ChIP-seq analysis reveals distinct H3K27me3 profiles that correlate with transcriptional activity

Young, Matthew D.; Willson, Tracy A.; Wakefield, Matthew J.; Trounson, Evelyn; Hilton, Douglas J.; Blewitt, Marnie E.; Oshlack, Alicia; Majewski, Ian J.

doi:10.1093/nar/gkr416

Cited by 252 publications

(237 citation statements)

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“…Altered methylation of the proximal-1 promoter region of StAR is crucial for regulating its expression (45)(46)(47) and conserved across species (48). Because H3K27me3 is an established transcriptional repressor (49)(50)(51), including of StAR (47), we investigated if the level of H3K27me3 upstream of the coding region of StAR was altered using a ChIP assay (47,51).…”

Section: Potential Mechanism For Fetal Programming Of Compensated Adultmentioning

confidence: 99%

“…To investigate a potential mechanism for reduced expression of StAR, we hypothesized that it was because of histone modifications in its proximal-1 promoter region, which are important in its regulation (45)(46)(47). Using ChIP, we showed that H3K27me3 upstream of the coding region of StAR, which is associated with transcriptional repression (47,(49)(50)(51), was increased in testes of DBP-exposed rats. Consistent with this finding, we found increased immunoexpression of H3K27me3 in adult Leydig cells of DBP-exposed rats and their stem cells in fetal life.…”

Section: -Hsd3mentioning

confidence: 99%

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Fetal programming of adult Leydig cell function by androgenic effects on stem/progenitor cells

Kilcoyne

Smith

Atanassova

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

158

135

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Fetal growth plays a role in programming of adult cardiometabolic disorders, which in men, are associated with lowered testosterone levels. Fetal growth and fetal androgen exposure can also predetermine testosterone levels in men, although how is unknown, because the adult Leydig cells (ALCs) that produce testosterone do not differentiate until puberty. To explain this conundrum, we hypothesized that stem cells for ALCs must be present in the fetal testis and might be susceptible to programming by fetal androgen exposure during masculinization. To address this hypothesis, we used ALC ablation/regeneration to identify that, in rats, ALCs derive from stem/progenitor cells that express chicken ovalbumin upstream promoter transcription factor II. These stem cells are abundant in the fetal testis of humans and rodents, and lineage tracing in mice shows that they develop into ALCs. The stem cells also express androgen receptors (ARs). Reduction in fetal androgen action through AR KO in mice or dibutyl phthalate (DBP) -induced reduction in intratesticular testosterone in rats reduced ALC stem cell number by ∼40% at birth to adulthood and induced compensated ALC failure (low/normal testosterone and elevated luteinizing hormone). In DBP-exposed males, this failure was probably explained by reduced testicular steroidogenic acute regulatory protein expression, which is associated with increased histone methylation (H3K27me3) in the proximal promoter. Accordingly, ALCs and ALC stem cells immunoexpressed increased H3K27me3, a change that was also evident in ALC stem cells in fetal testes. These studies highlight how a key component of male reproductive development can fundamentally reprogram adult hormone production (through an epigenetic change), which might affect lifetime disease risk.adult Leydig stem/progenitor cells | compensated Leydig cell failure | GATA4 | ethane dimethane sulfonate

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Section: Potential Mechanism For Fetal Programming Of Compensated Adultmentioning

confidence: 99%

Section: -Hsd3mentioning

confidence: 99%

Fetal programming of adult Leydig cell function by androgenic effects on stem/progenitor cells

Kilcoyne

Smith

Atanassova

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

158

135

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“…Previous studies have shown that differences in the distribution of histone methylation around the TSS often distinguish classes of genes, even when these genes cannot be separated by their expression levels (23)(24)(25)(26). Indeed, we observed an H3K4me3 profile in WT animals that distinguished between genes that decrease in expression in the mutant mice and genes that do not decrease.…”

Section: H3k4 Trimethylation Changes At the Dysregulated Promoters In Hdmentioning

