Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Cooperation of a polymerizing SAM domain and an intrinsically disordered region enables full SAMD1 function on chromatin

ABSTRACT: Transcription factors orchestrate gene expression through a myriad of complex mechanisms, encompassing collaborations with other transcription factors and the formation of multimeric complexes. The chromatin-binding protein SAMD1 [sterile alpha motif (SAM) domain-containing protein 1] binds to unmethylated CpG-rich DNA utilizing its N-terminal winged-helix (WH) domain. Additionally, its C-terminal SAM domain, which mediates interactions with itself and with L3MBTL3, is crucial for chromatin binding. The precise role of the SAM domain in this process remains unclear. Using structural analyses, we elucidated the distinct homopolymerization modes within the SAM domains of L3MBTL3 and SAMD1, alongside their heterodimerization architecture. Interestingly, SAMD1 necessitates not only the WH and SAM domain but also a proline/alanine-rich intrinsically disordered region (IDR) for efficient chromatin binding. The IDR is essential for the ability of SAMD1 to form large polymers, with its functionality determined by integrity rather than the specific sequence. Mutagenesis studies underscore the critical role of arginines within the IDR for polymerization, chromatin binding, and the biological function of SAMD1. These findings propose a model in which structured and unstructured regions of SAMD1 cooperate in a coordinated fashion to facilitate chromatin binding. This work provides new insights into the diverse mechanisms transcription factors employ to interact with chromatin and regulate gene expression.

ORGANISM(S): Mus musculus

PROVIDER: GSE254666 | GEO | 2025/04/07

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Shared Molecules

Only show the datasets with similarity scores above: 0.5

Threshold

0.5

Similar Datasets

The SAM domain-containing protein 1 (SAMD1) acts as a repressive chromatin regulator at unmethylated CpG islands

Project description:CpG-islands (CGIs) are key regulatory DNA elements at most promoters, but how they influence the chromatin status and transcription remains elusive. Here we identify and characterize SAMD1 (SAM domain-containing protein 1) as an unmethylated CGI-binding protein. SAMD1 possesses an atypical winged-helix domain that directly recognizes unmethylated CpG-containing DNA via simultaneous interactions with both the major and the minor groove. The SAM domain interacts with L3MBTL3, but it can also homopolymerize into a closed pentameric ring. At a genome-wide level, SAMD1 localizes to H3K4me3-decorated CGIs, where it acts as a repressor. SAMD1 tethers L3MBTL3 to chromatin and interacts with the KDM1A histone demethylase complex to modulate H3K4me2 and H3K4me3 levels at CGIs, thereby providing a mechanism for SAMD1-mediated transcriptional repression. Absence of SAMD1 impairs ES cell differentiation processes, leading to miss-regulation of key biological pathways. Together, our work establishes SAMD1 as a novel chromatin regulator acting at unmethylated CGIs.

2021-05-13 | GSE144396 | GEO

The SAM domain-containing protein 1 (SAMD1) acts as a repressive chromatin regulator at unmethylated CpG islands

Project description:CpG-islands (CGIs) are key regulatory DNA elements at most promoters, but how they influence the chromatin status and transcription remains elusive. Here we identify and characterize SAMD1 (SAM domain-containing protein 1) as an unmethylated CGI-binding protein. SAMD1 possesses an atypical winged-helix domain that directly recognizes unmethylated CpG-containing DNA via simultaneous interactions with both the major and the minor groove. The SAM domain interacts with L3MBTL3, but it can also homopolymerize into a closed pentameric ring. At a genome-wide level, SAMD1 localizes to H3K4me3-decorated CGIs, where it acts as a repressor. SAMD1 tethers L3MBTL3 to chromatin and interacts with the KDM1A histone demethylase complex to modulate H3K4me2 and H3K4me3 levels at CGIs, thereby providing a mechanism for SAMD1-mediated transcriptional repression. Absence of SAMD1 impairs ES cell differentiation processes, leading to mis-regulation of key biological pathways. Together, our work establishes SAMD1 as a novel chromatin regulator acting at unmethylated CGIs.

2021-05-13 | PXD016781 | Pride

SAMD1 suppresses epithelial-mesenchymal transition pathways in pancreatic ductal adenocarcinoma [ChIP-Seq]

Project description:Pancreatic ductal adenocarcinoma (PDAC) poses a significant threat due to its tendency to evade early detection, frequent metastasis, and the subsequent challenges in devising effective treatments. Processes that govern epithelial-mesenchymal transition (EMT) in PDAC hold promise for advancing novel therapeutic strategies. SAMD1 (SAM domain-containing protein 1) is a CpG island-binding protein that plays a pivotal role in the repression of its target genes. Here, we revealed that SAMD1 acts as a repressor of genes associated with epithelial-mesenchymal transition (EMT). Upon deletion of SAMD1 in PDAC cells, we observed significantly increased migration rates. SAMD1 exerts its effects by binding to specific genomic targets, including CDH2, encoding N-cadherin, which emerged as a driver of enhanced migration upon SAMD1 knockout. Furthermore, we discovered the FBXO11-containing E3 ubiquitin ligase complex as an interactor and negative regulator of SAMD1, which inhibits SAMD1 chromatin binding genome-wide. High FBXO11 expression in PDAC is associated with poor prognosis and increased expression of EMT-related genes, underlining an antagonistic relationship between SAMD1 and FBXO11. In summary, our findings provide insights into the regulation of EMT-related genes in PDAC, shedding light on the intricate role of SAMD1 and its interplay with FBXO11 in this cancer type.

