EGR1 recruits TET1 to shape the brain methylome during development and upon neuronal activity

Sun, Zhixiong; Xu, Xiguang; He, Jianlin; Murray, Alexander; Sun, Ming-an; Wei, Xiaoran; Wang, Xia; McCoig, Emmarose; Xie, Evan; Jiang, Xi; Li, Liwu; Zhu, Jinsong; Chen, Jianjun; Morozov, Alexei; Pickrell, Alicia M.; Theus, Michelle H.; Xie, Hehuang

doi:10.1038/s41467-019-11905-3

Cited by 115 publications

(89 citation statements)

References 61 publications

(83 reference statements)

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“…This is known for CGGBP1 [25] and its depletion can thus lead to a random in methylation levels. In addition, methylation regulation by CTCF, REST, SP1, EGR1 has been described [48][49][50][51] and in a double blind search we have found these factors to be significantly enriched in the differentially methylated genomic bins between CT and KD. Thus the TFBS commonly identified in the differentially methylated bins of HEK293T as well as fibroblasts lead us to identify functionally relevant non-stochastic methylation changes caused by CGGBP1 depletion.…”

Section: Discussionmentioning

confidence: 55%

CGGBP1-regulated cytosine methylation at CTCF-binding motifs resists stochasticity

Patel

Datta

et al. 2020

Preprint

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The human CGGBP1 is implicated in a variety of cellular functions. It regulates genomic integrity, cell cycle, gene expression and cellular response to growth signals. Evidence suggests that these functions of CGGBP1 manifest through binding to GC-rich regions in the genome and regulation of interspersed repeats. Recent works show that CGGBP1 is needed for cytosine methylation homeostasis and genome-wide occupancy patterns of the epigenome regulator protein CTCF. It has remained unknown if cytosine methylation regulation and CTCF occupancy regulation by CGGBP1 are independent or interdependent processes. By sequencing immunoprecipitated methylated DNA, we have found that some transcription factor-binding sites resist stochastic changes in cytosine methylation. Of these, we have analyzed the CTCF-binding sites thoroughly and show that cytosine methylation regulation at CTCF-binding DNA sequence motifs by CGGBP1 is deterministic. These CTCF-binding sites are positioned at locations where the spread of cytosine methylation in cis depends on the levels of CGGBP1. Our findings suggest that CTCF occupancy and functions are determined by CGGBP1-regulated cytosine methylation patterns.

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Section: Discussionmentioning

confidence: 55%

CGGBP1-regulated cytosine methylation at CTCF-binding motifs resists stochasticity

Patel

Datta

et al. 2020

Preprint

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“…ERG1 is required specifically for the consolidation of long-term memory (while the related transcription factor ERG3 is primarily essential for short-term memory). As reviewed by Sun et al [61], the short form of TET1, TET1s, is present in the brain. Sun et al [61] experimentally showed that EGR1 and TET1s form a complex, independently of attachment to DNA.…”

Section: Tet In Learning and Memorymentioning

confidence: 99%

“…As reviewed by Sun et al [61], the short form of TET1, TET1s, is present in the brain. Sun et al [61] experimentally showed that EGR1 and TET1s form a complex, independently of attachment to DNA. ERG1 undergoes rapid induction and appears to attach to binding sites at many genes upon neuronal activation.…”

Section: Tet In Learning and Memorymentioning

confidence: 99%

“…Both have some developmental deficiencies [62,63], and TET1 knockouts [41,43] and ERG1 knockouts [64] each have some learning and memory deficiencies. Sun et al [61] examined where differentially methylated regions occurred in the two types of knockout mice. Compared to wild-type mice, 322 and 2373 differentially methylated regions were identified in the brain frontal cortices (Figure 6) of EGR1 knockout and TET1 knockout mice respectively.…”

Section: Tet In Learning and Memorymentioning

confidence: 99%

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Demethylation in Early Embryonic Development and Memory

