Similar Datasets
Project description:We aimed at investigating the function of TIP60 in the in the mammalian hippocampus. For this, we used mice with a forebrain-specific deletion of Tip60 upon tamoxifen injection (Tip60 cKO). RNA-sequencing was applied to examine the transcriptome changes in the CA1 region upon Tip60 deletion. We observed massive transcriptional changes and identified a neurodegeneration-related signature at a time when there are no obvious morphological changes in Tip60 cKO mice. Later on these mice develop extensive neurodegeneration in hippocampal CA1.
2019-10-24 | GSE139298 | GEO
Project description:TIP60/KAT5 is required for the maintenance of homeostasis in hippocampal CA1
| PRJNA577464 | ENA
Project description:TIP60/KAT5 is required for neuronal viability in hippocampal CA1
| PRJNA579152 | ENA
Project description:Aberrant histone acetylation contributes to age-dependent cognitive decline and neurodegenerative diseases. We analyze the function of lysine acetyltransferase TIP60/KAT5 in neurons of the hippocampus using an inducible mouse model. TIP60-deficiency in the adult forebrain leads within days to extensive transcriptional dysfunction characterized by the presence of a neurodegeneration-related signature in CA1. Cell cycle- and immunity-related genes are upregulated while learning- and neuronal plasticity-related genes are downregulated. The dysregulated genes seen under TIP60-deficiency overlap with those in the well-characterized CK-p25 neurodegeneration model. We found that H4K12 is hypoacetylated at the transcriptional start sites of those genes whose expression is dampened in TIP60-deficient mice. Transcriptional dysregulation is followed over a period of weeks by activation of Caspase 3 and fragmentation of ?-actin in CA1 neurites, eventually leading to severe neuronal loss. TIP60-deficient mice also develop mild memory impairment. These phenotypes point to a central role of TIP60 in transcriptional networks that are critical for neuronal viability.
| S-EPMC6838100 | biostudies-literature
Project description:Hematopoietic stem cells (HSC) have the potential to replenish the blood system for the lifetime of the organism. Their two defining properties, self-renewal and differentiation, are tightly regulated by the epigenetic machineries. Here, using conditional gene knockout models, we demonstrate a critical requirement of lysine acetyltransferase 5 (also known as Tip60) for murine HSC maintenance both in the embryonic and adult stages, which depends on its acetyltransferase activity. Genome-wide chromatin and transcriptome profiling revealed that Tip60 co-localizes with c-Myc and that Tip60 deletion suppress the expression of Myc target genes, which are associated with critical biological processes for HSC maintenance, cell-cycle and DNA repair. Notably, acetylated H2A.Z (acH2A.Z) was enriched at the Tip60-bound active chromatin and Tip60 deletion induced a robust reduction in the acH2A.Z / H2A.Z ratio. These results uncover a critical epigenetic regulatory layer for HSC maintenance through Tip60 dependent H2A.Z acetylation to activate Myc target genes.
2020-06-19 | GSE120705 | GEO
Project description:Breast cancer is stratified into four distinct clinical subtypes, using three key biomarkers (Her2/Neu gene status, Estrogen and Progesterone receptor status). However, each subtype is a heterogeneous group, displaying significant variation in survival rates and treatment response. New biomarkers are required to provide more precise stratification of breast cancer cohorts to inform personalised treatment options/predict outcomes. Tip60 is a member of the MYST sub-family of histone acetyltransferases (HATs), and is directly involved in genome maintenance, gene regulation and DNA damage response/repair pathways (key chemotherapeutic influencing mechanisms). We aimed to determine if quantifying Tip60 staining patterns improved breast cancer stratification. We defined Tip60 protein in vivo, quantifying location (cytoplasmic, nuclear), percent of cells and staining intensity in a breast cancer tissue microarray (n = 337). A significant association of specific Tip60 staining patterns with breast cancer subtype, ER or PR status and Tumour grade was found. Importantly, low Tip60 mRNA expression correlated with poor overall survival and relapse free survival. We found Tip60 is a biomarker able to stratify breast cancer patients, and low Tip60 expression is a significant risk factor indicating a higher chance of disease reoccurrence. This work highlights Tip60 regulation as a key factor influencing the development of breast cancer.
