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Depletion of histone deacetylase 3 antagonizes PI3K-mediated tissue overgrowth through the acetylation of histone H4 at lysine 16

ABSTRACT: Histone acetylation is one of the best studied gene modifications and has been shown to be involved in numerous important biological processes. Herein，we demonstrate that Hdac3 regulates both organ and body size through the deacetylation of histone H4 at lysine 16 (H4K16ac). H4K16ac is affected by PI3K signaling cascades. Increasing H4K16ac by the depletion of Hdac3 counteracts PI3K-induced tissue overgrowth and PI3K-mediated alterations in the transcription profile. Using microarry, we compared the transcriptional profile between flies over-expressing PI3K and flies co-expressing PI3K and Hdac3 dsRNA. The findings provide further insight into the mechanism of PI3K-mediated growth and chromatin remodeling.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE38552 | GEO | 2012/06/20

SECONDARY ACCESSION(S): PRJNA168151

REPOSITORIES: GEO

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Depletion of histone deacetylase 3 antagonizes PI3K-mediated tissue overgrowth through the acetylation of histone H4 at lysine 16

Project description:Histone acetylation is one of the best studied gene modifications and has been shown to be involved in numerous important biological processes. HereinM-oM-<M-^Lwe demonstrate that Hdac3 regulates both organ and body size through the deacetylation of histone H4 at lysine 16 (H4K16ac). H4K16ac is affected by PI3K signaling cascades. Increasing H4K16ac by the depletion of Hdac3 counteracts PI3K-induced tissue overgrowth and PI3K-mediated alterations in the transcription profile. Using microarry, we compared the transcriptional profile between flies over-expressing PI3K and flies co-expressing PI3K and Hdac3 dsRNA. The findings provide further insight into the mechanism of PI3K-mediated growth and chromatin remodeling. Total RNA was isolated from Drosophila wing imaginal discs using Trizol reagent and hybridized on Affymetrix microarrays. We performed microarray gene expression profiling from drosophila 3rd wing disc of en-Gal4, PI3K overexpression, HDAC3 RNAi, and PI3K overexpression + Hdac3 RNAi.

2012-06-19 | E-GEOD-38552 | biostudies-arrayexpress

CDK4/6 inhibitor-mediated cell overgrowth triggers an osmotic stress response

Project description:Cell size and the cell cycle are intrinsically coupled and abnormal increases in cell size are associated with senescence and permanent cell cycle arrest. The mechanism by which overgrowth primes cells to withdraw from the cell cycle remains unknown. We investigate this here using CDK4/6 inhibitors that arrest cell cycle progression during G0/G1 and are used in the clinic to treat ER+/HER2- metastatic breast cancer. We demonstrate that CDK4/6 inhibition promotes cellular overgrowth during G0/G1, causing p38MAPK-p53-p21-dependent cell cycle withdrawal. We find that cell cycle withdrawal is triggered by two waves of p21 induction. First, overgrowth during a long-term G0/G1 arrest induces an osmotic stress response. This stress response produces the first wave of p21 induction. Second, when CDK4/6 inhibitors are removed, a fraction of cells escape long term G0/G1 arrest and enter S-phase where overgrowth-driven replication stress results in a second wave of p21 induction that causes cell cycle withdrawal from G2, or the subsequent G1. We propose a model whereby both waves of p21 induction contribute to promote permanent cell cycle arrest. This model could explain why cellular hypertrophy is associated with senescence and why CDK4/6 inhibitors have long-lasting effects in patients.

2023-11-27 | PXD036519 | Pride

Segmental overgrowth/vascular anomalies/dermatologic disorders

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De novo mutations of MSL3 cause a novel X-linked syndrome due to impaired histone H4 lysine 16 acetylation

Project description:Epigenetic regulation by histone acetylation plays a key role in cellular homeostasis and its misregulation is associated with human disease. Histone 4 Lysine 16 acetylation (H4K16ac) serves a unique role amongst the many histone modifications as it directly affects chromatin structure1. The Male Specific Lethal (MSL) complex associated MOF/KAT8 histone acetyl transferase is responsible for bulk H4K16ac in flies and mammals. Yet, its importance during human development and a potential involvement in human pathologies remains largely unknown. Here, we uncover that pathogenic variants in MSL3, a component of the MSL complex, are causative for a new recognizable X-linked syndrome affecting Histone 4 Lysine 16 acetylation (H4K16ac) in both male and female individuals. Common clinical features of the syndrome include global developmental delay comprising profound speech delay, delayed ability to walk and craniofacial dysmorphism. Using patient-derived primary fibroblasts, we demonstrate that de novo variants or deletions of MSL3 affect the assembly and enzymatic activity of the MSL complex, hence impacting on global H4K16ac levels. Transcriptome analysis from patient cells showed misregulation of cellular pathways involved in serotonergic signaling, morphogenesis, axon guidance and cell structure. Finally, using HDAC inhibitor treatment, we can rescue expression of downregulated target genes, offering potential therapeutic avenues for MSL3-mutated patients. Taken together, we characterize a novel syndrome, named ILyADe (Impaired Lysine 16 acetylation associated disorder), which is caused by mutations of an epigenetic regulator, allowing us for the first time to unravel the crucial role of H4K16ac during human development. ILyaDe thus constitutes a new class of syndromes associated with misregulation of a single epigenetic modification caused by a genetic alteration.

