NF-Y is necessary for hematopoietic stem cell proliferation and survival

Bungartz, Gerd; Land, Hannah S.; Scadden, David T.; Emerson, Stephen G.

doi:10.1182/blood-2011-06-359406

Cited by 81 publications

(61 citation statements)

References 37 publications

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“…In mammals, the NF-Y complex is required to activate developmentally regulated genes, and is described as a key regulator of cell cycle progression (Bhattacharya et al, 2003;Benatti et al, 2011;Bungartz et al, 2012). This study illustrates the fact that, during evolution, NF-YA, NF-YB, and NF-YC families of TFs have diversified and some members have specialized to control plant-specific pathways, such as root nodule development, a process that is only found in very few plant families, including the legumes.…”

Section: Discussionmentioning

confidence: 99%

A phylogenetically conserved group of NF-Y transcription factors interact to control nodulation in legumes

et al. 2015

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The endosymbiotic association between legumes and soil bacteria called rhizobia leads to the formation of a new root-derived organ called the nodule in which differentiated bacteria convert atmospheric nitrogen into a form that can be assimilated by the host plant. Successful root infection by rhizobia and nodule organogenesis require the activation of symbiotic genes that are controlled by a set of transcription factors (TFs). We recently identified Medicago truncatula nuclear factor-YA1 (MtNF-YA1) and MtNF-YA2 as two M. truncatula TFs playing a central role during key steps of the Sinorhizobium meliloti-M. truncatula symbiotic interaction. NF-YA TFs interact with NF-YB and NF-YC subunits to regulate target genes containing the CCAAT box consensus sequence. In this study, using a yeast two-hybrid screen approach, we identified the NF-YB and NF-YC subunits able to interact with MtNF-YA1 and MtNF-YA2. In yeast (Saccharomyces cerevisiae) and in planta, we further demonstrated by both coimmunoprecipitation and bimolecular fluorescence complementation that these NF-YA, -B, and -C subunits interact and form a stable NF-Y heterotrimeric complex. Reverse genetic and chromatin immunoprecipitation-PCR approaches revealed the importance of these newly identified NF-YB and NF-YC subunits for rhizobial symbiosis and binding to the promoter of MtERN1 (for Ethylene Responsive factor required for Nodulation), a direct target gene of MtNF-YA1 and MtNF-YA2. Finally, we verified that a similar trimer is formed in planta by the common bean (Phaseolus vulgaris) NF-Y subunits, revealing the existence of evolutionary conserved NF-Y protein complexes to control nodulation in leguminous plants. This sheds light on the process whereby an ancient heterotrimeric TF mainly controlling cell division in animals has acquired specialized functions in plants.

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Section: Discussionmentioning

confidence: 99%

A phylogenetically conserved group of NF-Y transcription factors interact to control nodulation in legumes

et al. 2015

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“…One could hypothesize that the NF-YAs isoform might be important for cancer stemness. The recent results with conditional KO mice in liver and hematopoietic cells indeed indicate that NF-YA is important for tissue maintenance, possibly by regulating stem cells [14,15]. Hematopoietic cancers arise mostly not from HSCs but from lineage-specific stem cells, which presumably already underwent a partial switch in isoforms: hence the presence of both NF-YA isoforms in hematopoietic-derived cell lines.…”

Section: Implication For Cancer?mentioning

confidence: 99%

“…All nucleotides of the pentanucleotide are critical for NF-Y binding, with immediate flanking sequences contributing substantially [11]. The early embryonic lethality of an NF-YA mouse knockout (KO) model due to defects in cell proliferation indicates that the TF is active in the very early stages of development [13]; more recently, tissue-specific KO experiments in liver and bone marrow confirm the importance of NF-YA in adult tissues as well [14,15]. The NF-YA isoform is believed to be the limiting and regulatory subunit of the trimer, and, unlike the HFD dimer, is absent in some postmitotic cells and tissues [reviewed in 16].…”

Section: Introductionmentioning

confidence: 99%

The Short Isoform of NF‐YA Belongs to the Embryonic Stem Cell Transcription Factor Circuitry

et al. 2012

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Totipotency of embryonic stem cells (ESCs) is controlled at the transcriptional level by a handful of transcription factors (TFs) that promote stemness and prevent differentiation. One of the most enriched DNA elements in promoters and enhancers of genes specifically active in ESCs is the CCAAT box, which is recognized by NF-Y, a trimer with histone-like subunits-NF-YB/NF-YC-and the sequence-specific NF-YA. We show that the levels of the short NF-YA isoform-NF-YAs-is high in mouse ESCs (mESCs) and drops after differentiation; a dominant negative mutant affects expression of important stem cells genes, directly and indirectly. Protein transfections of TAT-NF-YAs stimulate growth and compensate for withdrawal of leukemia inhibitory factor (LIF) in cell cultures. Bioinformatic analysis identifies NF-Y sites as highly enriched in genomic loci of stem TFs in ESCs. Specifically, 30%-50% of NANOG peaks have NF-Y sites and indeed NF-Y-binding is required for NANOG association to DNA. These data indicate that NF-Y belongs to the restricted circle of TFs that govern mESCs, and, specifically, that NF-YAs is the active isoform in these cells.

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“…This complex has general regulatory activities in gene expression and controls different sets of genes in different organisms or cell types. For instance, NF-Y in mammals can regulate the cell cycle, apoptosis, and cell self-renewal (1,2), especially in hematopoietic stem cells (28). In hepatocytes, inactivation of NF-Y leads to hepatocellular degeneration, lipid deposition, and endoplasmic reticulum stress (29).…”

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confidence: 99%

Diverse Hap43-Independent Functions of the Candida albicans CCAAT-Binding Complex

et al. 2013

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cThe CCAAT motif is ubiquitous in promoters of eukaryotic genomes. The CCAAT-binding complex (CBC) is conserved across a wide range of organisms, specifically recognizes the CCAAT motif, and modulates transcription directly or in cooperation with other transcription factors. In Candida albicans, CBC is known to interact with the repressor Hap43 to negatively regulate iron utilization genes in response to iron deprivation. However, the extent of additional functions of CBC is unclear. In this study, we explored new roles of CBC in C. albicans and found that CBC pleiotropically regulates many virulence traits in vitro, including negative control of genes responsible for ribosome biogenesis and translation and positive regulation of low-nitrogen-induced filamentation. In addition, C. albicans CBC is involved in utilization of host proteins as nitrogen sources and in repression of cellular flocculation and adhesin gene expression. Moreover, our epistasis analyses suggest that CBC acts as a downstream effector of Rhb1-TOR signaling and controls low-nitrogen-induced filamentation via the Mep2-Ras1-protein kinase A (PKA)/mitogen-activated protein kinase (MAPK) pathway. Importantly, the phenotypes identified here are all independent of Hap43. Finally, deletion of genes encoding CBC components slightly attenuated C. albicans virulence in both zebrafish and murine models of infection. Our results thus highlight new roles of C. albicans CBC in regulating multiple virulence traits in response to environmental perturbations and, finally, suggest potential targets for antifungal therapies as well as extending our understanding of the pathogenesis of other fungal pathogens.

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NF-Y is necessary for hematopoietic stem cell proliferation and survival

Cited by 81 publications

References 37 publications

A phylogenetically conserved group of NF-Y transcription factors interact to control nodulation in legumes

A phylogenetically conserved group of NF-Y transcription factors interact to control nodulation in legumes

The Short Isoform of NF‐YA Belongs to the Embryonic Stem Cell Transcription Factor Circuitry

Diverse Hap43-Independent Functions of the Candida albicans CCAAT-Binding Complex

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