A transcription factor based mechanism for mouse heterochromatin formation
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE40086 | GEO | 2012/09/16
SECONDARY ACCESSION(S): PRJNA172759
REPOSITORIES: GEO
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Project description:We identify Pax3 and Pax9 transcription factors (TFs) as important regulators of mouse heterochromatin. Simultaneous depletion of these factors results in loss of H3K9me3 from Major Satellite repeats and dramatic transcript overexpression. H3K9me3 enrichment at intergenic major satellite repeats is only present if these sequences retain intact Pax and other TF binding sites. H3K9me3 ChIP-seq in mouse ES cells wt and Pax3 KO and Pax3 KO/Pax9 KD
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Project description:Many repetitive DNA elements are packaged in heterochromatin, but depend on occasional transcription to maintain long-term silencing. The factors that promote transcription of repeat elements in heterochromatin are largely unknown. Here, we show that DOT1L, a histone methyltransferase that modifies lysine 79 of histone H3 (H3K79), is required for transcription of major satellite repeats to maintain pericentromeric heterochromatin (PCH), and that this function is essential for preimplantation development. DOT1L is a transcriptional activator at single-copy genes but does not have a known role in repeat element transcription. We show that H3K79me3 is specifically enriched at repetitive elements, that loss of DOT1L compromises pericentromeric major satellite transcription, and that this function depends on interaction between DOT1L and the chromatin remodeler SMARCA5. DOT1L inhibition causes chromosome breaks and cell cycle defects, and leads to embryonic lethality. Together, our findings uncover a vital new role for DOT1L in transcriptional activation of heterochromatic repeats.
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Project description:Repeat element transcription plays a vital role in early embryonic development. Upregulation of repeats such as MERVL characterises the 2 cell-like population in a mouse embryonic stem cell culture. Repeat element sequences contain binding sites for numerous transcription factors. We identify a the forkhead domain transcription factor FOXD3 as a regulator of repeat element transcription. FOXD3 binds to and recruits the histone methyl transferase Suv39h1 to MERVL and major satellite repeats in mouse embryonic stem cells, consequentially repressing the transcription of these repeats by establishment of the H3K9me3 heterochromatin modification. Notably, depletion of Foxd3 leads to the de-pression of MERVL and major satellite repeats and in turn the activation of a subset of genes expressed in the 2 cell state, shifting the balance between the stem cell and 2 cell-like population in culture. Thus FOXD3 acts as a negative regulator of repeat transcription, ascribing a novel function to this transcription factor.
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Project description:We assembled a quantitative map for the abundance and interactions of 16 factors related to PCH in living cells and found that stably bound complexes of the histone methyltransferase Suv39h1/2 demarcate the PCH state. From the experimental data we developed a predictive mathematical model that explains how chromatin-bound Suv39h1/2 complexes act as nucleation sites and propagate a spatially confined PCH domain with elevated histone H3 trimethylation levels via chromatin dynamics. Enrichment of HP1, Suv39h1/h2, H3K9me3 and H3K36me3 was assessed by ChIP-seq in NPCs derived from ESCs showing differential occupation at intergenic major satellite repeats and enrichment of heterochromatin factors.
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Project description:The skeletal myogenic lineage in developing embryos is specified within the somites and requires members of the Paired box (Pax) family of transcription factors. In particular, Pax3 is the first member of this family expressed in the central region of the dermomyotome and it is necessary for specification, migration and survival of the myogenic progenitors that will form the muscles of the limbs, diaphragm and tongue. To investigate Pax3 molecular functions in the developing mesoderm, we generated doxycycline-inducible mouse embryonic stem (ES) cells expressing untagged and HaFlag-tagged-Pax3. These cell lines were used to unbiasedly identify its interacting partners by tandem affinity purification followed by mass spectrometry.
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Project description:Heterochromatin stability is crucial for progenitor proliferation during development. It relays on the maintenance of local hubs of H3K9me. However, the mechanisms underlying the establishment of competent local levels of H3K9me remain poorly understood. To address this intriguing question, we used a neural stem cell (NSC) model to analyze the significance of the H3K9me2 demethylase PHF2, which is crucial for progenitor proliferation. Through mass spectroscopy and genome-wide assays, we uncovered that PHF2 interacts with heterochromatin components and it is enriched at pericentromeric heterochromatin (PcH) boundaries. This binding is essential for maintaining silenced the satellite repeats and to prevent DNA damage and genome instability. To do that, PHF2 balances H3K9me3 levels at these boundaries to ensure high H3K9me3 levels at satellite repeats. Mechanistically, we discover that while its catalytic and PHD domains are indispensable, the intrinsically disordered region within PHF2 is dispensable for stabilizing PcH. Altogether, our study sheds light on the intricate relationship between heterochromatin stability and progenitor proliferation during mammalian neurogenesis.
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Project description:Heterochromatin stability is crucial for progenitor proliferation during development. It relays on the maintenance of local hubs of H3K9me. However, the mechanisms underlying the establishment of competent local levels of H3K9me remain poorly understood. To address this intriguing question, we used a neural stem cell (NSC) model to analyze the significance of the H3K9me2 demethylase PHF2, which is crucial for progenitor proliferation. Through mass spectroscopy and genome-wide assays, we uncovered that PHF2 interacts with heterochromatin components and it is enriched at pericentromeric heterochromatin (PcH) boundaries. This binding is essential for maintaining silenced the satellite repeats and to prevent DNA damage and genome instability. To do that, PHF2 balances H3K9me3 levels at these boundaries to ensure high H3K9me3 levels at satellite repeats. Mechanistically, we discover that while its catalytic and PHD domains are indispensable, the intrinsically disordered region within PHF2 is dispensable for stabilizing PcH. Altogether, our study sheds light on the intricate relationship between heterochromatin stability and progenitor proliferation during mammalian neurogenesis.
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Project description:Heterochromatin stability is crucial for progenitor proliferation during early neurogenesis. It relays on the maintenance of local hubs of H3K9me. However, the current understanding of the processes involved in the formation of efficient localized levels of H3K9me remains limited. To address this intriguing question, we used a neural stem cell (NSC) to analyze the function of the H3K9me2 demethylase PHF2, which is crucial for progenitor proliferation. Through mass spectroscopy and genome-wide assays, we uncovered that PHF2 interacts with heterochromatin components and it is enriched at pericentromeric heterochromatin (PcH) boundaries. This binding is essential for maintaining silenced the satellite repeats thereby preventing DNA damage and genome instability. Depletion of PHF2 led to increased transcription of heterochromatic repeats, accompanied by a decrease in H3K9me3 levels and alterations in PcH organization. Further analysis revealed that PHF2's PHD and catalytic domains are crucial for maintaining PcH stability and preventing unscheduled repeat transcription, thereby safeguarding genome integrity. These results highlight the multifaceted nature of PHF2's functions in maintaining heterochromatin stability and regulating gene expression during neural development. Altogether, our study unravels the intricate relationship between heterochromatin stability and progenitor proliferation during mammalian neurogenesis, shedding light on its potential as a therapeutic target for neurodevelopmental disorders
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