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Low-level repressive histone marks fine-tune stemness gene transcription in neural stem cells [scRNA-seq]

ABSTRACT: Coordinated regulation of stemness gene activity by transcriptional and translational controls poise stem cells for a timely cell-state transition during differentiation. Although important for all stemness-to-differentiation transitions, mechanistic understanding of the fine-tuning of stemness gene transcription is lacking due to the compensatory effect of translational control. We used intermediate neural progenitor (INP) identity commitment to define the mechanisms that fine-tune stemness gene transcription in fly neural stem cells (neuroblasts). We demonstrate that the transcription factor FruitlessC (FruC) binds cis-regulatory elements of most genes uniquely transcribed in neuroblasts. Loss of fruC function alone has no effect on INP commitment but drives INP dedifferentiation when translational control is reduced. FruC negatively regulates gene expression by promoting low-level enrichment of the repressive histone mark H3K27me3 in gene cis-regulatory regions. Identical to fruC loss-of-function, reducing Polycomb Repressive Complex 2 activity increases stemness gene activity. We propose low-level H3K27me3 enrichment fine-tunes stemness gene transcription in stem cells, a mechanism likely conserved from flies to humans.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE218255 | GEO | 2023/06/23

REPOSITORIES: GEO

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Low-level repressive histone marks fine-tune stemness gene transcription in neural stem cells [CUT&Tag]

Project description:Coordinated regulation of stemness gene activity by transcriptional and translational controls poise stem cells for a timely cell-state transition during differentiation. Although important for all stemness-to-differentiation transitions, mechanistic understanding of the fine-tuning of stemness gene transcription is lacking due to the compensatory effect of translational control. We used intermediate neural progenitor (INP) identity commitment to define the mechanisms that fine-tune stemness gene transcription in fly neural stem cells (neuroblasts). We demonstrate that the transcription factor FruitlessC (FruC) binds cis-regulatory elements of most genes uniquely transcribed in neuroblasts. Loss of fruC function alone has no effect on INP commitment but drives INP dedifferentiation when translational control is reduced. FruC negatively regulates gene expression by promoting low-level enrichment of the repressive histone mark H3K27me3 in gene cis-regulatory regions. Identical to fruC loss-of-function, reducing Polycomb Repressive Complex 2 activity increases stemness gene activity. We propose low-level H3K27me3 enrichment fine-tunes stemness gene transcription in stem cells, a mechanism likely conserved from flies to humans.

2023-06-23 | GSE218253 | GEO

Stem cell intrinsic, Seven-up-triggered temporal factor gradients diversify intermediate neural progenitors

Project description:One neural stem cell can produce multiple transiently amplifying, intermediate neural progenitors (INP), which collectively yield diverse neuronal types. It is unclear if and how serially derived INPs contribute to neuron fate diversification. Drosophila type II neuroblasts, like mammalian neural stem cells, deposit neurons and also glia through INPs. The consecutively born INPs in a given lineage produce morphologically distinct progeny, presumably due to their inheritance of different temporal factors from the INP-producing progenitor. To uncover the underlying temporal fating mechanisms, we profiled type II neuroblasts' transcriptome across time. Our results reveal opposing temporal gradients of Imp and Syp RNA-binding proteins (descending and ascending, respectively). Maintaining high Imp throughout serial INP production expands the number of neurons/glia with early temporal fate at the expense of cells with late fate. Conversely, precocious upregulation of Syp reduces the number of cells with early fate. Further, we reveal that the transcription factor, Seven-up initiates progression of the Imp/Syp gradients. Interestingly, neuroblasts apparently locked in their beginning Imp/Syp levels can still yield progeny with a small range of early fates. We propose that the Seven-up-initiated Imp/Syp gradients create coarse temporal windows within type II neuroblasts to pattern INPs, which subsequently undergo fine-tuned subtemporal patterning.

2018-01-23 | GSE94445 | GEO

The deubiquitinase Usp9x regulates PRC2-mediated chromatin reprogramming during mouse development

Project description:Pluripotent cells of the mammalian embryo undergo extensive chromatin rewiring to prepare for lineage commitment after implantation. Repressive H3K27me3, deposited by Polycomb Repressive Complex 2 (PRC2), is reallocated from large blankets in pre-implantation embryos to mark promoters of developmental genes. The regulation of the global redistribution of H3K27me3 is poorly understood. Here we report a post-translational mechanism that destabilizes PRC2 to constrict H3K27me3 during lineage commitment. Using an auxin-inducible degron system, we show that the deubiquitinase Usp9x is required for mouse embryonic stem (ES) cell self-renewal. Usp9x-high ES cells have high PRC2 levels and bear a chromatin and transcriptional signature of the pre-implantation embryo, whereas Usp9x-low ES cells resemble the post-implantation, gastrulating epiblast. We show that Usp9x interacts with, deubiquitinates and stabilizes PRC2. Deletion of Usp9x in post-implantation embryos results in the derepression of genes that normally gain H3K27me3 after gastrulation, followed by the appearance of morphological abnormalities at E9.5, pointing to a recurrent link between Usp9x and PRC2 during development. Usp9x is a marker of “stemness” and is mutated in various neurological disorders and cancers. Our results unveil a Usp9x-PRC2 regulatory axis that is critical at peri-implantation and may be redeployed in other stem cell fate transitions and disease states.

