Transcriptome profiling of endothelial cells from wild-type, hhex mutants and hhex-overexpression zebrafish embryos
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA438687 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
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| SRR6848344.fastq.gz | Fastqsanger.gz | |||
| SRR6848345.fastq.gz | Fastqsanger.gz | |||
| SRR6848346.fastq.gz | Fastqsanger.gz | |||
| SRR6848347.fastq.gz | Fastqsanger.gz | |||
| SRR6848348.fastq.gz | Fastqsanger.gz |
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Project description:We used high throughput sequencing to identify differential expression in siblings, hhex mutants and hhex-overexpression endothelial cells at 48 hpf.
2018-05-17 | GSE111963 | GEO
Project description:The Hematopoietically-expressed homeobox (Hhex) transcription factor is overexpressed in human myeloid leukemias. Conditional knockout models of murine acute myeloid leukemia (AML) indicate that Hhex maintains leukemia stem cell self-renewal by enabling Polycomb-mediated epigenetic repression of the Cdkn2a tumor suppressor locus, encoding p16Ink4a and p19Arf. However, whether Hhex overexpression also affects hematopoietic differentiation is unknown. To study this, we retrovirally overexpressed Hhex in hematopoietic progenitors. This enabled serial replating of myeloid progenitors, leading to the rapid establishment of IL-3-dependent promyelocytic cell lines. Use of a Hhex-ERT2 fusion protein demonstrated that continuous nuclear Hhex is required for transformation, and structure function analysis demonstrated a requirement of the DNA binding and N-terminal repressive domains of Hhex for promyelocytic transformation. This included the N-terminal Pml interaction domain, although deletion of Pml failed to prevent Hhex-induced promyelocyte transformation, implying other critical partners. Furthermore, deletion of p16Ink4a or p19Arf did not promote promyelocyte transformation, indicating that repression of distinct Hhex target genes is required for this process. Indeed, transcriptome analysis showed that Hhex overexpression resulted in repression of several myeloid developmental genes. To test potential for Hhex overexpression to contribute to leukemic transformation, Hhex-transformed promyelocyte lines were rendered growth factor-independent using a constitutively active IL-3 receptor common b subunit (bcV449E). The resultant cell lines resulted in a rapid promyelocytic leukemia in vivo. Thus Hhex overexpression can contribute to myeloid leukemia via multiple mechanisms including differentiation blockade and enabling epigenetic repression of the Cdkn2a locus.
2018-01-30 | GSE109793 | GEO
Project description:Transcriptional profiling of 2.25 dpf (days post fertilzation) zebrafish embryos comparing wildtype (control) to med14 (mediator complex subunit 14) mutants. Goal was to determine the extent to which transcription was affected in med14 mutants by analyzing global gene expression. Background: Mediator is an evolutionarily conserved multi-subunit complex that physically links the RNA polymerase II transcriptional machinery to enhancer bound regulatory factors. While classically described as a core component of the transcriptional machinery, recent evidence suggests that Mediator may have context-dependent roles. In particular, a requirement for Mediator in the maintenance of embryonic and induced pluripotent stem cells has been noted. However, the in vivo consequences of loss of function of many Mediator subunits are unknown. Results: We identified med14, which encodes a Mediator subunit, as the gene affected in the zebrafish logelei (log) mutant. log mutants displayed a morphological arrest by 2 days of embryonic development. Surprisingly, microarray analysis showed that transcription was not broadly affected in log mutants. Transplanted log cells placed into a wild-type environment were able to survive into adulthood, suggesting a lack of global transcriptional defects in Med14-deficient cells. RNAi knockdown of the single med14 ortholog in planarians demonstrated that med14 was required for adult stem cell maintenance and regeneration. A broader assay of Mediator subunits revealed that many were required for stem cell maintenance in planarians. Multiple stem/progenitor cell populations were observed to be reduced or absent in zebrafish med14 mutant embryos, with embryonic fin regeneration defects also evident. Conclusions: Taken together, our results show a critical, evolutionarily conserved, function for Med14 (and perhaps Mediator in general) in evolutionarily conserved in vivo stem cell maintenance and regeneration, distinct from a ubiquitous role in transcription.
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Project description:We used the Dmrt2a inducible transgenic line Tg(hsp70:HA-dmrt2a) to do a brief dmrt2a overexpression at bud-stage in order to identify Dmrt2a immediate targets and understand its mechanism of action. Both wildtype and transgenic embryos received the same treatment. Zebrafish embryos were collected between 2 hours and 2 hours 30 minutes after heat-shock (Dmrt2a overexpression) and were microdissected in two regions: Region 1 (contains the somites and all associated tissues) and Region 2 (contains the tailbud, Kupffer's Vesicle and all associated tissues)
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Project description:Sequencing of Caenorhabditis elegans overexpression mutants.
