Histone chaperone APLF regulates induction of pluripotency in murine fibroblasts

Syed, Khaja Mohieddin; Joseph, Sunu; Mukherjee, Amitava; Majumder, Aditi; Teixeira, Jose M.; Dutta, Debasree; Pillai, M. Radhakrishna

doi:10.1242/jcs.194035

Cited by 15 publications

(18 citation statements)

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“…a MDAMB-231 cells were transduced with lentiviral particles expressing shRNA against APLF or empty pLKO.1 vector (empty vector). Lentiviral vectors containing shRNA targeting human APLF was cloned in the pLKO.1 (Addgene) vector [ 1 ]. Extent of knockdown was measured at the protein level by western blot.…”

Section: Results and Discussionmentioning

confidence: 99%

“…Interestingly, histone variant MacroH2A.1, a repressive chromatin mark, could regulate the Cyclin D1 expression in different types of cancer including melanoma and osteosarcoma. APLF could recruit MacroH2A.1 at DNA damage site [ 3 ] as well as within the promoters of transcription factor associated with EMT [ 1 ]. Upon downregulation of APLF, significant enrichment of MACROH2A.1 was observed at the CYCLIN D1 promoter in APLF-kd cells in comparison to control cells (Additional file 1 : Figure S4G).…”

Section: Results and Discussionmentioning

confidence: 99%

“…Recently, we demonstrated that reduced expression of histone chaperone APLF could enhance the kinetics and efficiency of reprogramming of mouse embryonic fibroblasts to induced pluripotent stem cells [ 1 ]. APLF act as a DNA repair factor involved in non- homologous end joining (NHEJ) mediated repair of DNA double strand breaks (DSBs) [ 2 ].…”

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confidence: 99%

“…As a histone chaperone, APLF specifically bind to histones H3/H4 tetramer and could recruit variants of histone H2A at the damaged sites on DNA [ 3 ]. We demonstrated that APLF downregulation augmented mesenchymal-to-epithelial transition (MET) associated with cellular reprogramming of mouse embryonic fibroblasts [ 1 ]. Thus, we hypothesized that APLF could induce the reverse phenomenon, epithelial-to-mesenchymal transition (EMT).…”

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Enhanced expression of histone chaperone APLF associate with breast cancer

et al. 2018

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DNA damage-specific histone chaperone Aprataxin PNK-like factor (APLF) regulates mesenchymal-to-epithelial transition (MET) during cellular reprogramming. We investigated the role of APLF in epithelial-to-mesenchymal transition (EMT) linked to breast cancer invasiveness and metastasis. Here, we show that a significant manifestation of APLF is present in tumor sections of patients with invasive ductal carcinoma when compared to their normal adjacent tissues. APLF was significantly induced in triple negative breast cancer (TNBC) cells, MDAMB-231, in comparison to invasive MCF7 or normal MCF10A breast cells and supported by studies on invasive breast carcinoma in The Cancer Genome Atlas (TCGA). Functionally, APLF downregulation inhibited proliferative capacity, altered cell cycle behavior, induced apoptosis and impaired DNA repair ability of MDAMB-231 cells. Reduction in APLF level impeded invasive, migratory, tumorigenic and metastatic potential of TNBC cells with loss in expression of genes associated with EMT while upregulation of MET-specific gene E-cadherin (CDH1). So, here we provided novel evidence for enrichment of APLF in breast tumors, which could regulate metastasis-associated EMT in invasive breast cancer. We anticipate that APLF could be exploited as a biomarker for breast tumors and additionally could be targeted in sensitizing cancer cells towards DNA damaging agents.Electronic supplementary materialThe online version of this article (10.1186/s12943-018-0826-9) contains supplementary material, which is available to authorized users.

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Section: Results and Discussionmentioning

confidence: 99%

Section: Results and Discussionmentioning

confidence: 99%

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Enhanced expression of histone chaperone APLF associate with breast cancer

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“…It could bind to histone H3/H4 and as well as the repressive MacroH2A variants [34]. We observed that the level of APLF was almost undetectable in mouse ESCs whereas, a significant expression was evident in the mouse embryonic fibroblasts (MEFs) [35]. On downregulation of APLF, the efficiency of reprogramming of MEFs to iPSCs was significantly enhanced to~10 times.…”

Section: Aplf: a Barrier Of Reprogrammingmentioning

confidence: 94%

Histone Chaperones Regulate Mammalian Gene Expression

Dutta¹,

Syed²,

Mukherjee³

2018

Gene Expression and Regulation in Mammalian Cells - Transcription Toward the Establishment of Novel Therapeutics

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Histone chaperones are fundamental molecules that aid in the synthesis, translocation, and exchange of histones across the barrier of cytoplasm to nucleus. Regulation in repair, replication, and nucleosome assembly constitute the widely associated functions of histone chaperones. Recently, they have been associated with transcriptional regulation. Different stages of mammalian development have been correlated to the expression of histone chaperones. From oocyte and sperm till the formation and development of zygote, different histone chaperones demonstrated distinct regulatory roles. Efficient models of studying mammalian development include differentiation of embryonic stem cells (ESCs) to different lineages. Both in vitro and in vivo differentiation of mammalian cells exhibit regulation by different subtypes of histone chaperones. Due to the ethical issues concerning the use of embryos for the derivation of ESCs, induced pluripotent stem cells (iPSCs) were derived from pre-existing differentiated cells by a phenomenon called cellular reprogramming. Cellular reprogramming is characterized by erasure of pre-existing epigenetic signature to a new modulated epigenome. Histone chaperones serve as either facilitator or barrier to reprogramming. Here, we will discuss how histone chaperones could regulate the gene expression pattern by regulating epigenetic modification during the complex process of mammalian development and reprogramming.

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