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NPA-induced vascular overgrowth in Arabidopsis

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2009-12-05 | E-GEOD-19262 | biostudies-arrayexpress

Intergenerationally maintained Histone H4 lysine 16 acetylation is instructive for future gene activation

Project description:Before zygotic genome activation (ZGA) the quiescent genome undergoes reprogramming to transition into the transcriptionally active state. However, the mechanisms underlying euchromatin establishment during early embryogenesis remain poorly understood. Here, we show that histone H4 lysine-16 acetylation (H4K16ac) is maintained from oocytes to fertilized embryos in Drosophila and mammals. H4K16ac forms large domains that control nucleosome accessibility of promoters prior to ZGA in flies. Maternal depletion of MOF acetyl-transferase leading to H4K16ac loss causes aberrant Pol II recruitment, compromises the 3D organization of the active genomic compartments during ZGA and consequently causes downregulation of post-zygotically expressed genes. Germline depletion of histone deacetylases revealed that other acetyl marks cannot compensate for H4K16ac loss in the oocyte. Moreover, zygotic re-expression of MOF was neither able to restore embryonic viability nor onset of X chromosome dosage compensation. Thus, maternal H4K16ac provides an instructive function to the offspring, priming future gene activation.

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A Histone Deacetylase 3-Dependent Pathway Delimits Peripheral Myelin Growth and Functional Regeneration [ChIP-Seq]

Project description:Schwann cell remyelination defects impair functional restoration after nerve damage, contributing to peripheral neuropathies. The mechanisms that mediate remyelination block remain elusive. Upon small-molecule epigenetic screening, we identified HDAC3, a histone-modifying enzyme, as a potent inhibitor of peripheral myelinogenesis. Inhibition of HDAC3 markedly enhances myelin growth and regeneration, and improves functional recovery after peripheral nerve injury. HDAC3 antagonizes myelinogenic neuregulin/PI3K/AKT signaling axis. Moreover, genome-wide profiling analyses reveal that HDAC3 represses pro-myelinating programs through epigenetic silencing, while coordinating with p300 histone acetyltransferase to activate myelination-inhibitory programs that include HIPPO signaling effector TEAD4 to inhibit myelin growth. Schwann-cell-specific deletion of either Hdac3 or Tead4 results in a profound increase in myelin thickness in sciatic nerves. Thus, our findings identify the HDAC3-TEAD4 network as a dual-function switch of cell-intrinsic inhibitory machinery that counters myelinogenic signals and maintains peripheral myelin homeostasis, highlighting the therapeutic potential of transient HDAC3 inhibition for improving peripheral myelin repair.

2018-02-11 | GSE93160 | GEO

A Histone Deacetylase 3-Dependent Pathway Delimits Peripheral Myelin Growth and Functional Regeneration [RNA-seq]

2018-02-11 | GSE93159 | GEO

RpS19a depletion alters the haematopoietic translatome to directly drive tissue overgrowth II

Project description:Counterintuitively, increased tumour predisposition is associated with ribosomal protein (RP) loss. Here, we provide the first evidence that RP depletion can directly drive tissue overgrowth. Haematopoietic compartment-specific knockdown (KD) of RpS19a in the Drosophila lymph gland not only results in haematopoietic stem and progenitor cell (HSPC) loss but also drives excess proliferation and tissue overgrowth. In accordance with continued ribosome assembly and protein synthesis, actively translating ribosomes (polysomes) are detected in RpS19a KD Drosophila S2 cells. The RpS19a KD ribosomes do, however, display heterogeneity and significantly altered stoichiometry of the associated translation initiation factors eIF4A and eIF5. Consistent with altered translation, in addition to increased association between polysomes and mRNA encoding growth promoting genes (e.g. Ras), we observe increased abundance of the ortholog of ribosomal (r)RNA small subunit methyltransferase NEP1. Although uncharacterised in Drosophila, in yeast and human NEP1 is implicated in methylation of 18S rRNA and, thus, 40S assembly and 80S ribosome stability. Moreover, NEP1 (EMG1) mutations in humans underpin Bowen-Conradi syndrome, a ribosomopathy associated with developmental defects, growth failure, and infantile death. Remarkably, NEP1 depletion suppresses the RpS19a KD phenotype, restoring both stem and progenitor cells and suppressing lymph gland overgrowth. We further demonstrate NEP1 depletion significantly decreases methylation of the 18S rRNA residue (Ψ1,279) that is implicated in ribosome assembly. Together, these data suggest the increased NEP1 expression associated with RpS19a KD promotes assembly of pro-proliferative “onco-ribosomes” to drive haematopoietic compartment overgrowth.

2024-06-30 | GSE236310 | GEO

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