AID stabilizes stem-cell phenotype by removing epigenetic memory of pluripotency genes

Kumar, Ritu; DiMenna, Lauren J.; Schrode, Nadine; Liu, Ting Chun; Franck, Philipp; Muñoz-Descalzo, Silvia; Hadjantonakis, Anna-Katerina; Zarrin, Ali A.; Chaudhuri, Jayanta; Elemento, Olivier; Evans, Todd

doi:10.1038/nature12299

Cited by 85 publications

(97 citation statements)

References 27 publications

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“…[5][6][7][8][9] Deletion of Tet2 in the hematopoietic compartment leads to enhanced HSC self-renewal and skewed differentiation toward myelomonocytic lineage in mice. [14][15][16] AID has also been reported to stabilize the pluripotent state in iPSC reprogramming, 19 demonstrating that AID is a critical player in stem cell biology. Taken together, these studies led us to hypothesize that AID might also regulate the hematopoietic system, especially in terms of HSC self-renewal and differentiation.…”

Section: Discussionmentioning

confidence: 99%

“…18 In addition, AID was reported to stabilize the pluripotent state in induced pluripotent stem cells (iPSCs) by removing epigenetic memory of pluripotency genes, suggesting the essential role of AID in iPSC reprogramming. 19 Given that AID has multifaceted functions including a role in active DNA demethylation, in lymphomagenesis, and in iPSC regulation, we hypothesized that AID may regulate stem/progenitor self-renewal and differentiation and suppress myeloid transformation. Here, we show that Aid loss in mice leads to alterations in differentiation including increased myeloid expansion and attenuation in erythroid output, but does not induce alterations in self-renewal or in susceptibility to transformation.…”

Section: Wtmentioning

confidence: 99%

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Aid is a key regulator of myeloid/erythroid differentiation and DNA methylation in hematopoietic stem/progenitor cells

Kunimoto¹,

McKenney

Meydan

et al. 2017

Blood

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• Aid loss leads to altered differentiation, transcription, and methylation in specific genetic loci in hematopoietic stem/progenitor cells.• Aid loss does not contribute to enhanced HSC self-renewal or cooperate with Flt3-ITD in myeloid leukemogenesis.Recent studies have reported that activation-induced cytidine deaminase (AID) and teneleven-translocation (TET) family members regulate active DNA demethylation. Genetic alterations of TET2 occur in myeloid malignancies, and hematopoietic-specific loss of Tet2 induces aberrant hematopoietic stem cell (HSC) self-renewal/differentiation, implicating TET2 as a master regulator of normal and malignant hematopoiesis. Despite the functional link between AID and TET in epigenetic gene regulation, the role of AID loss in hematopoiesis and myeloid transformation remains to be investigated. Here, we show that Aid loss in mice leads to expansion of myeloid cells and reduced erythroid progenitors resulting in anemia, with dysregulated expression of Cebpa and Gata1, myeloid/erythroid lineage-specific transcription factors. Consistent with data in the murine context, silencing of AID in human bone marrow cells skews differentiation toward myelomonocytic lineage. However, in contrast to Tet2 loss, Aid loss does not contribute to enhanced HSC self-renewal or cooperate with Flt3-ITD to induce myeloid transformation. Genome-wide transcription and differential methylation analysis uncover the critical role of Aid as a key epigenetic regulator. These results indicate that AID and TET2 share common effects on myeloid and erythroid lineage differentiation, however, their role is nonredundant in regulating HSC self-renewal and in myeloid transformation. (Blood. 2017;129(13):1779-1790

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Section: Discussionmentioning

confidence: 99%

Section: Wtmentioning

confidence: 99%

Aid is a key regulator of myeloid/erythroid differentiation and DNA methylation in hematopoietic stem/progenitor cells

Kunimoto¹,

McKenney

Meydan

et al. 2017

Blood

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“…Nuclear reprogramming events in a heterokaryon cell model was found to depend on DNA synthesis [131] and, to some extent, on the presence of AID, MBD4 and Gadd45 [132,133]. Yet, AID-deficient MEFs could be reprogrammed efficiently to iPSC although the demethylation and, hence, stable expression of induced pluripotency factors was affected [134][135][136][137]. These observations clearly indicate an involvement of AID-initiated BER in nuclear reprogramming but what exactly its contribution is remains uncertain.…”

