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Transcriptional reprogramming of neural stem cells by a PHF6/EphR signalling pathway [RNA-seq]

ABSTRACT: The plant homeodomain zinc finger protein,PHF6, is a transcriptional regulator, with its germline mutations causing the X-linked intellectual disability (XLID), Börjeson-Forssman-Lehmann syndrome (BFLS).The precise mechanisms by whichPHF6regulates transcription and how its mutant forms lead to XLID remain poorly characterized. Here, we show genome-wide binding of PHF6 in the developing cortex, most of which overlap (CA)n-microsatellite repeats near genes involved in central nervous system development and neurogenesis. Mice harbouring BFLS patient mutations exhibit defects in neurogenesis and altered neural stem cell fate. Mechanistically, we find that PHF6 regulatesa panel of Ephrin receptors (EphRs)and that PHF6regulation ofEphRis impaired in BFLS mice and ina conditionalPhf6knock-out mouse model. We report that mice harboring BFLS mutations exhibit an increase in embryonic neural stem cell (eNSC) self-renewal, a significant attenuation of newly born neurons, and thatEphRknockdown phenocopies the PHF6 loss-of-function defects in altering eNSC fate. Our results suggest that alterations in eNSC fate specification via a PHF6/EphRtranscriptional pathway leads to impaired neurogenesis in BFLS

ORGANISM(S): Mus musculus

PROVIDER: GSE247837 | GEO | 2024/02/07

REPOSITORIES: GEO

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Transcriptional reprogramming of neural stem cells by a PHF6/EphR signalling pathway [ChIP-Seq]

Project description:The plant homeodomain zinc finger protein,PHF6, is a transcriptional regulator, with its germline mutations causing the X-linked intellectual disability (XLID), Börjeson-Forssman-Lehmann syndrome (BFLS).The precise mechanisms by whichPHF6regulates transcription and how its mutant forms lead to XLID remain poorly characterized. Here, we show genome-wide binding of PHF6 in the developing cortex, most of which overlap (CA)n-microsatellite repeats near genes involved in central nervous system development and neurogenesis. Mice harbouring BFLS patient mutations exhibit defects in neurogenesis and altered neural stem cell fate. Mechanistically, we find that PHF6 regulatesa panel of Ephrin receptors (EphRs)and that PHF6regulation ofEphRis impaired in BFLS mice and ina conditionalPhf6knock-out mouse model. We report that mice harboring BFLS mutations exhibit an increase in embryonic neural stem cell (eNSC) self-renewal, a significant attenuation of newly born neurons, and thatEphRknockdown phenocopies the PHF6 loss-of-function defects in altering eNSC fate. Our results suggest that alterations in eNSC fate specification via a PHF6/EphRtranscriptional pathway leads to impaired neurogenesis in BFLS

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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.

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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).

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