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Project description:ciHMX overexpression in Ciona intestinalis embryos
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Project description:Background & Aims: Perturbations in pancreatic ductal bicarbonate secretion often result in chronic pancreatitis. Although the physiological mechanism of ductal secretion is known, its transcriptional control is not well characterized. Here, we investigate the role of the transcription factor Hematopoietically-expressed homeobox protein (Hhex) in pancreatic secretion and pancreatitis. Methods: We derived mice with pancreas-specific, Cre-mediated Hhex gene ablation to determine the requirement of Hhex in the pancreatic duct in early life and in adult stages. Histological and immunostaining analyses were used to detect the presence of pathology. Pancreatic primary ductal cells (PDCs) were isolated to discover differentially expressed transcripts upon acute Hhex ablation. Results: Hhex protein was detected throughout the embryonic and adult ductal trees. Ablation of Hhex in pancreatic progenitors resulted in postnatal ductal ectasia associated with acinar-to-ductal metaplasia, a progressive phenotype that ultimately resulted in chronic pancreatitis. Hhex ablation in adult mice, however, did not cause any detectable pathology. Ductal ectasia did not result from perturbations in primary cilia, but was consistent with the effects of primary ductal hypertension. RNA-seq analysis of Hhex-ablated PDCs indicated the G-protein coupled receptor Natriuretic peptide receptor 3, implicated in paracrine signaling, was upregulated 4.70-fold. Conclusions: Although Hhex is dispensable for adult pancreatic function, ablation of Hhex in pancreatic progenitors results in profound pancreatitis that is consistent with primary ductal hypertension. Our data highlight the critical role of paracrine signaling in maintaining ductal homeostasis, especially in early life, and support ductal hypersecretion as a novel etiology of pediatric chronic pancreatitis. Pancreatic primary ductal cells (PDCs) were isolated from uninduced adult HhexL/L;Sox9CreERT2 (n=2) and littermate control HhexL/L (n=2) mice. PDCs were treated with 500nM 4-hydroxytamoxifen in vitro for 4 days, and then RNA was collected for transcriptome analysis.
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Project description:Memory B cells (MBCs) are essential for long-lived humoral immunity. However, the transcription factors (TFs) involved in MBC differentiation are poorly defined. Here, by single cell RNAseq analysis, we identified a population of germinal center (GC) B cells in the process of differentiating into MBCs. Using an inducible Crispr/Cas9 screening approach we identified the hematopoietically-expressed homeobox gene Hhex as a transcription factor regulating MBC differentiation. The co-repressor Tle3 was also identified in the screen and was found to interact with Hhex to promote MBC development. Bcl6 directly repressed Hhex in GC B cells. Reciprocally, Hhex-deficient MBCs exhibited derepressed Bcl6 and reduced expression of Bcl6-repressed Bcl2. Overexpression of Bcl2 was able to rescue MBC differentiation in Hhex-deficient cells. We also identified Ski as an Hhex-induced transcription factor involved in MBC differentiation. These findings establish an important role for Hhex-Tle3 in regulating the transcriptional circuitry governing MBC differentiation.
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Project description:Hhex encodes a homeobox transcriptional regulator that plays a key role in embryonic development and hematopoiesis. Hhex is highly expressed in NK cells and germline deletion of Hhex results in significant defects in lymphoid development, including NK cells. However, whether Hhex is intrinsically required throughout NK cell development or for NK cell function remains unknown. To investigate this, we generated mice that specifically lack Hhex in NK cells. Hhex was intrinsically required for NK cell homeostasis, while NK cell differentiation, IL-15 responsiveness and cytotoxic function were largely normal in the absence of Hhex. Unexpectedly, increased IL-15 availability failed to rescue Hhex-deficient NK cell homeostasis, suggesting that Hhex regulates developmental pathways extrinsic to those dependent on IL-15. Gene expression and functional genetic approaches revealed that Hhex promoted NK cell survival by repressing BIM expression, a key apoptotic mediator in NK cells. This study identifies Hhex as a novel transcription factor essential for NK cell biology.
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Project description:Forebrain and optic cups were microdissected from zebrafish embryos at 21 hours post-fertilization (hpf) after heat-shock at 15 hpf to induce overexpression of BMP in heterozygous tg(hsp70l:bmp4) embryos vs wild type controls.
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