confidence: 99%

Targeting H3K4 trimethylation in Huntington disease

Vashishtha

Ng²,

Yildirim³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

148

173

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Transcriptional dysregulation is an early feature of Huntington disease (HD). We observed gene-specific changes in histone H3 lysine 4 trimethylation (H3K4me3) at transcriptionally repressed promoters in R6/2 mouse and human HD brain. Genome-wide analysis showed a chromatin signature for this mark. Reducing the levels of the H3K4 demethylase SMCX/Jarid1c in primary neurons reversed down-regulation of key neuronal genes caused by mutant Huntingtin expression. Finally, reduction of SMCX/Jarid1c in primary neurons from BACHD mice or the single Jarid1 in a Drosophila HD model was protective. Therefore, targeting this epigenetic signature may be an effective strategy to ameliorate the consequences of HD.polyglutamine | neurodegeneration H untington disease (HD), a neurodegenerative disease (1, 2) characterized by cognitive dysfunction, psychiatric symptoms, and choreic movements (2), exhibits brain region-specific neuronal degeneration in the striatum and cortex. Currently, no disease-modifying treatment is available. The genetic basis of HD is the expansion of an in-frame CAG repeat sequence encoding polyglutamine. Progressive transcriptional dysregulation in both cortex and striatum and atrophy of the cortex are characteristic features (3). Transcriptional repression of key neuronal transcripts, including neurotransmitters, growth factors, and their cognate receptors, is consistently observed and implicated in disease pathogenesis. Among the critical genes whose expression is repressed in HD mouse models and human brain tissue are the dopamine receptor 2 (Drd2), preproenkephalin (Penk1), the cannabinoid receptor (Cb2), and brain-derived neurotrophic factor (Bdnf) (4, 5).We hypothesized that a central event in the pathological program underlying transcriptional dysregulation includes alterations in chromatin structure in the regulatory regions of genes down-regulated in HD. To evaluate this hypothesis, we focused on H3K4 trimethylation (H3K4me3), a mark of transcription start sites (TSSs) and active chromatin (6-8). Growing evidence suggests that this mark is plastic and modulated in conditions of chronic stress, developmental disorders, psychiatric disorders (9-11) as well as during long-term memory consolidation from contextual fear conditioning (12), suggesting a critical function in brain.We first investigated H3K4me3 in the R6/2 mouse model of HD, which shows patterns of transcriptional dysregulation similar to postmortem HD brain (13,14). Using chromatin immunoprecipitation (ChIP), we examined H3K4me3 levels for Bdnf, which is expressed in the cortex, provides trophic support for GABAergic medium spiny neurons, and is expressed at lower levels in HD (5, 15). The potential significance of Bdnf in HD is reflected by transcriptional profiling (16) and therapeutic preclinical studies (17,18). Because H3K4me3 levels were lowered at Bdnf and other promoters in R6/2 mice and key neuronal genes in human HD brain cortex and striata, we expanded our approach to investigate the genome-wide relationship between H3K4me3 an...

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“…It also carries a partial "annotation" of genomic features such as promoters and enhancers (Heintzman et al, 2007), the exon/intron struc-ture (Andersson et al, 2009;Schwartz et al, 2009) or the concurrent deposition of characteristic histone modifications (e.g. H3K4me3 as marker of active transcription (Young et al, 2011;Tippmann et al, 2012)), altogether keeping track of ongoing activities.…”

Section: Introductionmentioning

confidence: 99%

Chromatin computation: Epigenetic inheritance as a pattern reconstruction problem

Arnold

Stadler

Prohaska

2013

Journal of Theoretical Biology

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Eukaryotic histones carry a diverse set of specific chemical modifications that accumulate over the life-time of a cell and have a crucial impact on the cell state in general and the transcriptional program in particular. Replication constitutes a dramatic disruption of the chromatin states that effectively amounts to partial erasure of stored information. To preserve its epigenetic state the cell reconstructs (at least part of) the histone modifications by means of processes that are still very poorly understood. A plausible hypothesis is that the different combinations of reader and writer domains in histone-modifying enzymes implement local rewriting rules that are capable of "recomputing" the desired parental modification patterns on the basis of the partial information contained in that half of the nucleosomes that predate replication.To test whether such a mechanism is theoretically feasible, we have developed a flexible stochastic simulation system (available at http://www.bioinf.uni-leipzig.de/Software/StoChDyn) for studying the dynamics of histone modification states. The implementation is based on Gillespie's approach, i.e., it models the master equation of a detailed chemical model. It is efficient enough to use an evolutionary algorithm to find patterns across multiple cell divisions with high accuracy.We found that it is easy to evolve a system of enzymes that can maintain a particular chromatin state roughly stable, even without explicit boundary elements separating differentially modified chromatin domains. However, the success of this task depends on several previously unanticipated factors, such as the length of the initial state, the specific pattern that should be maintained, the time between replications, and chemical parameters such as enzymatic binding and dissociation rates. All these factors also influence the accumulation of errors in the wake of cell divisions.

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ChIP-seq analysis reveals distinct H3K27me3 profiles that correlate with transcriptional activity

Cited by 252 publications

References 46 publications

Fetal programming of adult Leydig cell function by androgenic effects on stem/progenitor cells

Fetal programming of adult Leydig cell function by androgenic effects on stem/progenitor cells

Targeting H3K4 trimethylation in Huntington disease

Chromatin computation: Epigenetic inheritance as a pattern reconstruction problem

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