Haematopoietic stem cell-dependent Notch transcription is mediated by p53 through the Histone chaperone Supt16h

Espanola, Sophia; Song, Hyemin; Ryu, Eunjin; Saxena, Aditya; Kim, Eun Sun; Manegold, Jennifer E.; Nasamran, Chanond A; Sahoo, Debashis; Oh, Chang‐Kyu; Bickers, Cara; Shin, Unbeom; Grainger, Stephanie; Park, Yong Hwan; Pandolfo, Lauren; Kang, Mi-Sun; Kang, Sung-Myung; Myung, Kyungjae; Cooper, Kimberly L.; Yelon, Deborah; Traver, David; Lee, Yoonsung

doi:10.1038/s41556-020-00604-7

Cited by 10 publications

(3 citation statements)

References 64 publications

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“…Subsequently, the resulting Runx1 + 23 enhancer DNA fragment and the β-globin minimal promoter were simultaneously cloned into the Tol2 plasmid. These HSC-specific transgenic lines have been used to study embryonic HSC emergence [ 88 , 114 – 116 ], thrombocyte development [ 117 ], environmental regulation of HSCs [ 110 ], mechanosensory regulation of HSC specification [ 118 , 119 ], brain development related to DNA damage [ 120 ] and leukemia [ 121 ].…”

Section: Main Textmentioning

confidence: 99%

Transgenic fluorescent zebrafish lines that have revolutionized biomedical research

et al. 2021

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Since its debut in the biomedical research fields in 1981, zebrafish have been used as a vertebrate model organism in more than 40,000 biomedical research studies. Especially useful are zebrafish lines expressing fluorescent proteins in a molecule, intracellular organelle, cell or tissue specific manner because they allow the visualization and tracking of molecules, intracellular organelles, cells or tissues of interest in real time and in vivo. In this review, we summarize representative transgenic fluorescent zebrafish lines that have revolutionized biomedical research on signal transduction, the craniofacial skeletal system, the hematopoietic system, the nervous system, the urogenital system, the digestive system and intracellular organelles.

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Section: Main Textmentioning

confidence: 99%

Transgenic fluorescent zebrafish lines that have revolutionized biomedical research

et al. 2021

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“…The main functions of these factors are to maintain pluripotency and prevent improper differentiation through regulation of gene expression; however, a majority of their chromatin interactions occur at gene-distal genomic regions such as enhancers [66]. FACT has been shown to interact with several pluripotency-and development-associated factors, including OCT4 [60,61], WNT [67], and NOTCH [60,61,68]. In addition, FACT has been functionally implicated in maintaining stem cells in their undifferentiated state [44,45,47].…”

Section: Introductionmentioning

confidence: 99%

FACT regulates pluripotency through proximal and distal regulation of gene expression in murine embryonic stem cells

et al. 2023

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Background The FACT complex is a conserved histone chaperone with critical roles in transcription and histone deposition. FACT is essential in pluripotent and cancer cells, but otherwise dispensable for most mammalian cell types. FACT deletion or inhibition can block induction of pluripotent stem cells, yet the mechanism through which FACT regulates cell fate decisions remains unclear. Results To explore the mechanism for FACT function, we generated AID-tagged murine embryonic cell lines for FACT subunit SPT16 and paired depletion with nascent transcription and chromatin accessibility analyses. We also analyzed SPT16 occupancy using CUT&RUN and found that SPT16 localizes to both promoter and enhancer elements, with a strong overlap in binding with OCT4, SOX2, and NANOG. Over a timecourse of SPT16 depletion, nucleosomes invade new loci, including promoters, regions bound by SPT16, OCT4, SOX2, and NANOG, and TSS-distal DNaseI hypersensitive sites. Simultaneously, transcription of Pou5f1 (encoding OCT4), Sox2, Nanog, and enhancer RNAs produced from these genes’ associated enhancers are downregulated. Conclusions We propose that FACT maintains cellular pluripotency through a precise nucleosome-based regulatory mechanism for appropriate expression of both coding and non-coding transcripts associated with pluripotency.

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“…These transcription factors, along with chromatin modifiers, form the foundation of gene regulation and provide a molecular basis for pluripotency. FACT has been shown to interact with several pluripotency-and development-associated factors, including OCT4 (Ding et al, 2012;Pardo et al, 2010), WNT (Hossan et al, 2016), and NOTCH (Espanola et al, 2020); in particular, affinity mass spectrometry has demonstrated a direct, physical interaction between FACT and OCT4 (Ding et al, 2012;Pardo et al, 2010). In addition, FACT has recently been functionally implicated in maintaining stem cells in their undifferentiated state (Kolundzic et al, 2018;Mylonas and Tessarz, 2018;Shen et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

FACT regulates pluripotency through distal regulation of gene expression in murine embryonic stem cells

Klein¹,

Lardo²,

Hainer³

2021

Preprint

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The mammalian FACT complex is a highly conserved histone chaperone with essential roles in transcription elongation, histone deposition, and maintenance of stem cell state. FACT is essential for viability in pluripotent cells and cancer cells, but otherwise dispensable for most mammalian cell types. FACT deletion or inhibition can block reprogramming of fibroblasts to induced pluripotent stem cells, yet the molecular mechanisms through which FACT regulates cell fate decisions remain unclear. To determine the mechanism by which FACT regulates stem cell identity, we used the auxin-inducible degron systems to deplete murine embryonic stem cells of FACT subunit SPT16 and subjected depleted cells to genome-wide factor localization, nascent transcription analyses, and genome-wide nucleosome profiling. Inducible depletion of SPT16 reveals a critical role in regulating targets of the master regulators of pluripotency: OCT4, KLF4, MYC, NANOG, and SOX2. Depletion of SPT16 leads to increased nucleosome occupancy at genomic loci occupied by these transcription factors, as well as gene-distal regulatory sites defined by DNaseI hypersensitivity. This heightened occupancy suggests a mechanism of nucleosome filling, wherein the sites typically maintained in an accessible state by FACT are occluded through loss of FACT-regulated nucleosome spacing. 20% of transcription arising from gene-distal regions bound by these factors is directly dependent on FACT, and putative gene targets of these non-coding RNAs are highly enriched for pluripotency in pathway analyses. Upon FACT depletion, transcription of Pou5f1 (OCT4), Sox2, and Nanog are downregulated, suggesting that FACT not only co-regulates expression of the encoded proteins' targets, but also the pluripotency factors themselves. We find that FACT maintains cellular pluripotency through a complex regulatory network of both coding and non-coding transcription.

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Haematopoietic stem cell-dependent Notch transcription is mediated by p53 through the Histone chaperone Supt16h

Cited by 10 publications

References 64 publications

Transgenic fluorescent zebrafish lines that have revolutionized biomedical research

Transgenic fluorescent zebrafish lines that have revolutionized biomedical research

FACT regulates pluripotency through proximal and distal regulation of gene expression in murine embryonic stem cells

FACT regulates pluripotency through distal regulation of gene expression in murine embryonic stem cells

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