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MOF directs erythroid fate during hematopoiesis via RUNX1-GFI1b feedforward control (scRNA-Seq)

ABSTRACT: The balance between self-renewal and differentiation of hematopoietic stem cells (HSCs) is orchestrated by the combinatorial function of transcription factors and epigenetic regulators. Here, we report that the H4K16 acetyl-transferase MOF regulates chromatin accessibility and hematopoietic gene expression during erythroid commitment. Mof expression is controlled via a transcriptional feedforward pathway involving Runx1 and Gfi1b, which is crucial for the erythroid lineage bias. Single-cell RNA-seq of HSCs revealed that Mof haploinsufficient mice accumulate an otherwise rare HSC subset, indicating impaired differentiation.We propose that an intricate transcription factor network ensures dynamic chromatin targeting by MOF, which defines an essential epigenetic node regulating HSC plasticity, identity and differentiation. We propose that an intricate transcription factor network ensures dynamic chromatin targeting by MOF, which defines an essential epigenetic node regulating HSC plasticity, identity and differentiation. We propose that an intricate transcription factor network ensures dynamic chromatin targeting by MOF, which defines an essential epigenetic node regulating HSC plasticity, identity and differentiation. We propose that an intricate transcription factor network ensures dynamic chromatin targeting by MOF, which defines an essential epigenetic node regulating HSC plasticity, identity and differentiation.

ORGANISM(S): Mus musculus

PROVIDER: GSE118194 | GEO | 2020/03/13

REPOSITORIES: GEO

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MOF directs erythroid fate during hematopoiesis via RUNX1-GFI1b feedforward control (ChIP-Seq)

Project description:The balance between self-renewal and differentiation of hematopoietic stem cells (HSCs) is orchestrated by the combinatorial function of transcription factors and epigenetic regulators. Here, we report that the H4K16 acetyl-transferase MOF regulates chromatin accessibility and hematopoietic gene expression during erythroid commitment. Mof expression is controlled via a transcriptional feedforward pathway involving Runx1 and Gfi1b, which is crucial for the erythroid lineage bias. Single-cell RNA-seq of HSCs revealed that Mof haploinsufficient mice accumulate an otherwise rare HSC subset, indicating impaired differentiation.We propose that an intricate transcription factor network ensures dynamic chromatin targeting by MOF, which defines an essential epigenetic node regulating HSC plasticity, identity and differentiation. We propose that an intricate transcription factor network ensures dynamic chromatin targeting by MOF, which defines an essential epigenetic node regulating HSC plasticity, identity and differentiation. We propose that an intricate transcription factor network ensures dynamic chromatin targeting by MOF, which defines an essential epigenetic node regulating HSC plasticity, identity and differentiation. We propose that an intricate transcription factor network ensures dynamic chromatin targeting by MOF, which defines an essential epigenetic node regulating HSC plasticity, identity and differentiation.

2020-03-13 | GSE118192 | GEO

Single-cell RNA from Haematopoetic progenitor cells

Project description:The correct balance between self-renewal and differentiation of hematopoietic stem cells (HSC) is orchestrated by the crosstalk between extrinsic and intrinsic factors. A combination of transcriptional regulators and chromatin-based epigenetic changes provide a fine-tuning mechanism to determine HSC fate. We report that the histone H4 lysine 16 (H4K16) specific lysine acetyl-transferase MOF (KAT8) shows dynamic chromatin occupancy during HSC differentiation. MOF regulates erythroid commitment by regulating the expression of key haematopoietic genes. Indeed, loss of just one copy of Mof perturbs HSC commitment, leading to skewed granulocytic lineage commitment and impaired erythroid maturation in mice. Wild-type MOF and strikingly, enforced expression of the transcription factor GATA-1, rescued hematopoietic skewing of this granulocytic fate bias. Furthermore, single-cell RNA-seq of Mof haploinsufficient HSCs revealed an enrichment of a novel immature heterogeneous sub-population of cells with increased proliferation potential, indicative of an enhanced pro-leukemic state. Therefore, our results demonstrate an unprecedented role of MOF in the regulation of HSC plasticity, identity and differentiation.

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Genome-wide maps of chromatin state in HSC, HPC7 and lineage-committed cells

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MOF haploinsufficiency triggers diet-induced obesity resistance (RNA-seq)

Project description:Constant crosstalk between epigenetic regulators and metabolism homeostasis ensures that several tissues can respond and adapt to environmental cues. Decreased levels of the lysine acetyltransferase (KAT), MOF, was recently associated with cerebral development and syndromic intellectual disability. However, the consequences of having a chronic reduction of MOF levels are still unveiled. Here we characterized by FIA-MS/MS the metabolic profile of Mof heterozygous animals. We generated the profile of 8 different organs that have distinct metabolic demands. Overall, our analysis revealed that Mof heterozygous mice have impaired glucose homeostasis, fatty acids metabolism, and amino acid accumulation. When exposed ad libitum to high-fat diet those animals failed to gain fat mass, while the lean mass remains unalterable. At the molecular level, using the adipocyte model we found that Mof regulates the expression of PPARs and Slc2a4. In summary, we identified the first KAT that shows high-fat diet resistance and we propose that the chronic reduction of Mof impacts metabolic disorders.

