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Project description:MacroH2A histone variants have functions in differentiation, somatic cell reprogramming and cancer. However, at present, it is not clear how macroH2As affect gene regulation to exert these functions. We have parted from the initial observation that loss of total macroH2A1 led to a change in the morphology of murine myotubes differentiated ex vivo. The fusion of myoblasts to myotubes is a key process in embryonic myogenesis and highly relevant for muscle regeneration after acute or chronic injury. We have focused on this physiological process, to investigate the functions of the two splice isoforms of macroH2A1. Individual perturbation of the two isoforms in myotubes forming in vitro from myogenic C2C12 cells showed an opposing phenotype, with macroH2A1.1 enhancing, and macroH2A1.2 reducing, fusion. Differential regulation of a subset of fusion-related genes encoding components of the extracellular matrix and cell surface receptors for adhesion correlated with these phenotypes. We describe, for the first time, splice isoform-specific phenotypes for the histone variant macroH2A1 in a physiologic process and provide evidence for a novel underlying molecular mechanism of gene regulation.
| S-EPMC7290658 | biostudies-literature
Project description:MacroH2A histone variants have functions in differentiation, somatic cell reprogramming and cancer. However, at the present it is not clear how macroH2As affect gene regulation to exert these functions. Here, we have addressed the question of whether the two splice isoforms of macroH2A1 differentially regulate genes in a physiological context. We have focused on myotube formation that is a key process in embryonic myogenesis and highly relevant for muscle regeneration after acute or chronic injury. We have parted from the initial observation that loss of total macroH2A1 led to a change in the morphology of myotubes differentiated ex vivo that was indicative of reduced fusion. Individual perturbation of the two isoforms in myotubes forming in vitro from myogenic C2C12 cells showed an opposing phenotype with macroH2A1.1 enhancing and macroH2A1.2 reducing fusion. Transcriptomic analysis allowed us to associate this phenotype with the differential regulation of a subset of fusion-related genes encoding components of the extracellular matrix and cell surface receptors for adhesion. In conclusion, we describe for the first time splice isoform-specific phenotypes for the histone variant macroH2A1 in a physiologic process and provide evidence for a novel, yet unknown underlying molecular mechanism of gene regulation independent of PARP1.
2020-04-03 | GSE148044 | GEO
Project description:MacroH2A histone variants have functions in differentiation, somatic cell reprogramming and cancer. However, at the present it is not clear how macroH2As affect gene regulation to exert these functions. Here, we have addressed the question of whether the two splice isoforms of macroH2A1 differentially regulate genes in a physiological context. We have focused on myotube formation that is a key process in embryonic myogenesis and highly relevant for muscle regeneration after acute or chronic injury. We have parted from the initial observation that loss of total macroH2A1 led to a change in the morphology of myotubes differentiated ex vivo that was indicative of reduced fusion. Individual perturbation of the two isoforms in myotubes forming in vitro from myogenic C2C12 cells showed an opposing phenotype with macroH2A1.1 enhancing and macroH2A1.2 reducing fusion. Transcriptomic analysis allowed us to associate this phenotype with the differential regulation of a subset of fusion-related genes encoding components of the extracellular matrix and cell surface receptors for adhesion. In conclusion, we describe for the first time splice isoform-specific phenotypes for the histone variant macroH2A1 in a physiologic process and provide evidence for a novel, yet unknown underlying molecular mechanism of gene regulation independent of PARP1.
2020-04-03 | GSE147590 | GEO
Project description:The histone variant macroH2A1 regulates key genes for myogenic cell fusion in a splice-isoform dependent manner
| PRJNA622946 | ENA
Project description:The histone variant macroH2A1 regulates key genes for myogenic cell fusion in a splice-isoform dependent manner [ChIP-Seq]
| PRJNA622955 | ENA
Project description:The histone variant macroH2A1 regulates key genes for myogenic cell fusion in a splice-isoform dependent manner [RNA-Seq]
| PRJNA615657 | ENA
Project description:Epithelial-Mesenchymal Transition (EMT) is a biological program that plays key roles in various developmental and pathological processes. Although much work has been done on signaling pathways and transcription factors regulating EMT, the epigenetic regulation of EMT remains not well understood. Histone variants have been recognized as a key group of epigenetic regulators. Among them, macroH2A1 is involved in stem cell reprogramming and cancer progression. We postulated that macroH2A1 may play a role in EMT, a process involving reprogramming of cellular states. In this study, we demonstrate that expression of macroH2A1 is dramatically reduced during EMT induction in immortalized human mammary epithelial cells (HMLE). Moreover, ectopic expression of the macroH2A1.1 isoform, but not macroH2A1.2, can suppress EMT induction and reduce the stem-like cell population in HMLE. Interestingly, macroH2A1.1 overexpression cannot revert stable mesenchymal cells back to the epithelial state, suggesting a stage-specific role of macroH2A1.1 in EMT. We further pinpointed that the function of macroH2A1.1 in EMT suppression is dependent on its ability to bind the NAD+ metabolite PAR, in agreement with the inability to suppress EMT by macroH2A1.2, which lacks the PAR binding domain. Thus, our work discovered a previously unrecognized isoform-specific function of macroH2A1 in regulating EMT induction.
