Histone hyperacetylation and exon skipping: a calcium-mediated dynamic regulation in cardiomyocytes

Sharma, Alok; Nguyen, Hieu; Cai, Lu; Lou, Hua

doi:10.1080/19491034.2015.1081324

Cited by 8 publications

(5 citation statements)

References 39 publications

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“…How AS is regulated by environmental stimuli to sculpt cellular phenotypic properties, particularly in highly heterogeneous and progressing malignant tumors, is yet a poor understood area of emerging interest from both laboratory research and clinical sides. Recent studies in cardiomyocytes, neurons and endocrine cells have begun to shed light on the regulation of calcium signals on pre-mRNA alternative splicing [28,29]. Our results demonstrated that the generation of OPNc (Fig.…”

Section: Discussionsupporting

confidence: 55%

Epigenetic regulation of osteopontin splicing isoform c defines its role as a microenvironmental factor to promote the survival of colon cancer cells from 5-FU treatment

et al. 2020

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Background Drug resistance to 5-fluorouracil (5-FU) and recurrence after chemotherapy in colorectal cancer remain a challenge to be resolved for the improvement of patient outcomes. It is recognized that a variety of secretory proteins released from the tumor cells exposed to chemo-drugs into the tumor microenvironment (TME) contributed to the cell-to-cell communication, and altered the drug sensitivity. One of these important factors is osteopontin (OPN), which exists in several functional forms from alternative splicing and post-translational processing. In colon cancer cells, increased total OPN expression was observed during the progression of tumors, however, the exact role and regulation of the OPN splicing isoforms was not well understood. Methods We assayed precisely the abundance of major OPN splicing isoforms under 5-FU treatments in colon cancer cell lines with different sensitivities to 5-FU, and also evaluated the effects of the condition medium from OPN splicing isoforms overexpressed cells on cell functions. The methods of nuclear calcium reporter assays and ChIP (chromatin immunoprecipitation) assays were used to investigate the molecular mechanism underlining the production of OPN isoforms. Results We discovered that OPNc was a most increased splicing isoform to a significant abundance following 5-FU treatment of colon cancer cells. OPNc as a secretory protein in the conditioned medium exerted a more potent effect to promote cell survival in 5-FU than other OPN isoforms. The kinetic response of nuclear calcium signals could be used to indicate an immediate effect of the conditioned medium containing OPNc and other isoforms. Methyl-CpG binding protein 2 (MeCP2) was identified to regulate the splicing of opn gene, where the phosphorylation of MeCP2 at S421 site, possibly by calmodulin dependent protein kinase II (CaMKII) was required. Conclusions The results demonstrated that the production of OPNc was highly controlled under epigenetic regulations, where MeCP2 and the activation of nuclear calcium signaling were involved. It was also suggested that OPNc could transmit the stress signal of cells upon chemotherapy in TME and promoted the survival of adjacent colon cancer cells.

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Section: Discussionsupporting

confidence: 55%

Epigenetic regulation of osteopontin splicing isoform c defines its role as a microenvironmental factor to promote the survival of colon cancer cells from 5-FU treatment

et al. 2020

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“…This indicates a potential link between epigenetic regulation and the predominantly co-transcriptional occurrence of AS. Thus far, H3K36me3 [ 44 , 45 ], H3K4me3 [ 42 ], H3K9me3 [ 43 ], and the acetylation of H3 and H4 [ 46 – 50 ] have been revealed to regulate AS, either via the chromatin-adapter systems or by altering Pol II elongation rate. Here, we investigated the extent to which the HMs could associate with AS by integrative analyses on both transcriptome and epigenome data during hESC differentiation.…”

Section: Discussionmentioning

confidence: 99%

“…In addition to above roles in determining transcripts abundance, HMs are emerging as major regulators to define the transcripts structure by determining how the genome is spliced when being transcribed, adding another layer of regulatory complexity beyond the genetic splicing code [ 41 ]. A number of HMs, such as H3K4me3 [ 42 ], H3K9me3 [ 43 ], H3K36me3 [ 44 , 45 ], and hyperacetylation of H3 and H4 [ 46 – 50 ], have been proven to regulate AS by either directly recruiting chromatin-associated factors and SFs or indirectly modulating transcriptional elongation rate [ 38 ]. Together, these studies reveal that HMs determine not only what parts of the genome are expressed, but also how they are spliced.…”

