TIP55, a splice isoform of the KAT5 acetyltransferase, is essential for developmental gene regulation and organogenesis
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ABSTRACT:
PROVIDER: PRJNA437900 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6825342.fastq.gz | Fastqsanger.gz | |||
| SRR6825343.fastq.gz | Fastqsanger.gz | |||
| SRR6825344.fastq.gz | Fastqsanger.gz | |||
| SRR6825345.fastq.gz | Fastqsanger.gz | |||
| SRR6825346.fastq.gz | Fastqsanger.gz |
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Project description:Multiple varieties of most chromatin regulatory complexes are expressed in mammals, resulting from a combination of alternative splicing, differential incorporation of accessory subunits, and other processes. Despite this complexity, chromatin regulators are usually characterized in vivo using mutants that affect multiple forms. Here we examine the developmental functions of the TIP55 isoform of the KAT5 (TIP60) histone acetyltransferase. In contrast to the preimplantation developmental arrest of mice deficient for all four Kat5 transcripts, mice specifically deficient for Tip55 die around E11.5 and fail to develop beating hearts . Prior to developmental arrest, mice exhibit altered proliferation and cell death in heart and neural tube, respectively. Consistent with these findings, transcriptome profiling prior to the onset of overt morphological abnormalities reveals alterations in multiple tissue types. These findings reveal that although Tip55 is dispensable for the pre- and early post-implantation roles of Kat5, it is essential for organogenesis. Targeted mutations of additional Kat5 isoforms will be necessary to understand their specific functions. Furthermore, targeted mutations of individual isoforms of other chromatin remodeling enzymes will likely uncover new biological functions.
2018-09-28 | GSE111691 | GEO
Project description:Regulation of chromatin structure is critical for cell type-specific gene expression. Many chromatin regulatory complexes exist in several different forms, due to alternative splicing and differential incorporation of accessory subunits. However, in vivo studies often utilize mutations that eliminate multiple forms of complexes, preventing assessment of the specific roles of each. Here we examined the developmental roles of the TIP55 isoform of the KAT5 histone acetyltransferase. In contrast to the pre-implantation lethal phenotype of mice lacking all four Kat5 transcripts, mice specifically deficient for Tip55 die around embryonic day 11.5 (E11.5). Prior to developmental arrest, defects in heart and neural tube were evident in Tip55 mutant embryos. Specification of cardiac and neural cell fates appeared normal in Tip55 mutants. However, cell division and survival were impaired in heart and neural tube, respectively, revealing a role for TIP55 in cellular proliferation. Consistent with these findings, transcriptome profiling revealed perturbations in genes that function in multiple cell types and developmental pathways. These findings show that Tip55 is dispensable for the pre- and early post-implantation roles of Kat5, but is essential during organogenesis. Our results raise the possibility that isoform-specific functions of other chromatin regulatory proteins may play important roles in development.
| S-EPMC6175934 | biostudies-literature
Project description:Quiescence cancer stem-like cells may play key roles in promoting tumor cell heterogeneity and recurrence for many tumors, including glioblastoma (GBM). Here we show that the protein acetyltransferase KAT5 is a key regulator of transcriptional, epigenetic, and proliferative heterogeneity impacting transitions into G0-like states in GBM. KAT5 activity suppresses the emergence of quiescent subpopulations with neurodevelopmental progenitor characteristics, while promoting GBM stem-like cell (GSC) self-renewal through coordinately regulating E2F- and MYC- transcriptional networks with protein translation. KAT5 inactivation significantly decreases tumor progression and invasive behavior while increasing survival after standard of care. Further, increasing MYC expression in human neural stem cells stimulates KAT5 activity and protein translation, as well as confers sensitivity to homoharringtonine, to similar levels to those found in GSCs and high-grade gliomas. These results suggest that the dynamic behavior of KAT5 plays key roles in G0 ingress/egress, adoption of quasi-neurodevelopmental states, and aggressive tumor growth in gliomas.
2023-12-01 | GSE198524 | GEO
Project description:Alternative RNA splicing can generate distinct protein isoforms to allow for the differential control of cell processes across cell types. The chromosome segregation and cell division programs associated with somatic mitosis and germline meiosis display dramatic differences such as kinetochore orientation, cohesin removal, or the presence of a gap phase. These changes in chromosome segregation require alterations to the established cell division machinery. However, it remains unclear what aspects of kinetochore function and its regulatory control differ between the mitotic and meiotic cell divisions to rewire these core processes. Additionally, the alternative splice isoforms that differentially modulate distinct cell division programs have remained elusive. Here, we demonstrate that mammalian germ cells express an alternative mRNA splice isoform for the kinetochore component, DSN1, a subunit of the MIS12 complex that links the centromeres to spindle microtubules during chromosome segregation. This germline DSN1 isoform bypasses the requirement for Aurora kinase phosphorylation for its centromere localization due to the absence of a key regulatory region allowing DSN1 to display persistent centromere localization. Expression of the germline DSN1 isoform in somatic cells results in constitutive kinetochore localization, chromosome segregation errors, and growth defects, providing an explanation for its tight cell type-specific expression. Reciprocally, precisely eliminating expression of the germline-specific DSN1 splice isoform in mouse models disrupts oocyte maturation and early embryonic divisions coupled with a reduction in fertility. Together, this work identifies a germline-specific splice isoform for a chromosome segregation component and implicates its role in mammalian fertility.