| S-EPMC6405843 | biostudies-other
Project description:Stem cells establish cortical polarity and divide asymmetrically to simultaneously maintain themselves and generate differentiating offspring cells. Several chromatin modifiers have been identified as stemness factors in mammalian pluripotent stem cells, but whether these factors control stem cell polarity and asymmetric division has not been investigated so far. We addressed this question in Drosophila neural stem cells called neuroblasts. We identified the Tip60 chromatin remodeling complex and its interaction partner Myc to regulate target genes required for neuroblast maintenance. Knockdown of members of this complex results in loss of cortical polarity, symmetric neuroblast division and premature differentiation through nuclear entry of the transcription factor Prospero. We found that aPKC is the key target gene of Myc and the Tip60 complex subunit Domino regulating neuroblast polarity. Our transcriptome analysis further showed that Domino regulates the expression of mitotic spindle genes which were identified before as direct Myc targets. Our findings reveal an evolutionarily conserved functional link between Myc, the Tip60 complex and the molecular network controlling cell polarity and asymmetric cell division.
2018-07-06 | PXD009939 | Pride
Project description:The Tip60 (also known as Kat5) lysine acetyltransferase functions broadly as a transcriptional co-activator that acetylates histones. In contrast, Tip60 functions in embryonic stem cells (ESCs) both to silence genes that promote differentiation and to activate genes required for proliferation. The mechanism by which Tip60 functions as a repressor is unknown. Here we show that the class II histone deacetylase Hdac6 co-purifies with Tip60-p400 complex from ESCs and is necessary for complete silencing of most differentiation genes targeted by Tip60. In contrast to differentiated cells, where Hdac6 is mainly cytoplasmic and does not interact with Tip60, Hdac6 is largely nuclear in ESCs and neural stem cells (NSCs) and interacts with Tip60-p400 in both cell types. Hdac6 is enriched at promoters bound by Tip60-p400 in ESCs, but while Tip60 binds on both sides of transcription start sites (TSSs), Hdac6 binding overlaps with only the downstream Tip60 peak. Surprisingly, Hdac6 does not deacetylate histones at these sites, but rather is required for Tip60 binding. These data suggest that nuclear exclusion of Hdac6 during differentiation plays a major role in modulation of Tip60-p400 function. We determined the genome-wide localization of Tip60 and Hdac6 in mouse ES cells, and examined genomic binding profiles of Tip60 and Hdac6 upon indicated knockdown by ChIP-seq. We examined genomic binding profiles of p400 upon indicated knockdown by ChIP-seq.
2013-11-20 | E-GEOD-42209 | biostudies-arrayexpress
Project description:Genome-wide mapping of TIP60 complex subunits in K562 cells. The objectives of this study are to describe TIP60 genome wide localization, confirm MBTD1 co-localization with already known unique subunits and observe the impact of MBTD1 on TIP60 complex targeting to chromatin. The TIP60 acetyltransferase complex is a key regulator of genome expression and stability. Here, we identified MBTD1 as a new stable subunit of the complex and revealed interesting insights about TIP60 function during the repair of DNA double strand breaks. MBTD1 binds H4K20me1/2, helping TIP60 association to specific promoters but also the DNA repair process by homologous recombination. While pro-end joining factor 53BP1 engages chromatin through simultaneous binding of H4K20me2 and H2AK15ub, TIP60 regulates the resolution of 53BP1 foci after DNA damage through a related bivalent mechanism. MBTD1 competes with 53BP1 for the H4K20me2 mark, affecting its retention at the break cooperatively with H4 acetylation by TIP60. In addition, we show that H2AK15ub deposition by RNF168 inhibits chromatin acetylation by TIP60, whereas H2AK15 can also be acetylated by TIP60 in vivo, therefore blocking its ubiquitylation. Altogether, these results uncover an intricate mechanism orchestrated by the TIP60 complex to regulate 53BP1-dependent repair pathway selection, through incompatible bivalent binding/action on chromatin.
2016-04-30 | GSE69645 | GEO