Distal CpG islands can serve as alternative promoters to transcribe genes with silenced proximal promoters

Sarda, Shrutii; Das, Arabinda; Vinson, Charles; Hannenhalli, Sridhar

doi:10.1101/gr.212050.116

Cited by 33 publications

(28 citation statements)

References 77 publications

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“…It is worth noting that the minor isoform is usually longer (Additional file 1: Table S3), implying the inhibition of proximal CpG island as reported earlier [45]. As the switching between D1 active -passive states is of oscillatory nature, CpG islands are apparently not modified by DNA methylation as was the case in [45], nor are alternative histone modifications [46], since both isoforms are present in D1 neurons, so it might be some repressive transcription factor not yet assigned. It is also intriguing that the majority of the isoforms encode alternative functional proteins, which are expressed in D1 active state, but usually at significantly lower rates (Additional file 1: Table S3).…”

Section: D1 Msn Oscillating States Employ Alternative Transcripts Swisupporting

confidence: 63%

Dopamine response gene pathways in dorsal striatum MSNs from a gene expression viewpoint: cAMP-mediated gene networks

et al. 2020

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Background: Medium spiny neurons (MSNs) comprise the main body (95% in mouse) of the dorsal striatum neurons and represent dopaminoceptive GABAergic neurons. The cAMP (cyclic Adenosine MonoPhosphate)-mediated cascade of excitation and inhibition responses observed in MSN intracellular signal transduction is crucial for neuroscience research due to its involvement in the motor and behavioral functions. In particular, all types of addictions are related to MSNs. Shedding the light on the mechanics of the above-mentioned cascade is of primary importance for this research domain. Results: A mouse model of chronic social conflicts in daily agonistic interactions was used to analyze dorsal striatum neurons genes implicated in cAMP-mediated phosphorylation activation pathways specific for MSNs. Based on expression correlation analysis, we succeeded in dissecting Drd1-and Drd2-dopaminoceptive neurons (D1 and D2, correspondingly) gene pathways. We also found that D1 neurons genes clustering are split into two oppositely correlated states, passive and active ones, the latter apparently corresponding to D1 firing stage upon protein kinase A (PKA) activation. We observed that under defeat stress in chronic social conflicts the loser mice manifest overall depression of dopamine-mediated MSNs activity resulting in previously reported reduced motor activity, while the aggressive mice with positive fighting experience (aggressive mice) feature an increase in both D1-active phase and D2 MSNs genes expression leading to hyperactive behavior pattern corresponded by us before. Based on the alternative transcript isoforms expression analysis, it was assumed that many genes (Drd1, Adora1, Pde10, Ppp1r1b, Gnal), specifically those in D1 neurons, apparently remain transcriptionally repressed via the reversible mechanism of promoter CpG island silencing, resulting in alternative promoter usage following profound reduction in their expression rate. Conclusion: Based on the animal stress model dorsal striatum pooled tissue RNA-Seq data restricted to cAMP related genes subset we elucidated MSNs steady states exhaustive projection for the first time. We correspond the existence of D1 active state not explicitly outlined before, and connected with dynamic dopamine neurotransmission cycles. Consequently, we were also able to indicate an oscillated postsynaptic dopamine vs glutamate action pattern in the course of the neurotransmission cycles.

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Section: D1 Msn Oscillating States Employ Alternative Transcripts Swisupporting

confidence: 63%

Dopamine response gene pathways in dorsal striatum MSNs from a gene expression viewpoint: cAMP-mediated gene networks

et al. 2020

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“…This observation is in line with the recent 182 reports that DNA methylatransferases DNMT3a/b are associated with enhancers and are 183 important regulators of enhancer RNA production in hematopoietic stem cells [50]. Also, 184 distal regulatory regions can initiate transcription themselves, being in turn regulated 185 by DNA methylation [54], contributing to the similarity of TSS and enhcancers in terms 186 of CpG TL enrichment.…”

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confidence: 71%

“…Here, we report a high level of cell population heterogeneity 52 2/23 of methylation levels in CpG TL suggesting a novel flexible yet abundant mechanism of 53 transcriptional regulation. 54…”

Section: Introductionmentioning

confidence: 99%

CpG traffic lights are markers of regulatory regions in humans

Khamis

et al. 2016

Preprint

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DNA methylation is involved in regulation of gene expression. Although modern methods profile DNA methylation at single CpG sites, methylation levels are usually averaged over genomic regions in the downstream analyses. In this study we demonstrate that single CpG methylation can serve as a more accurate predictor of gene expression compared to average promoter / gene body methylation. CpG positions with significant correlation between methylation and expression of a gene nearby (named CpG traffic lights) are evolutionary conserved and enriched for exact TSS positions and active enhancers. Among all promoter types, CpG traffic lights are especially enriched in poised promoters. Genes that harbor CpG traffic lights are associated with development and signal transduction. Methylation levels of individual CpG traffic lights vary between cell types dramatically with the increased frequency of intermediate methylation levels, indicating cell population heterogeneity in CpG methylation levels. Being in line with the concept of the inherited stochastic epigenetic variation, methylation of such CpG positions might contribute to transcriptional regulation. Alternatively, one can hypothesize that traffic lights are markers of absent gene expression resulting from inactivation of their regulatory elements. The CpG traffic lights provide a promising insight into mechanisms of enhancer activity and gene regulation linking methylation of single CpG to expression.

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“…Promoter switching is a widespread and developmentally important phenomenon (47). Aberrant promoter usage is associated with pathologies, such as cancer (48). CTCF is a likely candidate to organize genic three-dimensional structure and protect from aberrant promoter firing, as it does at Zdbf2.…”

Section: Discussionmentioning

confidence: 99%

Dynamic enhancer partitioning instructs activation of a growth regulator during exit from naïve pluripotency

Greenberg

Teissander

Walter

et al. 2018

Preprint

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During early mammalian development, the genome undergoes profound transitions in chromatin states, topological organization and recruitment of cis regulatory factors involved in transcriptional control. How these three layers of gene regulation interact is the matter of intense research. The Zdbf2 gene-which is involved in growth control-provides a valuable model to study this question: upon exit from naïve pluripotency and prior to tissue differentiation, it undergoes a switch in usage from a distal to a proximal promoter, along with a switch in chromatin states, from polycomb to DNA methylation occupancy. Using an embryonic stem cell (ESC) culture system to mimic this period, we show here that four enhancers contribute to the Zdbf2 promoter switch, concomitantly with dynamic changes in chromosome architecture. Indeed, CTCF plays a key role in partitioning the locus in ESCs, to facilitate enhancer contact with the distal Zdbf2 promoter only. Partition relieving enhances proximal Zdbf2 promoter activity, as observed during differentiation or with mutants that lack local CTCF-based partition. Importantly, we show that CTCF-based regulation occurs independently of the polycomb and DNA methylation pathways. Our study reveals the importance of multi-layered regulatory frameworks to ensure proper spatio-temporal activation of developmentally important genes.

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Distal CpG islands can serve as alternative promoters to transcribe genes with silenced proximal promoters

Cited by 33 publications

References 77 publications

Dopamine response gene pathways in dorsal striatum MSNs from a gene expression viewpoint: cAMP-mediated gene networks

Dopamine response gene pathways in dorsal striatum MSNs from a gene expression viewpoint: cAMP-mediated gene networks

CpG traffic lights are markers of regulatory regions in humans

Dynamic enhancer partitioning instructs activation of a growth regulator during exit from naïve pluripotency

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