2024-06-27 | GSE239415 | GEO

SAMD1 suppresses epithelial-mesenchymal transition pathways in pancreatic ductal adenocarcinoma [RNA-Seq]

2024-06-27 | GSE239414 | GEO

SAMD1 suppresses epithelial-mesenchymal transition (EMT) in pancreatic ductal adenocarcinoma.

Project description:SAMD1, a CpG island-binding protein, plays a pivotal role in the repression of its target genes by influencing the activity of KDM1A. Despite its significant correlation with outcomes in various tumor types, SAMD1's role in cancer has remained largely unexplored. In this study, we focus on pancreatic ductal adenocarcinoma (PDAC) and reveal that SAMD1 is a repressor of genes associated with epithelial-mesenchymal transition (EMT). Upon depletion of SAMD1 in PDAC cells, we observed significantly increased migration rates. Furthermore, high SAMD1 expression in PDAC patients correlated with lower expression of EMT signature genes and better prognosis, further underscoring its suppressive role. In-depth analysis revealed that SAMD1 exerts its effects by binding to specific genomic targets, including CDH2, encoding N-Cadherin, which emerged as a driver of enhanced migration upon SAMD1 knockout. Our investigations further demonstrated reduced chromatin-binding activity of SAMD1 in PDAC cells, prompting a search for regulatory mechanisms. This led to the discovery of the FBXO11-containing E3 ubiquitin ligase complex as a novel interactor of SAMD1, critically influencing its chromatin binding genome-wide. High FBXO11 expression in PDAC is associated with poor prognosis and increased expression of EMT-related genes, implying an antagonistic relationship between SAMD1 and FBXO11. In summary, our findings provide new insights into the regulation of EMT-related genes in PDAC, shedding light on the intricate role of SAMD1 and its interplay with FBXO11 in this particular cancer type.

2024-07-12 | PXD044104 | Pride

The CpG Island-Binding Protein SAMD1 Contributes to an Unfavorable Gene Signature in HepG2 Hepatocellular Carcinoma Cells

Project description:The unmethylated CpG island-binding protein SAMD1 is upregulated in many human cancer types, but its cancer-related role has not yet been investigated. Here, we used the hepatocellular carcinoma cell line HepG2 as a cancer model and investigated the cellular and transcriptional roles of SAMD1 using ChIP-Seq and RNA-Seq. SAMD1 targets several thousand gene promoters, where it acts predominantly as a transcriptional repressor. HepG2 cells with SAMD1 deletion showed slightly reduced proliferation, but strongly impaired clonogenicity. This phenotype was accompanied by the decreased expression of pro-proliferative genes, including MYC target genes. Consistently, we observed a decrease in the active H3K4me2 histone mark at most promoters, irrespective of SAMD1 binding. Conversely, we noticed an increase in interferon response pathways and a gain of H3K4me2 at a subset of enhancers that were enriched for IFN-stimulated response elements (ISREs). We identified key transcription factor genes, such as IRF1, STAT2, and FOSL2, that were directly repressed by SAMD1. Moreover, SAMD1 deletion also led to the derepression of the PI3K-inhibitor PIK3IP1, contributing to diminished mTOR signaling and ribosome biogenesis pathways. Our work suggests that SAMD1 is involved in establishing a pro-proliferative setting in hepatocellular carcinoma cells. Inhibiting SAMD1’s function in liver cancer cells may therefore lead to a more favorable gene signature.

2022-04-06 | GSE190761 | GEO

Cooperation of a polymerizing SAM domain and an intrinsically disordered region enables full SAMD1 function on chromatin

Project description:Cooperation of a polymerizing SAM domain and an intrinsically disordered region enables full SAMD1 function on chromatin

| PRJNA1071481 | ENA

The SAM domain-containing protein 1 (SAMD1) acts as a repressive chromatin regulator at unmethylated CpG islands

Project description:The SAM domain-containing protein 1 (SAMD1) acts as a repressive chromatin regulator at unmethylated CpG islands

| PRJNA603553 | ENA

The histone acetyltransferase KAT6A is recruited to unmethylated CpG islands via a DNA binding winged helix domain [RNA-seq]

Project description:The lysine acetyltransferase KAT6A (MOZ, MYST3) belongs to the MYST family of chromatin regulators, facilitating histone acetylation. Dysregulation of KAT6A has been implicated in developmental syndromes and the onset of acute myeloid leukemia (AML). Previous work suggests that KAT6A is recruited to its genomic targets by a combinatorial function of histone binding PHD fingers, transcription factors and chromatin binding interaction partners. Here, we demonstrate that a winged helix (WH) domain at the very N-terminus of KAT6A specifically interacts with unmethylated CpG motifs. This DNA binding function leads to the association of KAT6A with unmethylated CpG islands (CGIs) genome-wide. Mutation of the essential amino acids for DNA binding completely abrogates the enrichment of KAT6A at CGIs. In contrast, deletion of a second WH domain or the histone tail binding PHD fingers only subtly influences the binding of KAT6A to CGIs. Overexpression of a KAT6A WH1 mutant has a dominant negative effect on H3K9 histone acetylation, which is comparable to the effects upon overexpression of a KAT6A HAT domain mutant. Taken together, our work revealed a previously unrecognized chromatin recruitment mechanism of KAT6A, offering a new perspective on the role of KAT6A in gene regulation and human diseases.

2022-12-20 | GSE206273 | GEO

The histone acetyltransferase KAT6A is recruited to unmethylated CpG islands via a DNA binding winged helix domain [ChIP-seq]

2022-12-20 | GSE206272 | GEO