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Frac-seq in mESCs with and without TIP60

ABSTRACT: Transcript buffering entails the reciprocal modulation of mRNA synthesis and degradation rates, ensuring a constant RNA concentration amidst changes in cellular conditions. While an increasing body of research supports a global, non-sequence-specific linkage between mRNA synthesis and degradation, the underlying mechanisms remain elusive. To explore this, we investigated alterations in RNA metabolism following the acute depletion of TIP60/KAT5, the transcriptional coactivator and acetyltransferase subunit of the NuA4 complex, in mouse embryonic stem cells. By combining RNA sequencing of nuclear, cytoplasmic, and newly synthesised transcript fractions with biophysical modelling, we show that TIP60 activates transcription of numerous genes, with substantially fewer genes undergoing transcriptional repression. Surprisingly, specific RNA species' transcription changes triggered by TIP60 depletion were counterbalanced by compensatory adjustments in RNA export and/or stability within the nucleus and in RNA stability within the cytoplasm. These discoveries imply that transcript buffering operates on a gene-specific level and suggest that cells continually monitor RNA molecule counts in nuclear and cytoplasmic compartments to maintain cellular homeostasis.

ORGANISM(S): Mus musculus

PROVIDER: GSE253312 | GEO | 2024/01/30

REPOSITORIES: GEO

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TT-seq in mESCs with and without TIP60

Project description:Transcript buffering entails the reciprocal modulation of mRNA synthesis and degradation rates, ensuring a constant RNA concentration amidst changes in cellular conditions. While an increasing body of research supports a global, non-sequence-specific linkage between mRNA synthesis and degradation, the underlying mechanisms remain elusive. To explore this, we investigated alterations in RNA metabolism following the acute depletion of TIP60/KAT5, the transcriptional coactivator and acetyltransferase subunit of the NuA4 complex, in mouse embryonic stem cells. By combining RNA sequencing of nuclear, cytoplasmic, and newly synthesised transcript fractions with biophysical modelling, we show that TIP60 activates transcription of numerous genes, with substantially fewer genes undergoing transcriptional repression. Surprisingly, specific RNA species' transcription changes triggered by TIP60 depletion were counterbalanced by compensatory adjustments in RNA export and/or stability within the nucleus and in RNA stability within the cytoplasm. These discoveries imply that transcript buffering operates on a gene-specific level and suggest that cells continually monitor RNA molecule counts in nuclear and cytoplasmic compartments to maintain cellular homeostasis.

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RNA-seq in mESCs with and without TIP60

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Rpb4 functions mainly in mRNA synthesis by RNA polymerase II

Project description:RNA polymerase II (Pol II) is the central enzyme that carries out eukaryotic mRNA transcription and consists of a 10-subunit catalytic core and a heterodimeric subcomplex of subunits Rpb4 and Rpb7 (Rpb4/7). Rpb4/7 has been proposed to shuttle from the nucleus to the cytoplasm, and to function there in mRNA translation and degradation. Here we provide evidence that Rpb4 mainly functions in nuclear mRNA synthesis by Pol II, and evidence arguing against an important cytoplasmic role. We used metabolic RNA labeling and comparative Dynamic Transcriptome Analysis (cDTA) to show that Rpb4 deletion in Saccharomyces cerevisiae causes a drastic defect in mRNA synthesis that is compensated by down-regulation of mRNA degradation, resulting in mRNA level buffering. Deletion of Rpb4 can be rescued by covalent fusion of Rpb4 to the Pol II core subunit Rpb2, which largely restores mRNA synthesis and degradation defects caused by Rpb4 deletion. Thus Rpb4 is a bona fide Pol II core subunit which functions mainly in mRNA synthesis.

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Hdac6 regulates Tip60-p400 function in stem cells (sequencing)

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.

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Frac-seq in mESCs with and without TIP60

Project description:Frac-seq in mESCs with and without TIP60

| PRJNA1065266 | ENA

Characterisation of the temporal hepatic transcriptome at subcellular level

Project description:In eukaryotes, RNA is synthesized in the nucleus, spliced, and exported to the cytoplasm where it is translated and finally degraded. Any of these steps could be subject to temporal regulation during the circadian cycle, generating daily fluctuations of RNA accumulation and impacting the distribution of transcripts in different subcellular compartments. Here, we performed a comprehensive analysis of nuclear and cytoplasmic, polyA and total, transcriptomes of mouse livers sampled along the daily cycle. These data provide a genome-wide temporal inventory of RNA subcellular enrichments, and revealed specific signatures of splicing, nuclear export and cytoplasmic mRNA stability related to transcript and gene lengths. Combined with a mathematical model describing rhythmic RNA profiles , we could test the rhyhtmicity of export rates and cytoplasmic degradation rates of ~1400 genes. While nuclear export times are usually much shorter than cytoplasmic half-lives, we found that that nuclear export contributes to the modulation and generation of rhythmic profiles of ~10% of the cycling nuclear mRNAs. This study provides an estimation of the nuclear and cytoplasmic life times in the liver and contributes to a better understanding of the dynamic regulation of the transcriptome during the feeding-fasting cycle.

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Effects of MBTD1 on gene expression

Project description:The NuA4/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 gleaned intriguing insights into TIP60’s function. Harboring a histone reader domain for H4K20me1/2, MBTD1 allows TIP60 to associate with specific gene promoters and to promote the repair of DNA double strand breaks by homologous recombination. Total RNA was analyzed on Illumina Human HT-12 V4.0 expression beadchip by McGill University and Genome Québec innovation Centre

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Hdac6 regulates Tip60-p400 function in stem cells (sequencing)

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Oncogenic ZMYND11-MBTD1 fusion protein anchors the NuA4/TIP60 histone acetyltransferase complex to the coding region of active genes

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