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Differential regulation and predictive potential of MacroH2A1 isoforms in colon cancer.

ABSTRACT: Histone variant macroH2A1 has two splice isoforms, macroH2A1.1 and macroH2A1.2, with tissue- and cell-specific expression patterns. Although macroH2A1.1 is mainly found in differentiated, nonproliferative tissues, macroH2A1.2 is more generally expressed, including in tissues with ongoing cell proliferation. Consistently, studies in breast and lung cancer have demonstrated a strong correlation between macroH2A1.1 levels and proliferation, which is not the case for macroH2A1.2. This is the first study to assess the differential regulation and predictive potential of macroH2A1 isoforms in colon cancer. We found that macroH2A1.1 mRNA was down-regulated in primary colorectal cancer samples compared to matched normal colon tissue, whereas macroH2A1.2 was up-regulated. At the protein level, down-regulation of macroH2A1.1 correlated significantly with patient outcome (P = 0.0012), and loss of macroH2A1.1 was associated with a worse outcome. Over the course of Caco-2 cell differentiation, macroH2A1.1 was up-regulated at both the RNA and protein levels, whereas macroH2A1.2 was slightly down-regulated at the RNA level and stable at the protein level. These changes were accompanied by an antiproliferative phenotype exhibiting features of cellular senescence. Loss of macroH2A1.1 in vitro was characterized by a phenotype associated with cell growth and metastasis. These data demonstrate that macroH2A1 isoforms are differentially regulated in colon cancer, reflecting the degree of cellular differentiation. Notably, macroH2A1.1 expression predicts survival in colon cancer, thus identifying macroH2A1.1 as a novel colon cancer biomarker.

SUBMITTER: Sporn JC

PROVIDER: S-EPMC3717782 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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Differential regulation and predictive potential of MacroH2A1 isoforms in colon cancer.

Sporn Judith C JC Jung Barbara B

The American journal of pathology 20120427 6

Histone variant macroH2A1 has two splice isoforms, macroH2A1.1 and macroH2A1.2, with tissue- and cell-specific expression patterns. Although macroH2A1.1 is mainly found in differentiated, nonproliferative tissues, macroH2A1.2 is more generally expressed, including in tissues with ongoing cell proliferation. Consistently, studies in breast and lung cancer have demonstrated a strong correlation between macroH2A1.1 levels and proliferation, which is not the case for macroH2A1.2. This is the first s ...[more]

PMID: 22542848

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Project description:Background: Gene expression in eukaryotic cells can be governed by histone variants, which replace replication-coupled histones, conferring unique chromatin properties. MacroH2A1 is a histone H2A variant containing a domain highly similar to H2A and a large non-histone (macro) domain. MacroH2A1, in turn, is present in two alternatively exon-spliced isoforms: macroH2A1.1 and macroH2A1.2, which regulate cell plasticity and proliferation in a remarkably distinct manner. The N-terminal and the C-terminal tails of H2A histones stem from the nucleosome core structure and can be target sites for several post-translational modifications (PTMs). MacroH2A1.1 and macroH2A1.2 isoforms differ only in a few amino acids and their ability to bind NAD-derived metabolites, a property allegedly conferring their different functions in vivo. Some of the modifications on the macroH2A1 variant have been identified, such as phosphorylation (T129, S138) and methylation (K18, K123, K239). However, no study to our knowledge has analyzed extensively, and in parallel, the PTM pattern of macroH2A1.1 and macroH2A1.2 in the same experimental setting, which could facilitate the understanding of their distinct biological functions in health and disease. Methods: We used a mass spectrometry-based approach to identify the sites for phosphorylation, acetylation, and methylation in green fluorescent protein (GFP)-tagged macroH2A1.1 and macroH2A1.2 expressed in human hepatoma cells. The impact of selected PTMs on macroH2A1.1 and macroH2A1.2 structure and function are demonstrated using computational analyses. Results: We identified K7 as a new acetylation site in both macroH2A1 isoforms. Quantitative comparison of histone marks between the two isoforms revealed significant differences in the levels of phosphorylated T129 and S170. Our computational analysis provided evidence that the phosphorylation status in the intrinsically disordered linker region in macroH2A1 isoforms might represent a key regulatory element contributing to their distinct biological responses. Conclusions: Taken together, our results report different PTMs on the two macroH2A1 splicing isoforms as responsible for their distinct features and distribution in the cell.

Dataset Information

Differential regulation and predictive potential of MacroH2A1 isoforms in colon cancer.

Publications

Differential regulation and predictive potential of MacroH2A1 isoforms in colon cancer.

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