2021-01-25 | GSE146800 | GEO

Epigenetic profiling of colorectal cancer initiating cells (CC-ICs) to identify bivalently marked genes (H3K4me3 and H3K27me3 ChIP-seq), and investigation of changes in transcriptome following EZH2 inhibition using RNA-seq.

Project description:Epigenetic regulation of transcription plays a crucial role in lineage commitment of embryonic stem cells. Promoters of key lineage-specific differentiation genes are found in a repressed bivalent state, having both activating H3K4me3 and repressive H3K27me3 histone marks, making them poised for transcription upon loss of H3K27me3 in response to environmental cues. Whether the tumour-initiating, self-renewing, cancer-initiating cells (C-ICs) have similar epigenetic regulatory mechanism that prevent lineage commitment is unknown. In order to investigate bivalently marked and repressed promoters, we used a patient-derived CC-IC enriched model to identify the changes in transcriptome following inhibition of EZH2, the H3K27 methyltransferase. We also performed ChIP-seq for H3K27me3 and H3K4me3 at baseline in order to identify repressed and bivalently marked promoters.

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Quantitative histone mass spectrometry identifies elevated histone H3 lysine 27 trimethylation in melanoma

Project description:Normal cell growth is characterized by a regulated epigenetic program that drives cellular activities such as gene transcription, DNA replication and DNA damage repair. Perturbation of this epigenetic program can lead to events such as mis-regulation of gene transcription and diseases such as cancer. To begin to understand the epigenetic program correlated to the development of melanoma, we performed a quantitative mass spectrometric analysis of histone posttranslational modifications mis-regulated in melanoma cell culture. Aggressive melanoma cells were found to have elevated histone H3 lysine 27 trimethylation (H3K27me3) as well as over-expressed methyltransferase EZH2 that adds the specific modification. The altered epigenetic program that led to elevated H3K27me3 in melanoma cell culture was found to directly silence transcription of the tumor suppressor gene RUNX3. The elevated level of H3K27me3 and silencing of RUNX3 transcription was also validated in advanced stage human melanoma tissues. The study presented underscores the utility of using high resolution mass spectrometry to identify mis-regulated epigenetic programs in diseases such as cancer, which could ultimately lead to the identification of biological markers for diagnostic and prognostic applications.

2016-07-22 | MSV000079979 | MassIVE

Chromatin and Transcriptional Signatures for Nodal Signaling During Endoderm Formation in hESCs

Project description:To elucidate the Nodal transcriptional network that governs endoderm formation, we used ChIP-Seq to identify genomic targets for SMAD2/3, SMAD3, SMAD4, FOXH1 and the active and repressive chromatin marks, H3K4me3 and H3K27me3, in human embryonic stem cells (hESCs) and derived endoderm. We demonstrate that while SMAD2/3, SMAD4 and FOXH1 target binding is highly dynamic, there is an optimal signature for driving endoderm commitment. Initially, this signature is marked by both H3K4me3 and H3K27me3 as a very broad bivalent domain in hESCs. Within the first 24 hours, at a few select promoters, SMAD2/3 accumulation coincides with H3K27me3 depletion so that these loci become selectively monovalent marked only by H3K4me3. The correlation between SMAD2/3 binding, monovalent formation and transcriptional activation suggests a mechanism by which SMAD proteins coordinate with chromatin at critical promoters to drive endoderm specification. Examination of 2 different histone modifications and 4 different transcription factor associations in 2 cell types. For transcription factor analysis, three biological replicate ChIPs were pooled from each antibody, as well as input controls, for both hESCs and derived endoderm. For histone modifications, two biological replicates for H3K4me3 and three for H3K27me3 were used.

2011-05-21 | E-GEOD-29422 | biostudies-arrayexpress

Integrative proteomics reveals a protective role of PRC2 for the ground state pluripotent epigenome

Project description:The ground state of pluripotency is defined as a basal proliferative state free of epigenetic restriction, represented by mouse embryonic stem cells (ESCs) cultured with two kinase inhibitors (so-called “2i”). Through comparison with serum-grown ESCs, we identify epigenetic features characterizing 2i ESCs by proteome profiling of chromatin including post-translational histone modifications. The most prominent difference is H3K27me3 and its enzymatic writer complex PRC2 that are highly abundant on eu- and heterochromatin in 2i ESCs, with H3K27me3 redistributing outside canonical PRC2 targets in a CpG-dependent fashion. Using PRC2-deficient 2i ESCs, we identify epigenetic crosstalk with H3K27me3, including significant increases in H4 acetylation and DNA methylation. This suggests that the unique H3K27me3 configuration protects 2i ESCs from preparation to lineage priming. Interestingly, removal of DNA methylation in PRC2-deficient 2i ESCs lacking H3K27me3 using 5-azacytidine hardly affected ESC viability and transcriptome, showing that ESCs are independent of both major repressive epigenetic marks.