2024-08-28 | PXD054119 | Pride
Project description:In solid tumors, quiescent/G0 cell populations likely play important roles in maintaining cellular heterogeneity and promoting recurrence after stand of care. However, little is known about the mechanisms of tumor cell G0 ingress and egress. To discover regulators of G0-like states for glioblastoma (GBM), we performed a genome-wide CRISPR-Cas9 screen in patient-derived GBM stem-like cells (GSCs) for genes that when inhibited trap cells in G0-like states. We identify the protein acetyltransferase KAT5 as a key regulator of G0 and cell cycle dynamics in GSCs and GSC-derived tumors. In primary gliomas, KAT5low cells display quiescent properties, while overall KAT5 activity increases as tumors become more aggressive. Further, we find that KAT5 activity suppresses the emergence of non-dividing subpopulations with oligodendrocyte progenitor and radial glial cell characteristics both in vitro and in a GSC tumor model. These results reveal that KAT5 activity regulates transitions between non-dividing, neurodevelopmental, and proliferative states in GBM tumors.
2023-12-01 | GSE198522 | GEO
Project description:In solid tumors, quiescent/G0 cell populations likely play important roles in maintaining cellular heterogeneity and promoting recurrence after stand of care. However, little is known about the mechanisms of tumor cell G0 ingress and egress. To discover regulators of G0-like states for glioblastoma (GBM), we performed a genome-wide CRISPR-Cas9 screen in patient-derived GBM stem-like cells (GSCs) for genes that when inhibited trap cells in G0-like states. We identify the protein acetyltransferase KAT5 as a key regulator of G0 and cell cycle dynamics in GSCs and GSC-derived tumors. In primary gliomas, KAT5low cells display quiescent properties, while overall KAT5 activity increases as tumors become more aggressive. Further, we find that KAT5 activity suppresses the emergence of non-dividing subpopulations with oligodendrocyte progenitor and radial glial cell characteristics both in vitro and in a GSC tumor model. These results reveal that KAT5 activity regulates transitions between non-dividing, neurodevelopmental, and proliferative states in GBM tumors.
2023-12-01 | GSE198523 | GEO
Project description:Characterization of splice isoform switching during human kidney development
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Project description:Alternative splicing is a mechanism in eukaryotes by which different forms of messenger RNAs (mRNAs) are generated from the same gene. Identification of alternative splice variants requires the identification of peptides specific for alternative splice forms. For this purpose, we generated a human database which contains only proteotypic tryptic peptides specific for alternative splice forms from Swiss-Prot entries. Using this database allows an easy access to the peptide sequences that matches the unique amino acid sequence of splice variants to MS data. Furthermore, we combined this database without isoform 1-specific peptides with human Swiss-Prot. This combined database can be used as a general database for searching of LC-MS data. LC-MS data derived from in-solution digests of two different cell lines (LNCaP, HeLa), and phosphoproteomics studies were analyzed using these two databases. Several non-isoform 1-specific peptides were found in both cell lines, some of them seemed to be cell line specific. Control and apoptotic phosphoproteomes from Jurkat T cells revealed several non-isoform 1-specific peptides and some of them showed clear quantitative differences between the two states.
2017-05-19 | PXD006026 | Pride
Project description:KAT5 encodes an essential lysine acetyltransferase previously called TIP60 involved in gene expression, DNA repair, chromatin remodeling, apoptosis and cell proliferation; but it remains unclear whether variants in this gene causes a genetic disease. Here, we study three individuals with heterozygous de novo missense variants in KAT5 that affect normally invariant residues, with one at the chromodomain (p.Arg53His) and two at or near the acetyl-CoA binding site (p.Cys369Ser and p.Ser413Ala). All three individuals have cerebral malformations, seizures, global developmental delay or intellectual disability, and severe sleep disturbance. Progressive cerebellar atrophy was also noted. Histone acetylation assays with purified mutant KAT5 demonstrated that the variants decrease or abolish the ability of the resulting NuA4/TIP60 multi-subunit complexes to acetylate the histone H4 tail in chromatin. Transcriptomic analysis in patient-derived fibroblasts showed deregulation of multiple genes controlling development. Moreover, there was also upregulated expression of PER1 (a key gene involved in circadian control), in agreement with sleep anomalies in all the patients. In conclusion, dominant missense KAT5 variants cause histone acetylation deficiency with transcriptional dysregulation of multiples genes, thereby leading to a neurodevelopmental syndrome with sleep disturbance, cerebellar atrophy and facial dysmorphisms suggesting a recognizable syndrome.
2020-07-11 | GSE154199 | GEO
Project description:Alternative RNA splicing can generate distinct protein isoforms to allow for the differential control of cell processes across cell types. The chromosome segregation and cell division programs associated with somatic mitosis and germline meiosis display dramatic differences such as kinetochore orientation, cohesin removal, or the presence of a gap phase. These changes in chromosome segregation require alterations to the established cell division machinery. However, it remains unclear what aspects of kinetochore function and its regulatory control differ between the mitotic and meiotic cell divisions to rewire these core processes. Additionally, the alternative splice isoforms that differentially modulate distinct cell division programs have remained elusive. Here, we demonstrate that mammalian germ cells express an alternative mRNA splice isoform for the kinetochore component, DSN1, a subunit of the MIS12 complex that links the centromeres to spindle microtubules during chromosome segregation. This germline DSN1 isoform bypasses the requirement for Aurora kinase phosphorylation for its centromere localization due to the absence of a key regulatory region allowing DSN1 to display persistent centromere localization. Expression of the germline DSN1 isoform in somatic cells results in constitutive kinetochore localization, chromosome segregation errors, and growth defects, providing an explanation for its tight cell type-specific expression. Reciprocally, precisely eliminating expression of the germline-specific DSN1 splice isoform in mouse models disrupts oocyte maturation and early embryonic divisions coupled with a reduction in fertility. Together, this work identifies a germline-specific splice isoform for a chromosome segregation component and implicates its role in mammalian fertility.
2025-02-07 | MSV000097075 | MassIVE