Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

UHRF1 ubiquitin ligase activity supports the maintenance of low-density CpG methylation [BiSulfite-seq]

ABSTRACT: The E3 ubiquitin ligase UHRF1 is an established cofactor for replication-coupled DNA methylation inheritance. The current model posits a stepwise pathway in which UHRF1 engages nucleosomes through histone and DNA binding. This multivalent nucleosome readout directs UHRF1 ubiquitin ligase activity toward several lysines on N-terminal tails of histone H3, binding sites for DNMT1 through tandem ubiquitin interacting motifs (UIM1 and UIM2). While this elegant chromatin regulatory mechanism is now taking shape, the extent to which ubiquitin signaling through UHRF1 contributes to DNMT1-dependent DNA methylation maintenance genome-wide is not known. Here, we present comparative, genome-scale analysis of DNA methylation inheritance in human colon cancer cells with compromised UHRF1 ubiquitin ligase and DNMT1 ubiquitin reading activities. We reveal that DNA methylation maintenance in contexts of low CpG density is particularly vulnerable to disruption of UHRF1 ubiquitin ligase activity. This low CpG density hypomethylation signature, a common feature of partially methylated domains (PMDs) in human cancers, is also seen when DNMT1 ubiquitin reading activity through UIM1 is disrupted. Notably, disrupting UIM2 function affects DNA methylation inheritance to a similar extent as a catalytically dead form of the enzyme. Collectively, these studies demonstrate that DNMT1-dependent DNA methylation inheritance is a ubiquitin-regulated process and suggest that a disrupted UHRF1-DNMT1 ubiquitin signaling axis contributes to the development of PMDs in human cancers.

ORGANISM(S): Homo sapiens

PROVIDER: GSE256031 | GEO | 2024/10/23

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

UHRF1 ubiquitin ligase activity supports the maintenance of low-density CpG methylation [ChIP-seq]

Project description:The E3 ubiquitin ligase UHRF1 is an established cofactor for replication-coupled DNA methylation inheritance. The current model posits a stepwise pathway in which UHRF1 engages nucleosomes through histone and DNA binding. This multivalent nucleosome readout directs UHRF1 ubiquitin ligase activity toward several lysines on N-terminal tails of histone H3, binding sites for DNMT1 through tandem ubiquitin interacting motifs (UIM1 and UIM2). While this elegant chromatin regulatory mechanism is now taking shape, the extent to which ubiquitin signaling through UHRF1 contributes to DNMT1-dependent DNA methylation maintenance genome-wide is not known. Here, we present comparative, genome-scale analysis of DNA methylation inheritance in human colon cancer cells with compromised UHRF1 ubiquitin ligase and DNMT1 ubiquitin reading activities. We reveal that DNA methylation maintenance in contexts of low CpG density is particularly vulnerable to disruption of UHRF1 ubiquitin ligase activity. This low CpG density hypomethylation signature, a common feature of partially methylated domains (PMDs) in human cancers, is also seen when DNMT1 ubiquitin reading activity through UIM1 is disrupted. Notably, disrupting UIM2 function affects DNA methylation inheritance to a similar extent as a catalytically dead form of the enzyme. Collectively, these studies demonstrate that DNMT1-dependent DNA methylation inheritance is a ubiquitin-regulated process and suggest that a disrupted UHRF1-DNMT1 ubiquitin signaling axis contributes to the development of PMDs in human cancers.

2024-10-23 | GSE256030 | GEO

UHRF1 ubiquitin ligase activity supports the maintenance of low-density CpG methylation [EPIC methylation]

2024-10-23 | GSE256028 | GEO

Hemi-methylated DNA regulates DNA methylation inheritance through allosteric control of H3 ubiquitylation by UHRF1