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confidence: 90%

Active DNA demethylation by DNA repair: Facts and uncertainties

2016

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Pathways that control and modulate DNA methylation patterning in mammalian cells were poorly understood for a long time, although their importance in establishing and maintaining cell type-specific gene expression was well recognized. The discovery of proteins capable of converting 5-methylcytosine (5mC) to putative substrates for DNA repair introduced a novel and exciting conceptual framework for the investigation and ultimate discovery of molecular mechanisms of DNA demethylation. Against the prevailing notion that DNA methylation is a static epigenetic mark, it turned out to be dynamic and distinct mechanisms appear to have evolved to effect global and locus-specific DNA demethylation. There is compelling evidence that DNA repair, in particular base excision repair, contributes significantly to the turnover of 5mC in cells. By actively demethylating DNA, DNA repair supports the developmental establishment as well as the maintenance of DNA methylation landscapes and gene expression patterns. Yet, while the biochemical pathways are relatively well-established and reviewed, the biological context, function and regulation of DNA repair-mediated active DNA demethylation remains uncertain. In this review, we will thus summarize and critically discuss the evidence that associates active DNA demethylation by DNA repair with specific functional contexts including the DNA methylation erasure in the early embryo, the control of pluripotency and cellular differentiation, the maintenance of cell identity, and the nuclear reprogramming.

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“…AID/APOBECs not only promote somatic hypermutation but also regulate gene expression epigenetically by directly deaminating 5-methylcytosine (5mC) or 5-hydroxymethylcytosine (5hmC) in concert with base-excision repair to exchange cytosine, thus promoting gene demethylation and removing epigenetic memory to stabilize the pluripotent state in embryonic stem cells [120,121] . EMT, a driving force behind the development of cancers, in its various forms is driven by the transcription factors Snail (SNAI1), Slug (SNAI2), ZEB1 (ZEB1), and ZEB2 (ZEB2).…”

Section: Aid/apobecs-regulated Demethylation and Emt Are Important Inmentioning

confidence: 99%

Cancer Evo-Dev, a novel hypothesis derived from studies on hepatitis B virus-induced carcinogenesis

Cao¹

2017

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How to cite this article: Cao GW. Cancer Evo-Dev, a novel hypothesis derived from studies on hepatitis B virus-induced carcinogenesis. Hepatoma Res 2017;3:241-59.Non-resolving inflammation, which may be maintained by infection, pollution, and metabolic stimulants and their interactions with immunogenetic predisposition, provides a fertile field for cancer development. This is strongly evident in hepatocellular carcinoma. Here, the framework of a hypothesis called Cancer Evo-Dev is presented, based on the advances in hepatitis B virusinduced hepatocarcinogenesis. Several aspects central to this theory are as follows: (1) immune imbalance caused by the interaction of immunogenetic predispositions and hepatitis B virus infection maintains non-resolving inflammation; (2) active inflammation executants promote mutations in viral and host genomes via disbalancing mutagenic forces including cytidine deaminases and mutation-repairing forces including uracil-DNA glycosylases, thus promoting cancer-related somatic mutations and viral mutations; (3) a small percentage of the cells whose somatic mutations alter the survival signalling adapt to the inflammatory microenvironment, de-differentiate via demethylating role of cytidine deaminases, and reversely develop into tumor-initiating cells (TICs); (4) under the cultivation of some factors like POSTN from tumorinfiltrating fibroblasts and M2 macrophages, TICs acquire the stemness, cancer-stem cells obtain distinct metastatic and drug-resistant potentials under the selection pressure from distinct microenvironments; (5) glycolysis persistence in the presence of oxygen provides essential energy for cell survival and the raw material for DNA synthesis. Thus, cancer development is characterized by an evolutionary process of "mutation-selection-adaptation". The framework of Cancer Evo-Dev can be verified in other cancers. Cancer Evo-Dev lays theoretical foundation for understanding the mechanisms by which inflammation promotes cancer development, and it also plays a role in specific prophylaxis, prediction, and targeted treatment of cancers. Key words:Inflammation, hepatitis B virus, mutations, hepatoma, Cancer Evo-Dev ABSTRACTArticle history:

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AID stabilizes stem-cell phenotype by removing epigenetic memory of pluripotency genes

Cited by 85 publications

References 27 publications

Aid is a key regulator of myeloid/erythroid differentiation and DNA methylation in hematopoietic stem/progenitor cells

Aid is a key regulator of myeloid/erythroid differentiation and DNA methylation in hematopoietic stem/progenitor cells

Active DNA demethylation by DNA repair: Facts and uncertainties

Cancer Evo-Dev, a novel hypothesis derived from studies on hepatitis B virus-induced carcinogenesis

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