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Transgenic mice with an R342X mutation in Phf6 have reduced protein levels and behavior deficits yet few prominent features of Börjeson-Forssman-Lehmann Syndrome (BFLS).

ABSTRACT: Transgenic mice with an R342X mutation in Phf6 have reduced protein levels and behavior deficits yet few prominent features of Börjeson-Forssman-Lehmann Syndrome (BFLS).

PROVIDER: PRJNA657849 | ENA |

REPOSITORIES: ENA

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Transgenic mice with an R342X mutation in Phf6 have reduced protein levels and behavior deficits yet few prominent features of Börjeson-Forssman-Lehmann Syndrome (BFLS).

Project description:The PHF6 mutation, R342X, is a recurrent cause of Börjeson-Forssman-Lehmann Syndrome (BFLS), a neurodevelopmental disorder (MIM#301900). We generated transgenic mice with the identical substitution using CRISPR technology. We show that the R342X mutation causes a reduction in PHF6 protein levels, in both mice and humans, from nonsense mediated decay and nonsense-associated alternative splicing. MRI studies indicated that R342X mice had a reduced brain volume on a mixed genetic background but developed hydrocephaly and a high incidence of postnatal death on a C57BL/6 background. Cortical development proceeded normally while hippocampus and hypothalamus relative brain volumes were reduced. Behavior testing demonstrated deficits in associative learning, spatial memory and an anxiolytic phenotype, although other BFLS clinical features were not observed in the R342X mice. We performed RNA-seq analysis on the cerebral cortices of neonatal R342X mice with the purpose of finding a relationship between gene expression profiles, the behavioral phenotype and the cortical morphology.

2022-11-28 | GSE156404 | GEO

RNA sequencing of isogenic Phf6 wild type and Phf6 knockout mouse T-ALL cells

Project description:Loss-of-function mutations Phf6 occur frequently in both adult and pediatric T-cell Acute Lymphoblastic Leukemia (T-ALL). Although Phf6 is widely expressed, little is known about its proposed function as epigenetic regulator and tumor suppressor. To address the role of Phf6 in the leukemia development, here we analyze by RNAseq the gene expression profiles of isogenic Phf6 wild type and Phf6 knockout leukemia cells transformed by overexpression of an oncogenic mutant form of the NOTCH1 receptor.

2019-07-31 | GSE117165 | GEO

PHF6 OCCUPANCYIN HUMAN T-CELL ACUTE LYMPHOBLASTIC LEUKEMIA

Project description:Here we identify the genome-wide occupancy of PHF6 in T-ALL cells. Human T-ALL cells were cross-linked with formaldehyde for 20 min. DNA was enriched by chromatin immunoprecipitation (ChIP) and analyzed by Solexa sequencing. A sample of whole cell extract (WCE) was sequenced and used as the background to determine enrichment. ChIP was performed using an antibody against total PHF6 (Bethyl A301-451A). This represents the ChIP-seq portion of this dataset.

2014-04-01 | E-GEOD-45864 | biostudies-arrayexpress

PHF6 knockdown in rat cortical neurons

Project description:E18 embryonic rat cortical neurons cultured in vitro are infected with lentivirus expressing control or PHF6shRNA-2, and harvested 5 days after infection pLL3.7 lentivirus expressing control or PHF6shRNA-2 was generated in 293T cells and concentrated using ultracentrifuge. In vitro cultured cortical neurons were infected and RNA was harvested 5 days after infection. PHF6 knockdown was validated by QPCR before sample was processed for microarray analysis.

2013-08-01 | E-GEOD-45953 | biostudies-arrayexpress

Gene expression in Phf6-deleted and Phf6-intact foetal mouse cortical neurons and foetal mouse cortex assessed by RNA-seq

Project description:This study assessed the impact of germline Phf6-deletion on gene expression in the E15.5 mouse cortex and the impact of Nestin-cre mediated Phf6-deletion on gene expression in cultured E16.5 mouse cortical neurons

2024-09-23 | GSE275729 | GEO

RNA-seq profiling of HSC, MPPs and HPC-1s from Phf6-deleted and Phf6-intact mice

Project description:The study profiled the effect of Phf6 deletion on gene expression in hematopoietic stem cells (HSCs), multipotent progenitor cells (MPPs) and hematopoietic progenitor cells (HPC-1). Phf6lox/Y;Tie2-creTg/+ mice were prepared on a C57BL/6 background so that Phf6 deletion could be selectively mediated by Tie2-cre. Cell populations were sorted from bone marrow samples using standard surface markers (Lin–SCA1+cKIT+(LSK) CD150+ CD48– for HSCs, Lin–SCA1+cKIT+(LSK) CD150– CD48– for MPPs and Lin–SCA1+cKIT+(LSK) CD150- CD48+ for HPC-1 cells). Phf6 intact and Phf6-delected cells of all three types were profiled by paired-end RNA-seq using an Illumina NextSeq 500 sequencer. RNA-seq libraries were prepared from the HPC-1 samples used a standard Illumina TruSeq library protocol whereas the libraries for the HSC and MPP samples used a SMART-seq ultra low input kit for cDNA synthesis and amplification. Statistical analysis of the TruSeq and SMART-seq samples was undertaken separately.