Project description:DNA methylation is a heritable chromatin modification essential to mammalian development that functions with histone post-translational modifications to regulate chromatin structure and gene expression programs. The epigenetic inheritance of DNA methylation requires the combined actions of DNMT1 and UHRF1, a histone- and DNA-binding RING E3 ubiquitin ligase that facilitates DNMT1 recruitment to sites of newly replicated DNA through the ubiquitylation of histone H3. UHRF1 binds DNA with modest selectivity towards hemi-methylated CpG dinucleotides (HeDNA); however, the contribution of HeDNA sensing to UHRF1 function remains elusive. Here, we reveal that the interaction of UHRF1 with HeDNA is required for DNA methylation inheritance but is dispensable for chromatin interaction, which is governed by reciprocal positive cooperativity between the UHRF1 histone- and DNA-binding domains. We further show that HeDNA functions as an allosteric regulator of UHRF1 ubiquitin ligase activity, directing ubiquitylation towards multiple lysines on the H3 tail adjacent to the UHRF1 histone-binding site. Collectively, our studies define a highly orchestrated epigenetic control mechanism involving modifications both to histones and DNA that facilitate UHRF1 chromatin targeting, H3 ubiquitylation, and DNA methylation inheritance.

2016-08-25 | PXD003983 | Pride

Critical role of the UBL-domain in stimulating the E3 ubiquitin ligase activity of UHRF1 towards chromatin

Project description:The RING E3 ubiquitin ligase UHRF1 controls DNA methylation through its ability to target the maintenance DNA methyltransferase DNMT1 to newly replicated chromatin. DNMT1 recruitment relies on ubiquitylation of histone H3 by UHRF1, however, how UHRF1 deposits ubiquitin onto the histone is unknown. Here, we demonstrate that the ubiquitin-like domain (UBL) of UHRF1 is essential for RINGmediated H3 ubiquitylation. Using chemical crosslinking and mass spectrometry, biochemical assays and recombinant chromatin substrates we show that the UBL participates in structural rearrangements of UHRF1 upon binding to chromatin and the E2 ubiquitin conjugating enzyme UbcH5a/UBE2D1. Similar to ubiquitin, the UBL exerts its effects through a hydrophobic patch that contacts a regulatory surface on the “backside” of the E2 to stabilise the E2-E3-chromatin complex. Our analysis of the enzymatic mechanism of UHRF1 uncovers an unexpected function of the UBLdomain and defines a new role for this domain in DNMT1-dependent inheritance of DNA methylation.

2018-11-04 | PXD011510 | Pride

Critical role of the UBL-domain in stimulating the E3 ubiquitin ligase activity of UHRF1 towards chromatin

Project description:The RING E3 ubiquitin ligase UHRF1 controls DNA methylation through its ability to target the maintenance DNA methyltransferase DNMT1 to newly replicated chromatin. DNMT1 recruitment relies on ubiquitylation of histone H3 by UHRF1, however, how UHRF1 deposits ubiquitin onto the histone is unknown. Here, we demonstrate that the ubiquitin-like domain (UBL) of UHRF1 is essential for RING-mediated H3 ubiquitylation. Using chemical crosslinking and mass spectrometry, biochemical assays and recombinant chromatin substrates we show that the UBL participates in structural rearrangements of UHRF1 upon binding to chromatin and the E2 ubiquitin conjugating enzyme UbcH5a/UBE2D1. Similar to ubiquitin, the UBL exerts its effects through a hydrophobic patch that contacts a regulatory surface on the “backside” of the E2 to stabilise the E2-E3-chromatin complex. Our analysis of the enzymatic mechanism of UHRF1 uncovers an unexpected function of the UBL-domain and defines a new role for this domain in DNMT1-dependent inheritance of DNA methylation.

2018-08-29 | GSE119120 | GEO

Identificaiton of novel acetylation sites in UHRF1 mediated by acetyltransferase MOF

Project description:The multi-domain protein UHRF1 (ubiquitin-like, containing PHD and RING finger domains, 1) recruits DNMT1 for DNA methylation maintenance during DNA replication. Here, we show that MOF (Males absent On the First) is an acetyltransferase of UHRF1 to acetylate UHRF1 at Lys670 in the pre-RING linker region whereas HDAC1 is a deacetylase of UHRF1 at the same site. The MOF/HDAC1-mediated acetylation in UHRF1 is cell-cycle regulated and peaks at G1/S phase, in line with the function of UHRF1 in recruiting DNMT1 to maintain DNA methylation. In addition, UHRF1 acetylation significantly enhances its E3 ligase activity and elimination of UHRF1 acetylation at these sites attenuates UHRF1-mediated H3 ubiquitination, which in turn impairs the DNMT1 recruitment and DNA methylation. Taken together, these findings not only identify MOF as a new acetyltransferase for UHRF1 but also reveal a novel mechanism underlying the regulation of DNA methylation maintenance through MOF-mediated UHRF1 acetylation.