2018-11-21 | PXD007154 | Pride

Extracellular-acidosis restricts one-carbon metabolism and preserves T cell stemness

Project description:The accumulation of acidic metabolic waste products within the tumor microenvironment profoundly inhibits effector functions of tumor-infiltrating lymphocytes (TILs). However, it is unclear whether extracellular-acidosis impacts T cell metabolic fitness and differentiation status. Here, we surprisingly found that prolonged acid exposure reprogrammed T cell intracellular metabolism and mitochondrial fitness, and preserved T cell stemness. Elevated extracellular-acidosis impaired methionine uptake and metabolism via downregulating SLC7A5, therefore altering H3K27me3 deposition at the promoters of crucial T cell stemness genes. These changes promoted the maintenance of a “stem-like memory” state and improved long-term in vivo persistence and anti-tumor efficacy. Our findings not only reveal the unexpected roles of extracellular-acidosis in the maintenance of stem-like properties of T cells, but also advance our understanding of the direct involvement of methionine metabolism in T cell stemness.

2023-01-17 | MTBLS6661 | MetaboLights

PRC2 coordinates lineage fidelity and DNA methylation during ESC differentiation (ChIP-Seq)

Project description:Polycomb Repressive Complex 2 (PRC2) catalyzes histone H3 lysine 27 tri-methylation, an epigenetic modification associated with gene repression. H3K27me3 is enriched at the promoters of a large cohort of developmental genes in embryonic stem cells (ESCs). Loss of H3K27me3 leads to a failure of ESCs to properly differentiate, which presents a major roadblock for dissecting the precise roles of PRC2 activity during lineage commitment. While recent studies suggest that loss of H3K27me3 leads to changes in DNA methylation in ESCs, how these two pathways coordinate to regulate gene expression programs during lineage commitment is poorly understood. Here, we analyzed gene expression and DNA methylation levels in several PRC2 mutant ESC lines that maintain varying levels of H3K27me3. We found that maintenance of intermediate levels of H3K27me3 allowed for proper temporal activation of lineage genes during directed differentiation of ESCs to spinal motor neurons (SMNs). However, genes that function to specify other lineages failed to be repressed, suggesting that PRC2 activity is necessary for lineage fidelity. We also found that H3K27me3 is antagonistic to DNA methylation in cis. Furthermore, loss of H3K27me3 leads to a gain in promoter DNA methylation in developmental genes in ESCs and in lineage genes during differentiation. Thus, our data suggest a role for PRC2 in coordinating dynamic gene repression while protecting against inappropriate promoter DNA methylation during differentiation. Embryonic Stem Cell (ESC) lines mutant for PRC2 core components Suz12 (Suz12GT and Suz12delta) and Eed (Eednull) were subjected to in vitro directed differentiation down the spinal motor neuron lineage. ESCs and day 5 differentiated cells from the three mutant lines and wild-type were used for H3K27me3 ChIP-seq.

2014-11-17 | E-GEOD-53505 | biostudies-arrayexpress

Cell-type-specific chromatin occupancy by the pioneer factor Zelda drives key developmental transitions in Drosophila

Project description:During early Drosophila embryogenesis, the essential pioneer factor Zelda defines hundreds of cis-regulatory regions and in doing so reprograms the zygotic transcriptome. While Zelda is essential later in development, it is unclear how the ability of Zelda to define cis-regulatory regions is shaped by cell-type specific chromatin architecture established during differentiation. Asymmetric division of neural stem cells (neuroblasts) in the fly brain provide an excellent paradigm for investigating the cell-type specific functions of this pioneer factor. Zelda is expressed in neuroblasts, and we show that Zelda synergistically functions with Notch to maintain neuroblasts in an undifferentiated state. Zelda misexpression can reprogram progenitor cells to neuroblasts, but this capacity is limited by transcriptional repressors critical for progenitor commitment. Zelda genomic occupancy in neuroblasts is reorganized as compared to the embryo, despite sharing many target genes in these two developmental stages. This reorganization is likely driven by differences in chromatin accessibility and cofactor availability. We propose that Zelda regulates essential transitions in the neuroblasts and embryo through a shared gene regulatory network by defining cell-type specific enhancers.

2021-11-05 | GSE150931 | GEO

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