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MOF haploinsufficiency triggers diet-induced obesity resistance (ChIP-seq)

Project description:Constant crosstalk between epigenetic regulators and metabolism homeostasis ensures that several tissues can respond and adapt to environmental cues. Decreased levels of the lysine acetyltransferase (KAT), MOF, was recently associated with cerebral development and syndromic intellectual disability. However, the consequences of having a chronic reduction of MOF levels are still unveiled. Here we characterized by FIA-MS/MS the metabolic profile of Mof heterozygous animals. We generated the profile of 7 different organs that have distinct metabolic demands. Overall our analysis reveled that Mof heterozygous mice have impaired glucose homeostasis, fatty acids metabolism, and amino acid accumulation. Furthermore, when exposed ad libitum to high-fat diet those animals failed to gain fat mass, while the lean mass remains unalterable. Accordingly, at the molecular level, using the adipocyte model we found that Mof regulates the expression of PPARs and Slc2a4. In summary, we identified the first KAT that shows high-fat diet resistance and we propose that the chronic reduction of Mof has a strong impact on metabolic disorders.

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MOF acetyl transferase regulates transcription and respiration in mitochondria

Project description:Histone acetylation is sensitive to metabolic cues, however interplay between histone acetyl transferases and cellular metabolism remains poorly understood. Here we report the localization of a classical nuclear HAT- MOF and members of Non-Specific Lethal complex in mitochondria. MOF regulates expression of oxidative phosphorylation (OXPHOS) genes, residing in both nuclear and mitochondrial genomes, selectively in aerobically respiring cells. Furthermore, MOF/KANSL1 depletion causes impaired mitochondrial translation and reduced respiration. MOF loss is catastrophic for tissues with high-energy consumption. In mouse hearts, Mof knockout causes hypertrophic cardiomyopathy, compromised ventricular contractility/ stroke volume and ultimately leads to cardiac failure within three weeks of birth. RNA-seq analysis of the cardiomyocytes revealed deregulation of mitochondrial nutrient metabolism and OXPHOS pathways. Consistently, electron microscopy on affected tissues revealed mitochondrial deterioration with high tissue heterogeneity, commonly observed in mitochondrial diseases. Thus, we reveal a novel function of MOF in mitochondrial homeostasis and propose MOF as a sensor connecting epigenetic regulation to metabolism. We generated mRNA-seq profile of Mof depleted HeLa cells adapted in glucose or galactose media. We also present nuclear RNA seq profile from Mof deleted cardiomyocytes.

2016-10-21 | E-GEOD-77784 | biostudies-arrayexpress

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H3K4 demethylase KDM5B regulates epigenetic plasticity and cancer cell identity

Project description:H3K4 demethylase KDM5B regulates epigenetic plasticity and cancer cell identity

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RNAseq analysis of murine ITPKB deficient versus wild type LT-HSC

Project description:Tight regulation of hematopoietic stem cell (HSC) homeostasis is essential for life-long hematopoiesis, for preventing blood cancers and for averting bone marrow failure. The underlying mechanisms are incompletely understood. Here, we identify production of inositol-tetrakisphosphate (IP4) by inositoltrisphosphate 3-kinase B (ItpkB) as essential for HSC quiescence and function. Young ItpkB-/- mice accumulated phenotypic HSC and showed extramedullary hematopoiesis. ItpkB-/- HSC were less quiescent and proliferated more than wildtype controls. They downregulated quiescence and stemness associated mRNAs, but upregulated activation, oxidative metabolism, protein synthesis and lineage associated transcripts. Although they showed no significant homing defects, ItpkB-/- HSC had a severely reduced competitive long-term repopulating potential. Aging ItpkB-/- mice lost hematopoietic stem and progenitor cells and died with severe anemia. Wildtype HSC normally repopulated ItpkB-/- hosts, incidating a HSC-intrinsic ItpkB requirement. ItpkB-/- HSC had reduced cobblestone-area forming cell activity in vitro and showed increased stem-cell-factor activation of the phosphoinositide 3-kinase (PI3K) effector Akt, reversed by exogenous provision of the known PI3K/Akt antagonist IP4. They also showed transcriptome changes consistent with hyperactive Akt/mTOR signaling. Thus, we propose that ItpkB ensures HSC quiescence by limiting cytokine-induced PI3K signaling in HSC.

2015-03-31 | GSE56613 | GEO

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