2024-03-06 | PXD040426 | Pride

DNMT1 IP-MS alalysis to identify ubiquitin-dependent interacting partners

Project description:Stable inheritance of DNA methylation is critical for maintaining the differentiated phenotypes in multicellular organisms. However, the molecular basis ensuring high fidelity of maintenance DNA methylation is largely unknown. Here, we demonstrate that two distinct modes of DNMT1 recruitment, one is DNA replication-coupled and the other is uncoupled mechanism, regulate the stable inheritance of DNA methylation. PCNA-associated factor 15 (PAF15) represents a primary target of UHRF1 and undergoes dual mono-ubiquitylation (PAF15Ub2) on chromatin. PAF15Ub2 specifically interacts with DNMT1 and controls the recruitment of DNMT1 in a DNA replication-coupled manner. Thus, loss of PAF15Ub2 results in impaired DNA methylation at sites replicating during early S phase. In contrast, outside of S phase or when PAF15 ubiquitylation is perturbed, UHRF1 ubiquitylates histone H3 to promote DNMT1 recruitment. Together, we identify replication-coupled and uncoupled mechanisms of maintenance DNA methylation, both of which collaboratively ensure the stable DNA methylation.

2020-02-25 | PXD015282 | Pride

Ubiquitome analysis of UHRF1 and UHRF2-deficient mESCs

Project description:The E3 ligase UHRF1 is an essential epigenetic cofactor for DNMT1 dependent maintenance DNA methylation, which provides a binding platform for DNMT1 by both cooperative binding of histones and hemi-methylated DNA as well as by ubiquitinating histone H3. Here, we conduct a comprehensive screen to identify novel ubiquitination targets of UHRF1 and its paralogue UHRF2 by comparing the ubiquitome of wildtype (wt), UHRF1- and UHRF2-deficient mouse embryonic stem cells. With an antibody-dependent enrichment of ubiquitin remnant motif-containing peptides followed by isobaric-labeling based quantitative mass spectrometry, we find both known and novel E3 ligase substrates of UHRF1 involved in a variety of biological processes such as RNA processing, DNA methylation and DNA damage repair.

2017-10-24 | PXD006593 | Pride

Effect of MOF mediated UHRF1 acetylation on global DNA methyaltion maintenance in mouse embryonic stem cells.

2024-03-05 | GSE225947 | GEO

Inhibition of DNMT1 methyltransferase activity via glucose-regulated O-GlcNAcylation alters the epigenome

Project description:The DNA methyltransferase activity of DNMT1 is vital for genomic maintenance of DNA methylation. We report here that DNMT1 function is regulated by O-GlcNAcylation, a protein modification that is sensitive to glucose levels, and that elevated O-GlcNAcylation of DNMT1 from high glucose environment leads to alterations to the epigenome. Using mass spectrometry and complementary alanine mutation experiments, we identified S878 as the major residue that is O-GlcNAcylated on DNMT1. Functional studies further revealed that O-GlcNAcylation of DNMT1-S878 results in an inhibition of methyltransferase activity, resulting in a general loss of DNA methylation that is preferentially at partially methylated domains (PMDs). This loss of methylation corresponds with an increase in DNA damage and apoptosis. These results establish O-GlcNAcylation of DNMT1 as a mechanism through which the epigenome is regulated by glucose metabolism and implicates a role for glycosylation of DNMT1 in metabolic diseases characterized by hyperglycemia.

2023-07-26 | PXD043031 | Pride

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data