Browsing by Author "HogenEsch, Harm"

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    The epigenetic regulator CXXC finger protein 1 is essential for murine hematopoiesis
    (PLoS, 2014-12-03) Chun, Kristin T.; Li, Binghui; Dobrota, Erika; Tate, Courtney; Lee, Jeong-Heon; Khan, Shehnaz; Haneline, Laura; HogenEsch, Harm; Skalnik, David G.; Department of Pediatrics, IU School of Medicine
    CXXC finger protein 1 (Cfp1), encoded by the Cxxc1 gene, binds to DNA sequences containing an unmethylated CpG dinucleotide and is an epigenetic regulator of both cytosine and histone methylation. Cxxc1-null mouse embryos fail to gastrulate, and Cxxc1-null embryonic stem cells are viable but cannot differentiate, suggesting that Cfp1 is required for chromatin remodeling associated with stem cell differentiation and embryogenesis. Mice homozygous for a conditional Cxxc1 deletion allele and carrying the inducible Mx1-Cre transgene were generated to assess Cfp1 function in adult animals. Induction of Cre expression in adult animals led to Cfp1 depletion in hematopoietic cells, a failure of hematopoiesis with a nearly complete loss of lineage-committed progenitors and mature cells, elevated levels of apoptosis, and death within two weeks. A similar pathology resulted following transplantation of conditional Cxxc1 bone marrow cells into wild type recipients, demonstrating this phenotype is intrinsic to Cfp1 function within bone marrow cells. Remarkably, the Lin- Sca-1+ c-Kit+ population of cells in the bone marrow, which is enriched for hematopoietic stem cells and multi-potential progenitor cells, persists and expands in the absence of Cfp1 during this time frame. Thus, Cfp1 is necessary for hematopoietic stem and multi-potential progenitor cell function and for the developmental potential of differentiating hematopoietic cells.
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    Notch-dependent repression of miR-155 in the bone marrow niche regulates hematopoiesis in an NF-κB-dependent manner
    (Elsevier, 2014-07-03) Wang, Lin; Zhang, Huajia; Rodriguez, Sonia; Cao, Liyun; Parish, Jonathan; Mumaw, Christen; Zollman, Amy; Kamocka, Gosia; Mu, Jian; Chen, Danny Z.; Srour, Edward F.; Chitteti, Brahmananda R.; HogenEsch, Harm; Tu, Xiaolin; Bellido, Teresita M.; Boswell, Scott; Manshouri, Taghi; Verstovsek, Srdan; Yoder, Mervin C.; Kapur, Reuben; Cardoso, Angelo A.; Carlesso, Nadia; Department of Pediatrics, IU School of Medicine
    The microRNA miR-155 has been implicated in regulating inflammatory responses and tumorigenesis, but its precise role in linking inflammation and cancer has remained elusive. Here, we identify a connection between miR-155 and Notch signaling in this context. Loss of Notch signaling in the bone marrow (BM) niche alters hematopoietic homeostasis and leads to lethal myeloproliferative-like disease. Mechanistically, Notch signaling represses miR-155 expression by promoting binding of RBPJ to the miR-155 promoter. Loss of Notch/RBPJ signaling upregulates miR-155 in BM endothelial cells, leading to miR-155-mediated targeting of the nuclear factor κB (NF-κB) inhibitor κB-Ras1, NF-κB activation, and increased proinflammatory cytokine production. Deletion of miR-155 in the stroma of RBPJ(-/-) mice prevented the development of myeloproliferative-like disease and cytokine induction. Analysis of BM from patients carrying myeloproliferative neoplasia also revealed elevated expression of miR-155. Thus, the Notch/miR-155/κB-Ras1/NF-κB axis regulates the inflammatory state of the BM niche and affects the development of myeloproliferative disorders.