T-cell-specific deletion of Mof blocks their differentiation and results in genomic instability in mice

Gupta, A.; Hunt, Clayton R.; Pandita, Raj K.; Pae, Juhee; Komal, Khushbu; Singh, Mayank; Shay, Jerry W.; Kumar, Rakesh; Ariizumi, Kiyoshi; Horikoshi, Nobuo; Hittelman, Walter N.; Guha, Chandan; Ludwig, Thomas; Pandita, Tej K.

doi:10.1093/mutage/ges080

Cited by 36 publications

(40 citation statements)

References 37 publications

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“…Purkinje cell-specific deletion of mouse MOF causes loss of these cells (Kumar et al, 2011). Ablation of MOF specifically in mouse T cells leads to defective cell differentiation and reduces T cell number and thymus size (Gupta et al, 2013). In mouse podocytes, MOF is required for cell-cycle progression in proliferating cells but is dispensable for terminally differentiated, postmitotic cells.…”

Section: Discussionmentioning

confidence: 99%

MOF Acetylates the Histone Demethylase LSD1 to Suppress Epithelial-to-Mesenchymal Transition

Luo

Shenoy

et al. 2016

Cell Reports

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The histone demethylase LSD1 facilitates epithelial-to-mesenchymal transition (EMT) and tumor progression by repressing epithelial marker expression. However, little is known about how its function may be modulated. Here, we report that LSD1 is acetylated in epithelial but not mesenchymal cells. Acetylation of LSD1 reduces its association with nucleosomes, thus increasing histone H3K4 methylation at its target genes and activating transcription. The MOF acetyltransferase interacts with LSD1 and is responsible for its acetylation. MOF is preferentially expressed in epithelial cells and is downregulated by EMT-inducing signals. Expression of exogenous MOF impedes LSD1 binding to epithelial gene promoters and histone demethylation, thereby suppressing EMT and tumor invasion. Conversely, MOF depletion enhances EMT and tumor metastasis. In human cancer, high MOF expression correlates with epithelial markers and a favorable prognosis. These findings provide insight into the regulation of LSD1 and EMT and identify MOF as a critical suppressor of EMT and tumor progression.

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Section: Discussionmentioning

confidence: 99%

MOF Acetylates the Histone Demethylase LSD1 to Suppress Epithelial-to-Mesenchymal Transition

Luo

Shenoy

et al. 2016

Cell Reports

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“…Another laboratory also independently reported that Mof is essential for the progression of embryonic development past the blastocyst stage and is also required for normal chromatin architecture (85). In subsequent studies, histone acetyltransferase MOF was found to be a key regulator of the embryonic stem cell core transcriptional network and for the survival of post-mitotic Purkinje or T-cells (80, 81). Embryonic stem cells with Mof deletion lose characteristic morphology, alkaline phosphate staining, and differentiation potential.…”

Section: Dna Damage Responsementioning

confidence: 99%

Pluripotent Stem Cells and DNA Damage Response to Ionizing Radiations

et al. 2016

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Pluripotent stem cells (PSCs) hold great promise in regenerative medicine, disease modeling, functional genomics, toxicological studies and cell-based therapeutics due to their unique characteristics of self-renewal and pluripotency. Novel methods for generation of pluripotent stem cells and their differentiation to the specialized cell types such as neuronal cells, myocardial cells, hepatocytes, and beta cells of the pancreas and many other cells of the body are constantly being refined. Pluripotent stem cell derived differentiated cells, including neuronal cells or cardiac cells are ideal for stem cell transplantation as autologous or allogeneic cells from healthy donors due to their minimum risks of rejection. DNA damage induced by ionizing radiation (IR), ultraviolet (UV) light, genotoxic stress, and other intrinsic and extrinsic factors trigger a series of biochemical reactions termed as DNA damage response (DDR). In order to maintain genomic stability, and avoid transmission of mutations into progenitors cells, stem cells have robust DNA damage response signaling – a contrast to somatic cells. Stem cell transplantation may over come the late effects related to radiation. This review will particularly focus on differential DNA damage response between stem cells and derived differentiated cells and the possible pathways that determine such differences.

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“…Although a high level of H4K16ac is observed in GV stage oocyte , whether it is necessary for oogenesis is unknown. K (lysine) acetyltransferase 8 (KAT8, also known as MOF or MYST1) is a highly conserved MYST family member specifically responsible for H4K16 acetylation (Gupta et al, 2013). KAT8 contains a chromodomain for DNA binding and a C-terminal HAT domain for histone acetylation (Su et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Histone acetyltransferase KAT8 is essential for mouse oocyte development by regulating ROS levels

Yin

Jiang

et al. 2017

Development

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Proper oocyte development is crucial for female fertility and requires timely and accurate control of gene expression. K (lysine) acetyltransferase 8 (KAT8), an important component of the X chromosome dosage compensation system in Drosophila, regulates gene activity by acetylating histone H4 preferentially at lysine 16. To explore the function of KAT8 during mouse oocyte development, we crossed Kat8 flox/flox mice with Gdf9-Cre mice to specifically delete Kat8 in oocytes. Oocyte Kat8 deletion resulted in female infertility, with follicle development failure in the secondary and preantral follicle stages. RNA-seq analysis revealed that Kat8 deficiency in oocytes results in significant downregulation of antioxidant genes, with a consequent increase in reactive oxygen species. Intraperitoneal injection of the antioxidant N-acetylcysteine rescued defective follicle and oocyte development resulting from Kat8 deficiency. Chromatin immunoprecipitation assays indicated that KAT8 regulates antioxidant gene expression by direct binding to promoter regions. Taken together, our findings demonstrate that KAT8 is essential for female fertility by regulating antioxidant gene expression and identify KAT8 as the first histone acetyltransferase with an essential function in oogenesis.

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T-cell-specific deletion of Mof blocks their differentiation and results in genomic instability in mice

Abstract: Ataxia telangiectasia patients develop lymphoid malignancies of both B-and T-cell origin. Similarly, ataxia telangiectasia mutated (Atm)-

Cited by 36 publications

References 37 publications

MOF Acetylates the Histone Demethylase LSD1 to Suppress Epithelial-to-Mesenchymal Transition

MOF Acetylates the Histone Demethylase LSD1 to Suppress Epithelial-to-Mesenchymal Transition

Pluripotent Stem Cells and DNA Damage Response to Ionizing Radiations

Histone acetyltransferase KAT8 is essential for mouse oocyte development by regulating ROS levels

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