Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

R-loop-induced DNA replication defects drive neuropathy in Koolen-de Vries syndrome

ABSTRACT: Koolen-de Vries syndrome (KdVS) is a neurodevelopmental disorder caused by KANSL1 haploinsufficiency. KANSL1 encodes a scaffold protein of the non-specific lethal (NSL) complex, which regulates transcription of constitutively expressed genes via acetylation of H4K5 and H4K8 around transcription start sites (TSS). How loss of KANSL1/NSL contributes to the neurodevelopmental defects in KdVS is unknown. Here, we find that KANSL1/NSL prevents the accumulation of R-loops (three-stranded DNA-RNA hybrid structures) at transcription start sites (TSSs) with low basal transcription and H4K5/H4K8 acetylation, where R-loops are typically not detected. If not suppressed, these R-loops delay DNA replication in early S-phase by stalling of the replisome. KdVS neural organoids also suffered from perturbed DNA replication concomitantly with neurodevelopmental defects, while KdVS neuronal cells showed reduced synaptic activity in a manner-dependent on R-loop accumulation. Our study offers insights into how KANSL1/NSL controls R-loop homeostasis to ensure faithful DNA replication during neuronal development, preventing neuropathy in KdVS patients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE289456 | GEO | 2026/02/10

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

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

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

2021-06-29 | PXD021943 | Pride

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

2021-06-29 | PXD022267 | Pride

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

2021-06-29 | PXD023865 | Pride

Complex-dependent histone acetyltransferase activity of KAT8 determines its role in transcriptional regulation and cellular homeostasis (ChIP-sequecing data)

2021-02-28 | GSE158736 | GEO

RNA-sequencing data of THP-1 cells after the knockdown of KANSL2, KANSL3 or KAT8

2021-02-28 | GSE158521 | GEO

ATAC-sequencing data of THP-1 cells after the knockout of MSL1

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 its catalytic activity and function depending on its associated proteins, and that it, as part of the NSL complex, catalyzes H4K5 and H4K8 acetylation required for the expression of genes essential for cell survival.

2021-02-28 | GSE157583 | GEO

Analysis of RNA-Seq with the deletion of components of the NSL complex

Project description:The human males absent on the first (MOF)-containing non-specific lethal (NSL) histone acetyltransferase complex consists of 9 subunits can acetylate histone H4K16, H4K5 and H4K8. NSL complex is essential for the multiple transcriptional regulation mechanisms. In this work, mRNA profiles of WT and NSL3 knockout 293T cells were generated by deep sequencing, in triplicate. qRT–PCR validation was performed using SYBR Green assays. we identified more than 100 genes as NSL complex transcriptional targets, including several transcription factors (TFs), such as Yin Yang 1 (YY1) which are mainly involved in cell proliferation, biological adhesion, and metabolic processes. the NSL complex regulates gene expression by forming a gene regulatory network with multiple TFs. It is conceivable that the NSL complex participates in the regulation of a variety of biological functions in cells.

2022-03-18 | GSE198646 | GEO

Analysis of histone modification with the deletion of components of the NSL complex

Project description:The human males absent on the first (MOF)-containing non-specific lethal (NSL) histone acetyltransferase complex consists of 9 subunits can acetylate histone H4K16, H4K5 and H4K8. It has been known that this complex shares WDR5 subunit with the MLL/SET histone methyltransferases, suggesting that NSL complex is essential for the multiple transcriptional regulation mechanisms. However, there are few reports on the function of NSL HAT in genome, It is necessary to clarify the details and specificity of histone H4 acetylation cooperates with H3K4 methylation to regulate gene transcription. In this work, Our results show that The NSL complex plays a critical role in regulating multiple histone modifications by using the CRISPR/Cas9 NSL3-KO 293T cell line and ChIP-Seq approach. The global levels of highly enriched H4K16ac, H4K5ac, H3K4me2 and H3K4me3 at TSSs (TSS ± 3 kb region) are inhibited by NSL3-KO. NSL3-KO seemed to have little effect on the enhancer mark H3K27ac and repressor mark H3K27me3, but H3K4me1 was greatly affected by NSL3-KO. Moreover, the NSL complex govern gene transcription and identified genes by a coordinative mode of H4K16ac and H3K4me2/me3. What’s more, De novo motif analysis of MOF and NSL3 targets indicated that the NSL complex forms a gene regulatory network with multiple transcription factors by regulating their genes expression or cooperating with some factors through binding to specific motif.

2022-03-18 | GSE198645 | GEO

Evolutionary conserved NSL complex/BRD4 axis controls transcription activation via histone acetylation

Project description:Cells rely on a diverse repertoire of genes for maintaining homeostasis, but the transcriptional networks underlying their expression remain poorly understood. The MOF acetyltransferase-containing Non-Specific Lethal (NSL) complex is a broad transcription regulator. It is essential in Drosophila and haploinsufficiency of the human KANSL1 subunit results in the Koolen-de Vries syndrome. Here, we perform a genome-wide RNAi screen and identify the BET protein BRD4 as evolutionary conserved co-factor of the NSL complex. Using Drosophila and mouse embryonic stem cells, we characterise a recruitment hierarchy, where NSL-deposited histone acetylation induces BRD4 recruitment for transcription of constitutively active genes. Transcriptome analyses in Koolen-de Vries patient-derived fibroblasts reveals perturbations with a cellular homeostasis signature that are evoked by the NSL complex/BRD4-axis. We propose that BRD4 represents a conserved bridge between the NSL complex and transcription activation and provide a new perspective in the understanding of their functions in healthy and diseased states.

2020-03-13 | GSE135771 | GEO

Evolutionary conserved NSL complex/BRD4 axis controls transcription activation via histone acetylation

2020-03-13 | GSE135815 | GEO