| S-EPMC5770377 | biostudies-literature
Project description:The regulation of ribosomal DNA transcription is an important step for the control of cell growth. Epigenetic marks such as DNA methylation and posttranslational modifications of canonical histones have been involved in this regulation, but much less is known about the role of histone variants. In this work, we show that the histone variant macroH2A1 is present on the promoter of methylated rDNA genes. The inhibition of the expression of macroH2A1 in human HeLa and HepG2 cells and in a mouse ES cell line resulted in an up to 5-fold increase of pre-rRNA levels. This increased accumulation of pre-rRNA is accompanied by an increase of the loading of RNA polymerase I and UBF on the rDNA without any changes in the number of active rDNA genes. The inhibition of RNA polymerase I transcription by actinomycin D or by knocking down nucleolin, induces the recruitment of macroH2A1 on the rDNA and the relocalization of macroH2A1 in the nucleolus. Interestingly, the inhibition of rDNA transcription induced by nucleolin depletion is alleviated by the inactivation of macroH2A1. These results demonstrate that macroH2A1 is a new factor involved in the regulation of rDNA transcription.
| S-EPMC3874179 | biostudies-literature
Project description:Alternative pre-mRNA splicing is a key mechanism for increasing proteomic diversity and modulating gene expression. Emerging evidence indicated that the splicing program is frequently dysregulated during tumorigenesis. Cancer cells produce protein isoforms that can promote growth and survival. The RNA-binding protein QKI5 is a critical regulator of alternative splicing in expanding lists of primary human tumors and tumor cell lines. However, its biological role and regulatory mechanism are poorly defined in gastric cancer (GC) development and progression. In this study, we demonstrated that the downregulation of QKI5 was associated with pTNM stage and pM state of GC patients. Re-introduction of QKI5 could inhibit GC cell proliferation, migration, and invasion in vitro and in vivo, which might be due to the altered splicing pattern of macroH2A1 pre-mRNA, leading to the accumulation of macroH2A1.1 isoform. Furthermore, QKI5 could inhibit cyclin L1 expression via promoting macroH2A1.1 production. Thus, this study identified a novel regulatory axis involved in gastric tumorigenesis and provided a new strategy for GC therapy.
| S-EPMC5078054 | biostudies-literature
Project description:The histone variant macroH2A1 contains a carboxyl-terminal ∼30-kDa domain called a macro domain. MacroH2A1 is produced as one of two alternatively spliced forms, macroH2A1.1 and macroH2A1.2. While the macro domain of macroH2A1.1 can interact with NAD(+)-derived small molecules, such as poly(ADP-ribose), macroH2A1.2's macro domain cannot. Here, we show that changes in the alternative splicing of macroH2A1 pre-mRNA, which lead to a decrease in macroH2A1.1 expression, occur in a variety of cancers, including testicular, lung, bladder, cervical, breast, colon, ovarian, and endometrial. Furthermore, reintroduction of macroH2A1.1 suppresses the proliferation of lung and cervical cancer cells in a manner that requires the ability of macroH2A1.1 to bind NAD(+)-derived metabolites. MacroH2A1.1-mediated suppression of proliferation occurs, at least in part, through the reduction of poly(ADP-ribose) polymerase 1 (PARP-1) protein levels. By analyzing publically available expression and splicing microarray data, we identified splicing factors that correlate with alterations in macroH2A1 splicing. Using RNA interference, we demonstrate that one of these factors, QKI, regulates the alternative splicing of macroH2A1 pre-mRNA, resulting in increased levels of macroH2A1.1. Finally, we demonstrate that QKI expression is significantly reduced in many of the same cancer types that demonstrate a reduction in macroH2A1.1 splicing.
| S-EPMC3187283 | biostudies-literature