Arsenic Induces Polyadenylation of Canonical Histone mRNA by Down-regulating Stem-Loop-binding Protein Gene Expression

Brocato, Jason; Fang, Lei; Chervona, Yana; Chen, Danqi; Kiok, Kathrin; Sun, Hong; Tseng, Hsiang-Chi; Xu, Da-Zhong; Shamy, Magdy; Jin, Chunyuan; Costa, Max

doi:10.1074/jbc.m114.591883

Cited by 38 publications

(60 citation statements)

References 64 publications

(70 reference statements)

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“…Recent studies have highlighted the role of iAs on the expression of histones. Arsenic exposure induced the polyadenylation of the canonical histone mRNAs, which otherwise do not have this tail (79). Implicated as a possible mechanism is the depletion of the stem-loop binding protein by iAs.…”

Section: Discussionmentioning

confidence: 99%

Quantitative Mass Spectrometry Reveals Changes in Histone H2B Variants as Cells Undergo Inorganic Arsenic-Mediated Cellular Transformation

Rea

Eleazer

Eckstein

et al. 2016

Molecular & Cellular Proteomics

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Exposure to inorganic arsenic, a ubiquitous environmental toxic metalloid, leads to carcinogenesis. However, the mechanism is unknown. Several studies have shown that inorganic arsenic exposure alters specific gene expression patterns, possibly through alterations in chromatin structure. While most studies on understanding the mechanism of chromatin-mediated gene regulation have focused on histone post-translational modifications, the role of histone variants remains largely unknown. Incorporation of histone variants alters the functional properties of chromatin. To understand the global dynamics of chromatin structure and function in arsenic-mediated carcinogenesis, analysis of the histone variants incorporated into the nucleosome and their covalent modifications is required. Here we report the first global mass spectrometric analysis of histone H2B variants as cells undergo arsenic-mediated epithelial to mesenchymal transition. We used electron capture dissociation-based top-down tandem mass spectrometry analysis validated with quantitative reverse transcription real-time polymerase chain reaction to identify changes in the expression levels of H2B variants in inorganic arsenic-mediated epithelial-mesenchymal transition. We identified changes in the expression levels of specific histone H2B variants in two cell types, which are dependent on dose and length of exposure of inorganic arsenic. In particular, we found increases in H2B variants H2B1H/1K/1C/1J/1O and H2B2E/2F, and significant decreases in H2B1N/1D/1B as cells undergo inorganic arsenic-mediated epithelial-mesenchymal transition. The analysis of these histone vari-

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Section: Discussionmentioning

confidence: 99%

Quantitative Mass Spectrometry Reveals Changes in Histone H2B Variants as Cells Undergo Inorganic Arsenic-Mediated Cellular Transformation

Rea

Eleazer

Eckstein

et al. 2016

Molecular & Cellular Proteomics

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“…Gene expression profiles were analyzed using 1.0 ST Affymetrix gene chips and results validated by Real-time reverse polymerase chain reaction (qRT-PCR). Surprisingly, we found that 90% of all histone genes were induced in the arsenic-treated PBMCs, and 8% of all the induced genes were histone genes [37]. …”

Section: Arsenic Exposure Causes Aberrant Polyadenylation Of H31 mentioning

confidence: 99%

“…As mentioned earlier, canonical histone mRNAs do not contain a poly(A) tail, which provides a feature that increases the half-life and stability of the mRNA. To investigate if histone mRNAs were acquiring a poly(A) tail due to arsenic exposure, a Northern blot was performed to examine H3.1 mRNA structure [37]. Bronchial epithelial lung cells (BEAS-2B) were utilized because of the known association of arsenic exposure and lung cancer [38] as well as the ability of this cell line to undergo malignant transformation after metal exposure [39–42].…”

Section: Arsenic Exposure Causes Aberrant Polyadenylation Of H31 mentioning

confidence: 99%

A Potential New Mechanism of Arsenic Carcinogenesis: Depletion of Stem-Loop Binding Protein and Increase in Polyadenylated Canonical Histone H3.1 mRNA