Section: Introductionmentioning

confidence: 99%

Alternative splicing links histone modifications to stem cell fate decision

Zhao

Olson

et al. 2018

Genome Biol

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BackgroundUnderstanding the embryonic stem cell (ESC) fate decision between self-renewal and proper differentiation is important for developmental biology and regenerative medicine. Attention has focused on mechanisms involving histone modifications, alternative pre-messenger RNA splicing, and cell-cycle progression. However, their intricate interrelations and joint contributions to ESC fate decision remain unclear.ResultsWe analyze the transcriptomes and epigenomes of human ESC and five types of differentiated cells. We identify thousands of alternatively spliced exons and reveal their development and lineage-dependent characterizations. Several histone modifications show dynamic changes in alternatively spliced exons and three are strongly associated with 52.8% of alternative splicing events upon hESC differentiation. The histone modification-associated alternatively spliced genes predominantly function in G2/M phases and ATM/ATR-mediated DNA damage response pathway for cell differentiation, whereas other alternatively spliced genes are enriched in the G1 phase and pathways for self-renewal. These results imply a potential epigenetic mechanism by which some histone modifications contribute to ESC fate decision through the regulation of alternative splicing in specific pathways and cell-cycle genes. Supported by experimental validations and extended datasets from Roadmap/ENCODE projects, we exemplify this mechanism by a cell-cycle-related transcription factor, PBX1, which regulates the pluripotency regulatory network by binding to NANOG. We suggest that the isoform switch from PBX1a to PBX1b links H3K36me3 to hESC fate determination through the PSIP1/SRSF1 adaptor, which results in the exon skipping of PBX1.ConclusionWe reveal the mechanism by which alternative splicing links histone modifications to stem cell fate decision.Electronic supplementary materialThe online version of this article (10.1186/s13059-018-1512-3) contains supplementary material, which is available to authorized users.

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“…However, inhibition of histone acetyltransferase (HAT) activity by inhibitors C646 and HAT inhibitor VII revealed no significant changes in intron 4 inclusion ( Fig 2C ) in FD cells. Because histone acetylation has been correlated with transcriptional activation and alternative splicing changes [ 16 – 22 ], we suggested that histone acetylation on GLA intron 4 might be involved in transcriptional activation rather than pre-mRNA splicing regulation. Further studies are needed to elucidate which modification on histone H3 is involved in the regulation of GLA alternative splicing.…”

Section: Resultsmentioning

confidence: 99%

Modulation the alternative splicing of GLA (IVS4+919G>A) in Fabry disease

Chang

Niu

et al. 2017

PLoS ONE

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While a base substitution in intron 4 of GLA (IVS4+919G>A) that causes aberrant alternative splicing resulting in Fabry disease has been reported, its molecular mechanism remains unclear. Here we reported that upon IVS4+919G>A transversion, H3K36me3 was enriched across the alternatively spliced region. PSIP1, an adapter of H3K36me3, together with Hsp70 and NONO were recruited and formed a complex with SF2/ASF and SRp20, which further promoted GLA splicing. Amiloride, a splicing regulator in cancer cells, could reverse aberrant histone modification patterns and disrupt the association of splicing complex with GLA. It could also reverse aberrant GLA splicing in a PP1-dependant manner. Our findings revealed the alternative splicing mechanism of GLA (IVS4+919G>A), and a potential treatment for this specific genetic type of Fabry disease by amiloride in the future.

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Histone hyperacetylation and exon skipping: a calcium-mediated dynamic regulation in cardiomyocytes

Cited by 8 publications

References 39 publications

Epigenetic regulation of osteopontin splicing isoform c defines its role as a microenvironmental factor to promote the survival of colon cancer cells from 5-FU treatment

Epigenetic regulation of osteopontin splicing isoform c defines its role as a microenvironmental factor to promote the survival of colon cancer cells from 5-FU treatment

Alternative splicing links histone modifications to stem cell fate decision

Modulation the alternative splicing of GLA (IVS4+919G>A) in Fabry disease

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