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Genome-wide analysis reveals NRP1 as a critical HIF1-E2F7 target gene in the regulation of motorneuron guidance in vivo

ABSTRACT: HIF1 is essential for regulation of the transcriptional response to hypoxia. Recently we showed that the transcriptional repressors E2F7 and E2F8 interact and transcriptionally cooperate with HIF1. Here we further explored this cooperation by performing genome-wide analysis, screening for novel HIF1-E2F7 targets. We show that specifically E2F7 is induced in hypoxia by HIF1. Furthermore, chip-sequencing for E2F7 and HIF1 revealed a large number of common targets of which a subset was also regulated by the complex as examined by microarray analysis. Our data show that the HIF1-E2F7 complex can function both as a repressor or activator. Notably, we identify neuropilin 1 (NRP1) as a novel HIF1-E2F7 target, which is repressed by HIF1-E2F7 in vitro and during zebrafish development, depending on E2F-binding sites present in the NRP1 promoter. In addition we show that regulation of NRP1 by the HIF1-E2F7 complex is required for normal axon guidance of spinal motorneurons in vivo. ChIP-seq analysis of HIF1a and E2F7 binding

ORGANISM(S): Homo sapiens

SUBMITTER: Michal Mokry

PROVIDER: E-GEOD-66956 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Genome-wide analysis reveals NRP1 as a critical HIF1-E2F7 target gene in the regulation of motorneuron guidance in vivo

Project description:HIF1 is essential for regulation of the transcriptional response to hypoxia. Recently we showed that the transcriptional repressors E2F7 and E2F8 interact and transcriptionally cooperate with HIF1. Here we further explored this cooperation by performing genome-wide analysis, screening for novel HIF1-E2F7 targets. We show that specifically E2F7 is induced in hypoxia by HIF1. Furthermore, chip-sequencing for E2F7 and HIF1 revealed a large number of common targets of which a subset was also regulated by the complex as examined by microarray analysis. Our data show that the HIF1-E2F7 complex can function both as a repressor or activator. Notably, we identify neuropilin 1 (NRP1) as a novel HIF1-E2F7 target, which is repressed by HIF1-E2F7 in vitro and during zebrafish development, depending on E2F-binding sites present in the NRP1 promoter. In addition we show that regulation of NRP1 by the HIF1-E2F7 complex is required for normal axon guidance of spinal motorneurons in vivo.

2015-12-11 | GSE66956 | GEO

E2F7 represses a transcriptional network of oscillating cell cycle genes to control S-phase progression.

Project description:E2F transcription factors are known to be important for timely activation of G1/S and G2/M genes required for cell cycle progression, but transcriptional mechanisms for deactivation of cell cycle regulated genes are unknown. Here, we show that E2F7 is highly expressed during mid to late S-phase, occupies promoters of G1/S regulated genes and represses its transcription. ChIP-seq analysis revealed that E2F7 binds preferentially to genomic sites containing the TTCCCGCC motif, which closely resemble the E2F consensus site. We identified 89 target genes that carry E2F7 binding sites close to the transcriptional start site and that are directly repressed by short term induction of E2F7. Most of these target genes are known to be activated by E2Fs and are involved in DNA replication, metabolism and DNA repair. Importantly, induction of E2F7 during G0-G1/S resulted in S-phase arrest and DNA damage, whereas expression of E2F7 during G2/M failed to disturb cell cycle progression. These findings provide strong evidence that E2F7 controls directly the downswing of oscillating G1/S genes during S-phase progression. 2 samples: E2F7 ChIP-seq and input control, E2F7 ChIP-seq sample was sequenced in 2 independent runs and data were combined for the analysis

2012-01-04 | E-GEOD-32673 | biostudies-arrayexpress

WB001A: Genome-wide analysis reveals NRP1 as a critical HIF1-E2F7 target gene in the regulation of motor neuron guidance in vivo

