCF regulation in the CNS. Briefly, mouse CTCF displays higher expression in the nervous system compared to other tissues [49] and associates with a large number of brain-specific genomic loci [50].…”

Section: Regulation Of Mammalian Ctcf To Control Chromatin Organizatimentioning

confidence: 99%

Function and regulation of chromatin insulators in dynamic genome organization

Chen

Lei

2019

Current Opinion in Cell Biology

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Chromatin insulators are DNA-protein complexes that play a crucial role in regulating chromatin organization. Within the past two years, a plethora of genome-wide conformation capture studies has helped reveal that insulators are necessary for proper genome-wide organization of topologically associating domains, which are formed in a manner distinct from that of compartments. These studies have also provided novel insights into the mechanics of how CTCF/ cohesin-dependent loops form in mammals, strongly supporting the loop extrusion model. In combination with single-cell imaging approaches in both Drosophila and mammals, the dynamics of insulator-mediated chromatin interactions are also coming to light. Insulator-dependent structures vary across individual cells and tissues, highlighting the need to study the regulation of insulators in particular temporal and spatial contexts throughout development.

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The emerging roles for the chromatin structure regulators CTCF and cohesin in neurodevelopment and behavior

Cited by 25 publications

References 69 publications

The conserved DNMT1-dependent methylation regions in human cells are vulnerable to neurotoxicant rotenone exposure

The conserved DNMT1-dependent methylation regions in human cells are vulnerable to neurotoxicant rotenone exposure

The conserved DNMT1 dependent methylation regions in human cells are vulnerable to environmental rotenone

Function and regulation of chromatin insulators in dynamic genome organization

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