Brocato

Chen

Liu

et al. 2015

Biol Trace Elem Res

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Canonical histones are synthesized with a peak in S-phase, whereas histone variants are formed throughout the cell cycle. Unlike messenger RNA (mRNA) for all other genes with a poly(A) tail, canonical histone mRNAs contain a stem-loop structure at their 3’-ends. This stem-loop structure is the binding site for the stem-loop binding protein (SLBP), a protein involved in canonical histone mRNA processing. Recently, we found that arsenic depletes SLBP by enhancing its proteasomal degradation and epigenetically silencing the promoter of the SLBP gene. The loss of SLBP disrupts histone mRNA processing and induces aberrant polyadenylation of canonical histone H3.1 mRNA. Here, we present new data supporting the idea that the lack of SLBP allows the H3.1 mRNA to be polyadenylated using the downstream poly(A) signal. SLBP was also depleted in arsenic-transformed bronchial epithelial cells (BEAS-2B), which led us to hypothesize the involvement of SLBP and polyadenylated H3.1 mRNA in carcinogenesis. Here, for the first time, we report that overexpression of H3.1 polyadenylated mRNA and knockdown of SLBP enhances anchorage-independent cell growth. A pcDNA-H3.1 vector with a poly(A) signal sequence was stably transfected into BEAS-2B cells. Polyadenylated H3.1 mRNA and exogenous H3.1 protein levels were significantly increased in cells containing the pcDNA-H3.1 vector. A soft agar assay revealed that cells containing the vector formed significantly higher numbers of colonies compared to wild-type cells. Moreover, small hairpin RNA for SLBP (shSLBP) was used to knockdown the expression of SLBP. Cells stably transfected with the shSLBP vector grew significantly more colonies in soft agar than cells transfected with a control vector. This data suggests that upregulation of polyadenylated H3.1 mRNA holds potential as a mechanism to facilitate carcinogenesis by toxicants such as arsenic that deplete SLBP.

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“…Histone H3.1 transcription levels are highest during S phase, while H3.3 expression levels are consistently low throughout the cell cycle (78)(79)(80)(81)(82)(83). Functionally, histone H3.1 is ubiquitously present in genomic chromatin, while histone H3.3 is incorporated into DNA promoter regions to specifically facilitate transcriptional activation (84,85).…”

Section: Histone Variantsmentioning

confidence: 99%

“…Under normal conditions, SLBP binds to the stem-loop on histone transcripts preventing their degradation. With iAs exposure, SLBP expression levels are reduced allowing more proteasomal degradation of the protein (80,86). With less SLBP present, canonical histone transcripts with the stem loop are degraded, leaving those with a polyadenylated tail (H3.1) intact.…”

Section: Histone Variantsmentioning

confidence: 99%

Epigenomic reprogramming in inorganic arsenic-mediated gene expression patterns during carcinogenesis

Eckstein

Eleazer

Rea

et al. 2017

Reviews on Environmental Health

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Abstract Arsenic is a ubiquitous metalloid that is not mutagenic but is carcinogenic. The mechanism(s) by which arsenic causes cancer remain unknown. To date, several mechanisms have been proposed, including the arsenic-induced generation of reactive oxygen species (ROS). However, it is also becoming evident that inorganic arsenic (iAs) may exert its carcinogenic effects by changing the epigenome, and thereby modifying chromatin structure and dynamics. These epigenetic changes alter the accessibility of gene regulatory factors to DNA, resulting in specific changes in gene expression both at the levels of transcription initiation and gene splicing. In this review, we discuss recent literature reports describing epigenetic changes induced by iAs exposure and the possible epigenetic mechanisms underlying these changes.

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Arsenic Induces Polyadenylation of Canonical Histone mRNA by Down-regulating Stem-Loop-binding Protein Gene Expression

Cited by 38 publications

References 64 publications

Quantitative Mass Spectrometry Reveals Changes in Histone H2B Variants as Cells Undergo Inorganic Arsenic-Mediated Cellular Transformation

Quantitative Mass Spectrometry Reveals Changes in Histone H2B Variants as Cells Undergo Inorganic Arsenic-Mediated Cellular Transformation

A Potential New Mechanism of Arsenic Carcinogenesis: Depletion of Stem-Loop Binding Protein and Increase in Polyadenylated Canonical Histone H3.1 mRNA

Epigenomic reprogramming in inorganic arsenic-mediated gene expression patterns during carcinogenesis

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