Enhancer transcribed RNAs arise from hypomethylated, Tet-occupied genomic regions

Pulakanti, Kirthi; Pinello, Luca; Stelloh, Cary; Blinka, Steven; Allred, Jeremy; Milanovich, Samuel; Kiblawi, Sid; Peterson, Jonathan; Wang, Alexander; Yuan, Guo Cheng; Rao, Sridhar

doi:10.4161/epi.26597

Cited by 62 publications

(96 citation statements)

References 58 publications

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“…Despite the correlation of these histone marks with enhancer transcription, Zhu et al found that eRNA was the single most predictive indicator of enhancer activity, with eRNA synthesis being more signifi cantly associated with increased expression at nearby genes than histone marks in multiple cell types. These results are supported by a separate study by Pulakanti et al where it was found that eRNA synthesis correlated with H3K27Ac deposition, hypomethylation, and occupancy of the DNA hydroxylase Tet1 in embryonic stem cells, all of which are traditional markers for transcriptional activity (Pulakanti et al 2013 ).…”

Section: Enhancer Transcription As a Marker Of Activitysupporting

confidence: 77%

Macrophage Activation as a Model System for Understanding Enhancer Transcription and eRNA Function

Allison

Glass

2015

Long Noncoding RNAs

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Macrophages are innate immune cells that sense the presence of pathogens through conserved pattern recognition receptors, which include TLR4. Activation of TLR4 by bacterial lipopolysaccharide induces the expression of thousands of genes that function to initiate infl ammation and coordinate innate and adaptive immune responses. Transcriptional activation of TLR4-responsive genes is mediated by signal-dependent transcription factors, such as NFκB, which bind to DNA regulatory elements termed enhancers. Recent fi ndings indicate that macrophage enhancers are actively transcribed in concert with nearby genes. Similar observations have been reported for other cell types, raising the general question of whether enhancer transcription and/or the resulting enhancer RNAs (eRNAs) are of functional importance. Here, we review the use of macrophage activation as an experimental system for addressing these questions and highlight areas for future research.

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Section: Enhancer Transcription As a Marker Of Activitysupporting

confidence: 77%

Macrophage Activation as a Model System for Understanding Enhancer Transcription and eRNA Function

Allison

Glass

2015

Long Noncoding RNAs

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“…Reads were aligned to mm9 by using the command line (-e 70 -k 1 -m 1 -n 2 -best -concise) on the software BowTie. Peaks were then identified by using MACS (model-based analysis of ChIP-seq) (66), using a two-sided comparison with input DNA when available, with default parameters (27).…”

Section: Quantitative Reverse Transcription-pcr (Rt-pcr)mentioning

confidence: 99%

Dynamic Switching of Active Promoter and Enhancer Domains Regulates Tet1 and Tet2 Expression during Cell State Transitions between Pluripotency and Differentiation

Sohni

Bartoccetti

Khoueiry

et al. 2015

Molecular and Cellular Biology

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The Tet 5-methylcytosine dioxygenases catalyze DNA demethylation by producing 5-hydroxymethylcytosine and further oxidized products. Tet1 and Tet2 are highly expressed in mouse pluripotent cells and downregulated to different extents in somatic cells, but the transcriptional mechanisms are unclear. Here we defined the promoter and enhancer domains in Tet1 and Tet2. Within a 15-kb "superenhancer" of Tet1, there are two transcription start sites (TSSs) with different activation patterns during development. A 6-kb promoter region upstream of the distal TSS is highly active in naive pluripotent cells, autonomously reports Tet1 expression in a transgenic system, and rapidly undergoes DNA methylation and silencing upon differentiation in cultured cells and native epiblast. A second TSS downstream, associated with a constitutively weak CpG-rich promoter, is activated by a neighboring enhancer in naive embryonic stem cells (ESCs) and primed epiblast-like cells (EpiLCs). Tet2 has a CpG island promoter with pluripotency-independent activity and an ESC-specific distal intragenic enhancer; the latter is rapidly downregulated in EpiLCs. Our study reveals distinct modes of transcriptional regulation at Tet1 and Tet2 during cell state transitions of early development. New transgenic reporters using Tet1 and Tet2 cis-regulatory domains may serve to distinguish nuanced changes in pluripotent states and the underlying epigenetic variations.T he study of transcription regulation is fundamental to understand how gene expression and phenotype are regulated during development. ENCODE (encyclopedia of DNA elements) studies recently revealed that the mammalian genome is more complex than previously annotated, in which different transcription start sites (TSSs) often mark core promoters, both intra-and intergenic, to drive the expression of alternative mRNA isoforms (1, 2). Distal elements known as enhancers are often recruitment platforms for cell-type-specific transcription factors and interact with promoter-bound factors to stabilize the association of RNA polymerase II (Pol II) at TSSs (3).Embryonic stem cells (ESCs) derived from the inner cell mass (ICM) of mouse blastocysts represent a unique model of transcription regulation. The widespread presence of "open" chromatin achieved through feed-forward and autoregulatory loops involving transcription factors appears crucial for the transcriptome to adapt rapidly to inductive differentiation signals, allowing the cells to generate all early embryonic lineages (4, 5). This pluripotent state is dependent on the master transcription factors Oct4, Sox2, and Nanog (OSN), which often bind cooperatively at target sites on enhancers. In early mammalian development, the triad of OSN, by binding to different enhancers, orchestrates two states of pluripotency, the "naive" and "primed" conditions resembling the pre-and postimplantation epiblasts, respectively (6, 7). Furthermore, OSN together with Klf4, Esrrb, and Mediator coactivator, all highly expressed in naive ESCs, densely occupy extended d...