Project description:In this study, we explored the existence of a transcriptional network co-regulated by E2F7 and HIF1Î±, as we show that expression of E2F7, like HIF1Î±, is induced in hypoxia, and because of the previously reported ability of E2F7 to interact with HIF1Î±. Our genome-wide analysis uncovers a transcriptional network that is directly controlled by HIF1Î± and E2F7, and demonstrates both stimulatory and repressive functions of the HIF1Î± -E2F7 complex. Among this network we reveal Neuropilin 1 (NRP1) as a HIF1Î±-E2F7 repressed gene. By performing in vitro and in vivo reporter assays we demonstrate that the HIF1Î±-E2F7 mediated NRP1 repression depends on a 41 base pairs 'E2F-binding site hub', providing a molecular mechanism for a previously unanticipated role for HIF1Î± in transcriptional repression. To explore the biological significance of this regulation we performed in situ hybridizations and observed enhanced nrp1a expression in spinal motorneurons (MN) of zebrafish embryos, upon morpholino-inhibition of e2f7/8 or hif1Î±. Consistent with the chemo-repellent role of nrp1a, morpholino-inhibition of e2f7/8 or hif1Î± caused MN truncations, which was rescued in TALEN-induced nrp1a(hu10012) mutants, and phenocopied in e2f7/8 mutant zebrafish. Therefore, we conclude that repression of NRP1 by the HIF1Î±-E2F7 complex regulates MN axon guidance in vivo. The following samples were analyzed by microarrays: RNA isolated from HeLa cells transfected with either control (scr), E2F7, HIF1a, E2F7 and E2F8, or E2F7 and HIF1a siRNAs. Cells were harvested 48h after transfection, and were grown the last 16h in hypoxia. RNA isolated from scr-transfected, normoxic HeLa cells was used as common reference RNA. Within each group of two biological replicates, sample versus common reference hybridisations were performed in balanced dye-swap. Microarrays used were human whole genome gene expression microarrays V1 (Agilent, Belgium).

2016-01-04 | E-GEOD-66750 | biostudies-arrayexpress

WB001A: Genome-wide analysis reveals NRP1 as a critical HIF1-E2F7 target gene in the regulation of motor neuron guidance in vivo

Project description:In this study, we explored the existence of a transcriptional network co-regulated by E2F7 and HIF1α, as we show that expression of E2F7, like HIF1α, is induced in hypoxia, and because of the previously reported ability of E2F7 to interact with HIF1α. Our genome-wide analysis uncovers a transcriptional network that is directly controlled by HIF1α and E2F7, and demonstrates both stimulatory and repressive functions of the HIF1α -E2F7 complex. Among this network we reveal Neuropilin 1 (NRP1) as a HIF1α-E2F7 repressed gene. By performing in vitro and in vivo reporter assays we demonstrate that the HIF1α-E2F7 mediated NRP1 repression depends on a 41 base pairs 'E2F-binding site hub', providing a molecular mechanism for a previously unanticipated role for HIF1α in transcriptional repression. To explore the biological significance of this regulation we performed in situ hybridizations and observed enhanced nrp1a expression in spinal motorneurons (MN) of zebrafish embryos, upon morpholino-inhibition of e2f7/8 or hif1α. Consistent with the chemo-repellent role of nrp1a, morpholino-inhibition of e2f7/8 or hif1α caused MN truncations, which was rescued in TALEN-induced nrp1a(hu10012) mutants, and phenocopied in e2f7/8 mutant zebrafish. Therefore, we conclude that repression of NRP1 by the HIF1α-E2F7 complex regulates MN axon guidance in vivo.

2016-01-04 | GSE66750 | GEO

ChIP-chip from lymph node-derived primary lymphocytes with anti-E2F2 and anti-SV40TAg

Project description:E2F2 is essential for the maintenance of T lymphocyte quiescence. To identify the full set of E2F2 target genes, and to gain further understanding of the role of E2F2 in transcriptional regulation, we have performed ChIP-chip analyses across the genome of lymph node-derived T lymphocytes. Here we show that during quiescence, E2F2 binds the promoters of a large number of genes involved in DNA metabolism and cell cycle regulation, concomitant with their transcriptional silencing. We performed 3 ChIP-chip experiments with an antibody against E2F2 and another 3 ChIP-chip experiments with an antibody against SV40TAg (irrelevant antibody).

2014-01-09 | E-GEOD-53888 | biostudies-arrayexpress

Chromatin immunoprecipitation of human cell lines with oestrogen receptor (ER), the E2F transcription factor 4 (E2F4),

Project description:The Goal of the experiment was to validate the predicted regulatory modules identified by an algorithm.For this we took advantage of the the genome-wide location analysis technique (or ?ChIP/chip?). We selected modules predicted to be bound by the estrogen receptor (ER), the E2F transcription factor 4 (E2F4), the signal transducer and activator of transcription 3 (STAT3), and the hypoxia-inducible factor 1 HIF1), to print a DNA microarray. In the current study, the microarray was then probed by ChIP/chip for ER and E2F4.

