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H4K16ac activates retrotransposons and contributes to their cis regulatory function [ATAC-seq]

ABSTRACT: Mammalian genomes harbour a large number of transposable elements (TEs) and their remnants. Most TEs are incapable of retrotransposition, however, they have evolved as cis-regulatory elements (CREs), enabling them to recruit host-encoded factors. Understanding the contribution of TEs in the regulation of the mammalian genome is an active area of research. Here we show that the male-specific lethal (MSL) complex-mediated acetylation of histone H4 lysine 16 (H4K16ac) regulates the transcription of TEs. Furthermore, H4K16ac marked TEs function as a rich source of cis regulatory elements in the human genome, wherein H4K16ac acts by maintaining the permissive chromatin structure and promoting the transcription of these TEs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE200767 | GEO | 2023/04/13

REPOSITORIES: GEO

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H4K16ac activates retrotransposons and contributes to their cis regulatory function [RNA-seq]

Project description:Mammalian genomes harbour a large number of transposable elements (TEs) and their remnants. Most TEs are incapable of retrotransposition, however, they have evolved as cis-regulatory elements (CREs), enabling them to recruit host-encoded factors. Understanding the contribution of TEs in the regulation of the mammalian genome is an active area of research. Here we show that the male-specific lethal (MSL) complex-mediated acetylation of histone H4 lysine 16 (H4K16ac) regulates the transcription of TEs. Furthermore, H4K16ac marked TEs function as a rich source of cis regulatory elements in the human genome, wherein H4K16ac acts by maintaining the permissive chromatin structure and promoting the transcription of these TEs.

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H4K16ac activates retrotransposons and contributes to their cis regulatory function [CUT&TAG]

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H4K16ac modification profile difference between Peg3-WT and KO MEF cells

Project description:PEG3 (Paternally Expressed Gene 3) is an imprinted gene encoding a DNA-binding protein. Two components of the mammalian MSL (Male-Specific Lethal) complex, Msl1 and Msl3, are known to be the genomic targets of PEG3. In this report, we performed genome-wide ChIP-seq experiments profiling H4K16ac levels using a set of MEF cells (Mouse Embryonic Fibroblast), the WT and KO of Peg3. The results indicated that about 10% of the mouse gene catalog showed high levels of H4K16ac levels in Peg3-KO MEFs than in Peg3-WT MEFs. This further suggests that mammalian Peg3 may control its downstream genes through the MSL complex.

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Complex-dependent histone acetyltransferase activity of KAT8 determines its role in transcriptional regulation and cellular homeostasis [TMT11plex whole proteome analysis]

Project description:Histone acetylation is associated with open chromatin and transcriptionally active genes. Specifically, acetylation of lysine 16 on histone H4 (H4K16ac) has been shown to prevent the assembly of nucleosomal arrays in vitro. This modification is catalyzed by the MYST-family histone acetyltransferase KAT8 (also known as MOF and MYST1), which is part of two distinct chromatin-associated complexes: NSL and MSL. While extensively studied in Drosophila, the functions of H4K16ac and the two KAT8-containing complexes in mammalian cells are not well understood. Here, we demonstrate a surprising complex-dependent activity of KAT8. We found that KAT8 catalyzes H4K5 and H4K8 acetylation as part of the NSL complex, whereas it catalyzes the bulk of H4K16 acetylation as part of the MSL complex. Furthermore, we show that the core proteins of the MSL complex and H4K16ac are not required for cell proliferation and global chromatin accessibility, whereas the NSL complex is essential for cell survival, as it is enriched at the promoters of housekeeping genes and is required for their transcription initiation. In summary, we show that KAT8 switches catalytic activity and function depending on its associated proteins, and that, as part of the NSL complex, it catalyzes H4K5 and H4K8 acetylation required for the expression of genes essential for cell survival

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Complex-dependent histone acetyltransferase activity of KAT8 determines its role in transcriptional regulation and cellular homeostasis [AP-MS]

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Complex-dependent histone acetyltransferase activity of KAT8 determines its role in transcriptional regulation and cellular homeostasis [histone dataset]

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Drosophila MSL complex globally acetylates H4 Lys16 on the male X chromosome for dosage compensation

Project description:Drosophila MSL complex binds the single male X chromosome to upregulate gene expression to equal that from the two female X chromosomes. However, it has been puzzling that ~25% of transcribed genes on the X do not stably recruit MSL complex. Here, we find that almost all active genes on the X are associated with robust H4 Lys16 acetylation (H4K16ac), the histone modification catalyzed by MSL complex. The distribution of H4K16ac is much broader than that of MSL complex, and our results favor the idea that chromosome-wide H4K16ac reflects transient association of MSL complex, occurring through spreading or chromosomal looping. Our results parallel those of localized Polycomb repressive complex and its more broadly distributed H3K27me3 chromatin mark, suggesting a common principle for the establishment of active and silenced chromatin domains For ChIP-on-chip experiments in larvae, 1000 third instar larvae were collected and chromatin was prepared as described previously. Five IPs were performed for each of the two biological replicates. For SL2 cells and male larvae, one ChIP-on-chip experiment was performed using anti-H4K16ac from Serotec (AHP417) (1-2 ul/IP). However, this antibody was discontinued, and an additional experiment for each was performed using anti-H4K16ac from Upstate/Millipore (07-329) (3 ul/IP). Both replicates for Kc cells and female larvae were also performed using anti-H4K16ac from Upstate/Millipore. Replicate experiments were highly reproducible.

2009-06-10 | E-GEOD-14884 | biostudies-arrayexpress

Drosophila MSL complex globally acetylates H4 Lys16 on the male X chromosome for dosage compensation

2009-06-10 | GSE14884 | GEO

Genomic properties of variably-methylated retrotransposons in mouse

Project description:Transposable elements (TEs) are enriched in cytosine methylation, preventing their mobility within the genome. Two examples of TEs that escape this regulation are the murine-specific intracisternal A particle (IAP) elements Avy and AxinFu, which exhibit inter-individual variability in methylation associated with phenotypic variation. To determine the frequency of this phenomenon, its underlying mechanisms, and its effects on gene expression, we previously conducted a screen identifying variably methylated IAPs (VM-IAPs). Here, we fully validate these elements, categorising VM-IAPs for the first time into those exhibiting tissue specificity (tsVM-IAPs) and those showing uniform methylation among tissues (constitutive- or cVM-IAPs) with both types having the potential to regulate the genome in cis. Using our validated set of VM-IAPs, we explore how variable methylation is established and identify sequences enriched within cVM-IAPs, implicating genetics as a determinant of variability. CTCF, a methylation-sensitive transcription factor known for its role in facilitating chromatin interactions, is enriched at VM-IAPs and we show that CTCF binding is inversely correlated with methylation at cVM-IAPs. We uncover dynamic physical interactions between lowly-methylated cVM-IAPs and other genomic loci, suggesting that VM-IAPs have the potential for long-range genomic regulation. Lastly, screening for variably methylated regions in other TEs shows that this phenomenon is largely limited to IAPs, which are amongst the youngest and most active endogenous retroviruses. We propose that a recently evolved interplay between genetic sequence, CTCF binding, and DNA methylation at young TEs has the potential to cause inter-individual variability in transcriptional outcomes with implications for phenotypic variation.

2021-03-02 | GSE159110 | GEO

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