Chromatin Switches during Neural Cell Differentiation and Their Dysregulation by Prenatal Alcohol Exposure

Gavin, David P.; Grayson, Dennis R.; Varghese, Sajoy P.; Guizzetti, Marina

doi:10.3390/genes8050137

Cited by 13 publications

(7 citation statements)

References 206 publications

(299 reference statements)

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“…We hypothesized that acute alcohol exposure at postnatal day 7 could affect mRNA expression levels of chromatin-modifying enzymes, due to the importance of establishing epigenetic marks associated with neurogenesis and gliogenesis. PAE has been shown to alter histone modifications and DNA methylation, supporting this hypothesis (reviewed in Basavarajappa and Subbanna, 2016;Gavin et al, 2017;Lussier et al, 2017). Our experiments focused on the cortex and cerebellum because these brain regions control processes vulnerable to ethanol-induced dysfunction.…”

Section: Ethanol Induced Differential Expression Of a Limited Set Of supporting

confidence: 61%

“…Histone PTMs such as acetylation, methylation, phosphorylation, ubiquitination, and SUMOylation also affect chromatin state and accessibility of genes for transcription (Kouzarides, 2007;Bannister and Kouzarides, 2011;Bowman and Poirier, 2015). Histone acetylation and methylation of histone H3 at lysines 4 (H3K4), 9 (H3K9), and 27 (H3K27) are of particular interest due to their role in regulating developmental transcription, differentiation, and pluripotency, including neuronal differentiation and the neurogenesis/gliogenesis switch (Vastenhouw and Schier, 2012;Gavin et al, 2017). Additionally, core histones H2A and H3 can be exchanged for different variants that affect chromatin structure and can impact brain development (Jin et al, 2005;Henikoff and Smith, 2015).…”

Section: Introductionmentioning

confidence: 99%

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Neonatal Alcohol Exposure in Mice Induces Select Differentiation- and Apoptosis-Related Chromatin Changes Both Independent of and Dependent on Sex

et al. 2020

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Prenatal alcohol exposure (PAE) affects many aspects of physiology and behavior, including brain development. Specifically, ethanol can influence expression of genes important for brain growth, including chromatin modifiers. Ethanol can also increase apoptotic cell death in the brain and alter epigenetic profiles such as modifications to histones and DNA methylation. Although differential sex outcomes and disruptions to the function of multiple brain regions have been reported in fetal alcohol spectrum disorder (FASD), the majority of our knowledge on molecular epigenetic and apoptotic dysregulation in PAE is based on data from males and is sometimes limited to assessments of the whole brain or one brain region. Here, we examined histone modifications, DNA methylation, and expression of genes involved in differentiation and proliferation related-chromatin modifications and apoptosis in the cerebral cortex and cerebellum of C57BL/6J mice exposed to an acute alcohol challenge on postnatal day 7, with a focus on differential outcomes between sexes and brain regions. We found that neonatal alcohol exposure altered histone modifications, and impacted expression of a select few chromatin modifier and apoptotic genes in both the cortex and cerebellum. The results were observed primarily in a sex-independent manner, although some additional trends toward sexual dimorphisms were observed. Alcohol exposure induced trends toward increased bulk H3K4me3 levels, increased Kmt2e expression, and elevated levels of Casp6 mRNA and bulk gH2A.X. Additional trends indicated that ethanol may impact Kdm4a promoter DNA methylation levels and bulk levels of the histone variant H2A.Z, although further studies are needed. We comprehensively examined effects of ethanol exposure across different sexes and brain regions, and our results suggest that major impacts of ethanol on bulk chromatin modifications underlying differentiation and apoptosis may be broadly applicable across the rodent cortex and cerebellum in both sexes.

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Section: Ethanol Induced Differential Expression Of a Limited Set Of supporting

confidence: 61%

Section: Introductionmentioning

confidence: 99%

Neonatal Alcohol Exposure in Mice Induces Select Differentiation- and Apoptosis-Related Chromatin Changes Both Independent of and Dependent on Sex

et al. 2020

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“…including an increase in repressive histone marks, a local change in nucleosome occupancy, or a general increase in histones' levels (Fiszbein et al, 2016;Gavin et al, 2017;Yoon et al, 2018). It was reported that the nuclei of ESCs macroscopically appear to contain less condensed chromatin, whereas well-defined foci of compact heterochromatin become evident in ESC-derived NPCs (Meshorer et al, 2006).…”

