RNA-dependent dynamic histone acetylation regulates MCL1 alternative splicing

Khan, Dilshad H.; González, Carolina; Cooper, Charlton; Sun, Jian-Min; Chen, Hou Yu; Healy, Shannon; Xu, Wayne; Smith, Karen; Workman, Jerry L.; Leygue, Etienne; Davie, James R.

doi:10.1093/nar/gkt1134

Cited by 49 publications

(65 citation statements)

References 74 publications

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“…ZFP318 binding to HDAC2 (21) is potentially similar to the recently demonstrated interaction between the RNA-binding protein HuR and HDAC2 to influence alternative mRNA splicing (34). A large amount of alternative splicing occurs cotranscriptionally when pre-mRNAs are still chromatin associated, where it is governed by two-way cooperation between RNA-binding splicing factors such as HuR or SRSF proteins, the extent of histone acetylation along intragenic chromatin, and the speed of RNA polymerase II (Pol II) transcript elongation along chromatin (34)(35)(36)(37)(38).…”

Section: Discussionsupporting

confidence: 53%

Zinc-finger protein ZFP318 is essential for expression of IgD, the alternatively splicedIghproduct made by mature B lymphocytes

Enders¹,

Short²,

Miosge³

et al. 2014

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

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IgD and IgM are produced by alternative splicing of long primary RNA transcripts from the Ig heavy chain (Igh) locus and serve as the receptors for antigen on naïve mature B lymphocytes. IgM is made selectively in immature B cells, whereas IgD is coexpressed with IgM when the cells mature into follicular or marginal zone B cells, but the transacting factors responsible for this regulated change in splicing have remained elusive. Here, we use a genetic screen in mice to identify ZFP318, a nuclear protein with two U1-type zinc fingers found in RNA-binding proteins and no known role in the immune system, as a critical factor for IgD expression. A point mutation in an evolutionarily conserved lysine-rich domain encoded by the alternatively spliced Zfp318 exon 10 abolished IgD expression on marginal zone B cells, decreased IgD on follicular B cells, and increased IgM, but only slightly decreased the percentage of B cells and did not decrease expression of other maturation markers CD21, CD23, or CD62L. A targeted Zfp318 null allele extinguished IgD expression on mature B cells and increased IgM. Zfp318 mRNA is developmentally regulated in parallel with IgD, with little in pro-B cells, moderate amounts in immature B cells, and high levels selectively in mature follicular B cells. These findings identify ZFP318 as a crucial factor regulating the expression of the two major antibody isotypes on the surface of most mature B cells.IgHm | IgHd | immunoglobulin isotype |

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Section: Discussionsupporting

confidence: 53%

Zinc-finger protein ZFP318 is essential for expression of IgD, the alternatively splicedIghproduct made by mature B lymphocytes

Enders¹,

Short²,

Miosge³

et al. 2014

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

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“…Next we sought to investigate the effect of EtOH exposure on alternative splicing patterns of candidate genes which have been shown to be regulated by SRSF1 and involved in regulation of apoptosis. Among the possible candidate genes, we analyzed the alternative splicing of Bcl2-like protein 11 (BCL2L11 or BIM), macrophage-stimulating protein receptor (MST1R), bridging integrator 1 (BIN1), and myeloid cell leukemia 1 (Mcl-1) (Anczukow et al, 2012; Khan et al, 2014; Karni et al, 2007). SH-SY5Y cells were exposed to 50 mM EtOH for up to 8h.…”