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“…We found an increase of 5-hydroxy-methyl-CpG (Fig. 6C), which was recently suggested to take part in the function of activated enhancers (40). In addition, by performing ChIP analysis, we observed slight increases of histone H3K4m3 (Fig.…”

Section: Resultsmentioning

confidence: 67%

Early-life physical activity reverses metabolic and Foxo1 epigenetic misregulation induced by gestational sleep disturbance

Mutskov

Wang

Carreras

et al. 2015

American Journal of Physiology-Regulatory, Integrative and Comp

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life physical activity reverses metabolic and Foxo1 epigenetic misregulation induced by gestational sleep disturbance. Am J Physiol Regul Integr Comp Physiol 308: R419 -R430, 2015. First published January 7, 2015 doi:10.1152/ajpregu.00426.2014.-Sleep disorders are highly prevalent during late pregnancy and can impose adverse effects, such as preeclampsia and diabetes. However, the consequences of sleep fragmentation (SF) on offspring metabolism and epigenomic signatures are unclear. We report that physical activity during early life, but not later, reversed the increased body weight, altered glucose and lipid homeostasis, and increased visceral adipose tissue in offspring of mice subjected to gestational SF (SFo). The reversibility of this phenotype may reflect epigenetic mechanisms induced by SF during gestation. Accordingly, we found that the metabolic master switch Foxo1 was epigenetically misregulated in SFo livers in a temporally regulated fashion. Temporal Foxo1 analysis and its gluconeogenetic targets revealed that the epigenetic abnormalities of Foxo1 precede the metabolic syndrome phenotype. Importantly, regular physical activity early, but not later in life, reversed Foxo1 epigenetic misregulation and altered the metabolic phenotype in gestationally SF-exposed offspring. Thus, we have identified a restricted postnatal period during which lifestyle interventions may reverse the Foxo1 epigenetically mediated risk for metabolic dysfunction later in the life, as induced by gestational sleep disorders. epigenetics; Foxo1 gene; offspring metabolism effect; pregnancy sleep disruption; reverse epigenetic effects; physical activity THE TERM "EPIGENETICS" REFERS to DNA and histone modifications and noncoding RNA, which result in heritable changes in gene expression among the next generation without a change in the DNA sequence (5,17,29). The environment, such as diet and early life experiences, can influence the epigenome. Epigenetic abnormalities have been found to be causative factors in cancer, as well as contributing factors in autoimmune diseases, metabolic pathways, and aging. Disruption of the balance of epigenetic networks can lead to inappropriately heightened expression or silencing of genes, resulting in "epigenetic diseases". In contrast to genetic events, the potential reversibility of epigenetic states offers exciting opportunities for new therapeutic targets (9, 19).Sleep disorders are highly prevalent among pregnant women in late gestation and are characterized by increased awakenings during the night and sleep maintenance insomnia, which are potentially fraught with adverse pregnancy outcomes (13,21,38,45). Among the disorders that impose additional disruption of sleep integrity during pregnancy, sleep-disordered breathing is particularly prevalent and has emerged as a contributor to gestational diabetes mellitus, preeclampsia, as well as adverse perinatal outcomes (28, 42). However, the impact of poor sleep quality and continuity during pregnancy could transcend the gestational period and adve...

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Enhancer transcribed RNAs arise from hypomethylated, Tet-occupied genomic regions

Cited by 62 publications

References 58 publications

Macrophage Activation as a Model System for Understanding Enhancer Transcription and eRNA Function

Macrophage Activation as a Model System for Understanding Enhancer Transcription and eRNA Function

Dynamic Switching of Active Promoter and Enhancer Domains Regulates Tet1 and Tet2 Expression during Cell State Transitions between Pluripotency and Differentiation

Early-life physical activity reverses metabolic and Foxo1 epigenetic misregulation induced by gestational sleep disturbance

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