Section: Kinetic Coupling Is Enhanced In Neuronsmentioning

confidence: 99%

A slow transcription rate causes embryonic lethality and perturbs kinetic coupling of neuronal genes

et al. 2019

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The rate of RNA polymerase II (RNAPII) elongation has an important role in the control of alternative splicing (AS); however, the in vivo consequences of an altered elongation rate are unknown. Here, we generated mouse embryonic stem cells (ESCs) knocked in for a slow elongating form of RNAPII. We show that a reduced transcriptional elongation rate results in early embryonic lethality in mice. Focusing on neuronal differentiation as a model, we observed that slow elongation impairs development of the neural lineage from ESCs, which is accompanied by changes in AS and in gene expression along this pathway. In particular, we found a crucial role for RNAPII elongation rate in transcription and splicing of long neuronal genes involved in synapse signaling. The impact of the kinetic coupling of RNAPII elongation rate with AS is greater in ESC‐differentiated neurons than in pluripotent cells. Our results demonstrate the requirement for an appropriate transcriptional elongation rate to ensure proper gene expression and to regulate AS during development.

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“…Various mechanisms might promote the switch from a more open to a more close chromatin during cell differentiation, including an increase in repressive histone marks, a local change in nucleosome occupancy, or a general increase in histones levels 55,56 .…”

Section: Discussionmentioning

confidence: 99%

Slow transcriptional elongation causes embryonic lethality and perturbs kinetic coupling of long neural genes

Maslon

Braunchsweig

Aitken

et al. 2018

Preprint

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Running title: Transcriptional elongation rate controls gene expression and AS during development Maslon et al. 2 The rate of RNA Polymerase II (RNAPII) elongation has an important role in the control of Alternative splicing (AS); however, the in vivo consequences of an altered elongation rate are unknown. Here, we generated mouse embryonic stem cells (ESCs) knocked-in for a slow elongating form of RNAPII. We show that a reduced transcriptional elongation rate results in early embryonic lethality in mice and impairs the differentiation of ESCs into the neural lineage. This is accompanied by changes in splicing and in gene expression in ESCs and along the pathway of neuronal differentiation. In particular, we found a crucial role for RNAPII elongation rate in transcription and splicing of long neuronal genes involved in synapse signaling. The impact of the kinetic coupling of RNAPII elongation rate with AS is more predominant in ESC-differentiated neurons than in pluripotent cells. Our results demonstrate the requirement for an appropriate transcriptional elongation rate to ensure proper gene expression and to regulate AS during development. Supplemental material is available for this article. Maslon et al. 3Alternative splicing (AS) is a highly regulated process that generates RNA diversity and is a major contributor to protein isoform diversity. Its regulation not only depends on the interaction of trans-acting factors with regulatory RNA cis-acting sequences but also on multiple layers of regulation, which include DNA methylation, chromatin structure and modification, and transcription 1,2 . The co-transcriptional nature of pre-mRNA splicing led to the suggestion that the rate of transcription elongation acts to control AS in mammalian cells 3,4 . Notably, there is a functional relationship between the transcriptional and the splicing machineries, as evidenced by the role of splicing factors, such as TCERG1/CA150 5 and SRSF2 6 , in stimulating transcriptional elongation. A role for transcription elongation rate influencing splicing fidelity and cotranscriptionality was also observed in yeast 7,8 .Recent studies revisited the contribution of the kinetics of RNAPII elongation to the regulation of AS, giving rise to two complementary models 2,9 . The "window of opportunity" or kinetic model of AS regulation proposes that the rate of RNAPII elongation influences the outcome of alternative splicing selection. Use of a mutant form of RNAPII (C4/R749H) with a slower elongation rate leads to an increased 10 or decreased 11 inclusion of alternative cassette exons into mature mRNA. A complementary model, termed 'Goldilocks', concluded based on the study of RNAPII mutants with both slow and fast elongation rates, that an optimal rate of transcriptional elongation is required for normal co-transcriptional pre-mRNA splicing 12 . In both models, recruitment of splicing regulators to cis-acting RNA sequences as well as nascent RNA folding are influenced by the elongation rate of RNAPII [13][14][15] . The global impact of RNAP...

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Chromatin Switches during Neural Cell Differentiation and Their Dysregulation by Prenatal Alcohol Exposure

Cited by 13 publications

References 206 publications

Neonatal Alcohol Exposure in Mice Induces Select Differentiation- and Apoptosis-Related Chromatin Changes Both Independent of and Dependent on Sex

Neonatal Alcohol Exposure in Mice Induces Select Differentiation- and Apoptosis-Related Chromatin Changes Both Independent of and Dependent on Sex

A slow transcription rate causes embryonic lethality and perturbs kinetic coupling of neuronal genes

Slow transcriptional elongation causes embryonic lethality and perturbs kinetic coupling of long neural genes

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