2019-02-20 | GSE126316 | GEO

Transcriptome changes caused by PHF6 knockout in THP1 human AML cell line

Project description:CRISPR Cas9 guided knockout (KO) of PHF6 in human THP1 AML cell line. We performed bulk RNA-Seq on knockout (PHF6 KO) and wildtype (CTRL) clones derived from THP1 cells transduced with lentiviral vectors encoding Cas9 protein and either PHF6 gRNAs or non-targeting gRNAs. Our results reveal that PHF6 knockout upregulates self-renewal gene sets and downregulates myeloid differentiation gene sets.

2024-09-18 | GSE277149 | GEO

Phf6-null hematopoietic stem cells have enhanced self-renewal capacity and oncogenic potentials

Project description:Plant homeodomain finger gene 6 (PHF6) encodes a 365-amino-acid protein containing two plant homology domain fingers. Germline mutations of human PHF6 cause Börjeson–Forssman–Lehmann syndrome, a congenital neurodevelopmental disorder. Loss-of-function mutations of PHF6 are detected in patients with acute leukemia, mainly of T cell lineage and in a small proportion of myeloid lineage. The functions of PHF6 in physiological hematopoiesis and leukemogenesis remain incompletely defined. To address this question, we generated a conditional Phf6 knockout mouse model and investigated the impact of Phf6 loss on the hematopoietic system. We found that Phf6 knockout mice at 8-week age had reduced numbers of CD4+ and CD8+ T cells in the peripheral blood compared to the wild-type littermates. There were decreased granulocyte-monocytic progenitors but increased Lin-c-Kit+Sca-1+ (LSK) cells in the marrow of young Phf6 knockout mice. Functional studies including competitive repopulation unit and serial transplantation assays revealed an enhanced reconstitution and self-renewal capacity in Phf6 knockout hematopoietic stem cells (HSCs). Aged Phf6 knockout mice had myelodysplasia-like presentations including decreased platelet counts, megakaryocyte dysplasia, and enlarged spleen related to extramedullary hematopoiesis. Moreover, we found that Phf6 loss lowered the threshold of NOTCH1-induced leukemic transformation at least partially through increased leukemia-initiating cells. Transcriptome analysis on the restrictive rare HSC subpopulations revealed upregulated cell cycling and oncogenic functions, with alteration of expression of key genes in those pathways. In summary, our studies demonstrate the in vivo crucial roles of Phf6 in physiological and malignant hematopoiesis.

2019-08-21 | GSE129465 | GEO

PHF6 and JAK3 mutations cooperate to drive T-cell acute lymphoblastic leukemia progression (ChIP-Seq)

Project description:Chromatin immunoprecipitation sequencing (ChIP-seq) analysis of HA-PHF6-overexpressing (PHF6 OE) K562 cells showed that PHF6 directly bound to the ADGRB1 (BAI1) gene

2022-02-09 | GSE159549 | GEO

Genome-wide chromatin accessibility profiling of LT-HSCs isolated from WT and Phf6-deficient mice

Project description:The plant homeodomain 6 gene (PHF6) is frequently mutated in human T-cell acute lymphoblastic leukemia (T-ALL); however, its specific functional role in leukemia development remains to be established. Here, we show that loss of PHF6 is an early mutational event in leukemia transformation. Mechanistically, genetic inactivation of Phf6 in the hematopoietic system enhances hematopoietic stem cell (HSC) long-term self-renewal and hematopoietic recovery after chemotherapy by rendering Phf6 knockout HSCs more quiescent and less prone to stress-induced activation. Consistent with a leukemia-initiating tumor suppressor role, inactivation of Phf6 in hematopoietic progenitors lowers the threshold for the development of NOTCH1-induced T-ALL. Moreover, loss of Phf6 in leukemia lymphoblasts activates a leukemia stem cell transcriptional program and drives enhanced T-ALL leukemia-initiating cell activity. These results implicate Phf6 in the control of HSC homeostasis and long-term self-renewal and support a role for PHF6 loss as a driver of leukemia-initiating cell activity in T-ALL.

2021-06-23 | GSE178739 | GEO

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