2006-05-01 | E-MEXP-471 | biostudies-arrayexpress

Homo sapiens

Project description:Genome-wide analysis reveals NRP1 as a critical HIF1-E2F7 target gene in the regulation of motorneuron guidance in vivo

| PRJNA278464 | ENA

alternative promoter array HeLa HIF1 ChIP-chip

Project description:DNA binding profiling of endogenous HIF1A on proximal promoters in human HeLa cells exposed to 1% oxygen (hypoxia), using normoxic cells (21% oxygen) as reference. Biological background: The Hypoxia Inducible Factor Family of transcription factors is proposed as the main orchestrator of the cellular response to hypoxia. HIFs are heterodimers of a HIF alpha and a HIF beta subunit. HIF alpha protein stability is regulated by oxygen-dependent proteasomal degradation, and hence HIFs are strongly stabilized in hypoxia. Purpose of the study: a number of HIF1 ChIP-chip studies have been reported, employing various cell types, array platforms and HIF antibodies, and the overlap of HIF binding locations in these studies is relatively small. The aim of this study was to characterize HIF1 binding in an additional cell line (HeLa), and employing a different HIFalpha antibody. Experimental design: We conducted a total of six hybridizations employing four biological replicates. For two biological replicates, we performed dye-swap technical replicate experiments. Results summary: We identified 55 HIF binding locations in HeLa cells (FDR<2%). While this number is relatively low compared to previous studies, presumably due to limiting antibody sensitivity, the overlap with data from other cell lines is comparable to our HeLa data.

2012-05-20 | E-MEXP-3499 | biostudies-arrayexpress

Batf3 maintains Irf8 autoactivation for commitment of a novel clonogenic progenitor of CD8+DCs

Project description:The transcription factors Batf3 and IRF8 are required for development of CD8α+ conventional dendritic cells (cDCs), but the basis for their actions was unclear. Here, we identify two novel Zbtb46+ progenitors that separately generate CD8α+ and CD4+ cDCs and arise directly from the common DC progenitor (CDP). Irf8 expression in the CDP depends on prior PU.1-dependent autoactivation, and specification of pre-CD8 DC progenitors requires IRF8 but not Batf3. However, upon pre-CD8 DC specification, Irf8 autoactivation becomes Batf3-dependent at a CD8α+ cDC-specific enhancer containing multiple AP1-IRF composite elements (AICEs) within the Irf8 superenhancer. CDPs from Batf3-/- mice that specify toward pre-CD8 DCs fail to complete CD8α+ cDC development due to decay of Irf8 autoactivation, and divert to the CD4+ cDC lineage. Examination of histone modifications (H3K27ac and H3K4me1) and 2 transcription factors (Batf3 and Irf8) and the p300 co-factor binding in 3 different dendritic cell subsets

2015-06-08 | E-GEOD-66899 | biostudies-arrayexpress

High throughput sequencing of human HepG2 DNA immunoprecipitated with FOXA2, HNF4a and NRF2/GABP

Project description:In each cell type the expression of genes is regulated by the action of a large number of transcription factors, but so far we have only a rudimentary knowledge of the location of the gene regulatory elements where they bind. This can now be addressed with genome-wide ChIP experiments. In a previous ChIP-chip study of USF1 and USF2 we found evidence also of binding of GABP, FOXA2 and HNF4a within the enriched regions. Here we have applied ChIP-seq for these transcription factors and identified 3064 peaks of enrichment for GABP, 7266 for FOXA2 and 18783 for HNF4a. HNF4a and FOXA2 binding was found in at least half of the regions previously identified as bound by USF2 but not USF1, showing that they frequently bind the same regulatory elements. GABP peaks were found at transcription start sites whereas 94 % of FOXA2 and 90 % of HNF4a peaks were located at other positions. We developed a method based on the high resolution achieved by ChIP-seq to accurately define TFBS within peaks, and found the predicted sites to have an elevated conservation level compared to peak centers; however the majority of bindings were not evolutionary conserved. An unexpected interaction between HNF4a and GABP was seen at TSS, with as many as 1/3 of the HNF4a positive promoters being bound also by GABP, and co-immunoprecipitations show that these factors are in the same complex in the nucleus.

2009-06-09 | E-MTAB-115 | biostudies-arrayexpress

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