Bernstein¹,

Bernstein²

2020

DNA Methylation Mechanism

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DNA repair processes arose early in evolution. During evolution, DNA base excision repair apparently acquired additional roles in demethylation of cytosines in DNA. Demethylation is central to two mammalian fundamental processes. Embryonic reprogramming and neuronal memory require rapid gene expression alterations depending in part on demethylations. The active demethylation reactions in both processes primarily depend, first, on the family of 5-methylcytosine oxidases sharing the acronym ten-eleven translocation (TET methylcytosine dioxygenases) and, second, on DNA base excision repair enzymes. In mice, within 6 h of fertilization, the paternal chromosomes are close to 100% actively demethylated through TET and repair activity. (Methylation of maternal DNA is blocked during subsequent cycles of replication, so methyl groups on maternal DNA, passively, becomes highly diluted over the next 4 days.) Rats subjected to one instance of contextual fear conditioning create an especially strong long-term memory. At 24 h after training, 9.2% of the genes in the rat genomes of hippocampus neurons are differentially methylated, including over 500 genes with demethylation. The emergence of embryonic development in evolution depended on preexisting DNA methylation/demethylation pathways to modify gene expression. The further emergence of memory likely evolved from the earlier set of methylation/demethylation capabilities associated with embryonic development.

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“…TET1 has previously been reported to interact with the SIN3A PAH1 domain by amphipathic helix formation [52] and with OGT via C-terminal TET1 residues [53]. Other TET1-interacting proteins have been identified [29,31,32,[54][55][56][57]. These include thymine DNA glycosylase, which binds TET1 through at least two sites [54].…”

Section: Tet1mentioning

confidence: 99%

TET1 interacts directly with NANOG via independent regions containing hydrophobic and aromatic residues

Pantier

Mullin

Hall-Ponsele

et al. 2020

Preprint

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AbstractThe DNA demethylase TET1 is highly expressed in embryonic stem cells. Knockout experiments indicate that TET1 is important for lineage commitment, and paradoxically, also for reprogramming to naïve pluripotency. TET1 binds to promoters through a CXXC domain which recognises unmethylated CpG dinucleotides. TET1 also binds to enhancers, presumably via interactions with partner proteins. The transcription factor NANOG interacts with TET1 and is predominantly localised at enhancers in ESCs. Therefore, NANOG may contribute to TET1 biological activity in pluripotent cells. However, the regions of TET1 involved in protein-protein interactions are mostly unknown. Here, we characterise the physical interaction between TET1 and NANOG using embryonic stem cells and bacterial expression systems. TET1 and NANOG interact through multiple binding sites that act independently. Critically, mutating conserved hydrophobic and aromatic residues within TET1 and NANOG abolishes the interaction. Comparative ChIP-seq analysis identifies genomic loci bound by both TET1 and NANOG, that correspond predominantly to pluripotency enhancers. Importantly, around half of NANOG transcriptional target genes are associated with TET1-NANOG co-bound sites. These results indicate a mechanism by which TET1 protein is targeted to specific sites of action at enhancers by direct interaction with a transcription factor.HighlightsNANOG and TET1 have regulatory roles in maintaining and reprogramming pluripotencyTET1 and NANOG interact via multiple independent binding regionsTET1 and NANOG interactions are mediated by aromatic and hydrophobic residuesTET1 residues that bind NANOG are highly conserved in mammalsCo-localisation of TET1 and NANOG on chromatin is enriched at NANOG target genes

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EGR1 recruits TET1 to shape the brain methylome during development and upon neuronal activity

Cited by 115 publications

References 61 publications

CGGBP1-regulated cytosine methylation at CTCF-binding motifs resists stochasticity

CGGBP1-regulated cytosine methylation at CTCF-binding motifs resists stochasticity

Demethylation in Early Embryonic Development and Memory

TET1 interacts directly with NANOG via independent regions containing hydrophobic and aromatic residues

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