Section: Resultsmentioning

confidence: 99%

Alcohol-Mediated Missplicing of Mcl-1 Pre-mRNA is Involved in Neurotoxicity

Sariyer

DeSimone

Donadoni

et al. 2017

Alcohol Clin Exp Res

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Background Heavy and chronic ethanol (EtOH) exposure can cause significant structural and functional damage to the adult brain. The most devastating consequence of EtOH exposure is the neurotoxicity associated with the depletion of neurons. Regulation of splice variants in the brain can modulate protein functions, which may ultimately affect behaviors associated with alcohol dependence and EtOH-mediated neurotoxicity. Since alcohol consumption is associated with neurotoxicity, it is possible that altered splicing of survival and pro-survival factors during the development of alcoholism may contribute to the neurotoxicity. Methods Primary human neurons and a neuroblastoma cell line were exposed to different concentrations of EtOH for various time periods. Cell viability and neuronal marker expression were analyzed by MTT assay and immunoblotting, respectively. Effect of EtOH exposure on splicing regulatory protein expression and alternative splicing of candidate genes were analyzed by a biochemical approach. Transcriptional activity of SRSF1 gene was determined by reporter gene analysis. Results Our results suggest that EtOH exposure to neuronal cells at 25 mM and higher concentrations are detrimental. In addition, EtOH exposure caused a dramatic reduction in serine-arginine rich splicing factor 1 (SRSF1) expression levels. Furthermore, EtOH exposure led to pre-mRNA missplicing of Mcl-1, a pro-survival member of the Bcl-2 family, by downregulating the expression levels of serine/arginine rich splicing factor 1 (SRSF1). Moreover, ectopic expression of both SRSF1 and MCL-1L isoform was able to recover EtOH-mediated neurotoxicity. Conclusions Our results suggest that ethanol exposure can lead to pre-mRNA missplicing of Mcl-1 in neuronal cells. Our results indicate that ethanol exposure of neurons leads to a decrease in the ratio of Mcl-1L/Mcl-1S by favoring pro-apoptotic Mcl-1S splicing over anti-apoptotic Mcl-1L isoform suggesting that Mcl-1S may play a crucial role in neurotoxicity associated with alcohol consumption.

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“…Additional accumulated evidence has associated histone acetylation with cotranscriptional splicing. Inhibition of HDAC1, HDAC2, or SRSF1 (the SR protein formerly known as SF2/ASF) expression results in alternative splicing of MCL1 (158). Further evidence was provided by a genome-wide study in which HDAC inhibition altered the splicing pattern of more than 700 genes and reduced cotranscriptional association of the splicing regulator SRSF5 (formerly known as SRp40) with its target exons (144).…”

Section: Histone Modifications and Dna Methylationmentioning

confidence: 99%

Regulation of Alternative Splicing Through Coupling with Transcription and Chromatin Structure

Naftelberg

Schor²,

Ast³

et al. 2015

Annu. Rev. Biochem.

399

354

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Alternative precursor messenger RNA (pre-mRNA) splicing plays a pivotal role in the flow of genetic information from DNA to proteins by expanding the coding capacity of genomes. Regulation of alternative splicing is as important as regulation of transcription to determine cell- and tissue-specific features, normal cell functioning, and responses of eukaryotic cells to external cues. Its importance is confirmed by the evolutionary conservation and diversification of alternative splicing and the fact that its deregulation causes hereditary disease and cancer. This review discusses the multiple layers of cotranscriptional regulation of alternative splicing in which chromatin structure, DNA methylation, histone marks, and nucleosome positioning play a fundamental role in providing a dynamic scaffold for interactions between the splicing and transcription machineries. We focus on evidence for how the kinetics of RNA polymerase II (RNAPII) elongation and the recruitment of splicing factors and adaptor proteins to chromatin components act in coordination to regulate alternative splicing.

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RNA-dependent dynamic histone acetylation regulates MCL1 alternative splicing

Cited by 49 publications

References 74 publications

Zinc-finger protein ZFP318 is essential for expression of IgD, the alternatively splicedIghproduct made by mature B lymphocytes

Zinc-finger protein ZFP318 is essential for expression of IgD, the alternatively splicedIghproduct made by mature B lymphocytes

Alcohol-Mediated Missplicing of Mcl-1 Pre-mRNA is Involved in Neurotoxicity

Regulation of Alternative Splicing Through Coupling with Transcription and Chromatin Structure

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