HDAC3 and HDAC8 PROTAC dual degrader reveals roles of histone acetylation in gene regulation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA947763 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23944226_1.fastq.gz | Fastqsanger.gz | |||
| SRR23944226_2.fastq.gz | Fastqsanger.gz | |||
| SRR23944227_1.fastq.gz | Fastqsanger.gz | |||
| SRR23944227_2.fastq.gz | Fastqsanger.gz | |||
| SRR23944228_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 60 |
Similar Datasets
Project description:HDAC3 and HDAC8 are members of class I deacetylases involved in several biological mechanisms and represent a highly sought-after therapeutic target for drug development. It is historically challenging to develop selective deacetylase inhibitors due to their conserved catalytic domains. HDAC3 also has deacetylase-independent activity, which cannot be blocked by conventional enzymatic inhibitors. Recent advance in proteolysis-targeting chimeras (PROTACs) provides an opportunity to eliminate the whole protein selectively, abolishing both enzymatic and scaffolding function. Here, we report a novel HDAC3/8 dual degrader YX968 that induces highly potent, rapid, and selective degradation of both HDAC3 and HDAC8 without trigging pan-HDAC inhibitory effects. Unbiased quantitative proteomics experiments further confirmed its high selectivity. This dual-specific degrader specifically ablates cellular pathways attributed to HDAC3 and HDAC8 and exhibits high potency in killing cancer cells. YX968 represents a new probe for dissecting the complex biological functions of HDAC3 and HDAC8.
2023-07-18 | GSE211758 | GEO
Project description:HDAC3 and HDAC8 are members of class I deacetylases involved in several biological mechanisms and represent a highly sought-after therapeutic target for drug development. It is historically challenging to develop selective deacetylase inhibitors due to their conserved catalytic domains. HDAC3 also has deacetylase-independent activity, which cannot be blocked by conventional enzymatic inhibitors. Recent advances in proteolysis-targeting chimeras (PROTACs) provide an opportunity to eliminate the whole protein selectively, abolishing both enzymatic and scaffolding functions. Here, we report a novel HDAC3/8 dual degrader YX968 that induces highly potent, rapid and selective degradation of both HDAC3 and HDAC8 without trigging pan-HDAC inhibitory effects. Unbiased quantitative proteomics experiments further confirmed its high selectivity. This dual-specific degrader specifically ablates cellular pathways attributed to HDAC3 and HDAC8 and exhibits high potency in killing cancer cells. YX968 represents a new probe for dissecting the complex biological functions of HDAC3 and HDAC8.
2023-03-20 | MSV000091511 | MassIVE
Project description:HDAC3 and HDAC8 are members of class I deacetylases involved in several biological mechanisms and represent a highly sought-after therapeutic target for drug development. It is historically challenging to develop selective deacetylase inhibitors due to their conserved catalytic domains. HDAC3 also has deacetylase-independent activity, which cannot be blocked by conventional enzymatic inhibitors. Recent advances in proteolysis-targeting chimeras (PROTACs) provides an opportunity to eliminate the whole protein selectively, abolishing both enzymatic and scaffolding functions. Here, we report a novel HDAC3/8 dual degrader YX968 that induces highly potent, rapid and selective degradation of both HDAC3 and HDAC8 without trigging pan-HDAC inhibitory effects. Unbiased quantitative proteomics experiments further confirmed its high selectivity. This dual-specific degrader specifically ablates cellular pathways attributed to HDAC3 and HDAC8 and exhibits high potency in killing cancer cells. YX968 represents a new probe for dissecting the complex biological functions of HDAC3 and HDAC8.
2023-07-18 | PXD040941 | Pride
Project description:RNA-seq experiments were performed to assess effects of degradation of HDAC3 and HDAC8 on transcriptome
2023-07-01 | GSE228026 | GEO
Project description:Discovery of a Highly Potent and Selective HDAC3 and HDAC8 PROTAC Dual Degrader
| PRJNA872026 | ENA
Project description:HDAC3 and HDAC8 have critical biological functions and represent highly sought-after therapeutic targets. Because histone deacetylases (HDACs) have a very conserved catalytic domain, developing isozyme-selective inhibitors remains challenging. HDAC3/8 also have deacetylase-independent activity, which cannot be blocked by conventional enzymatic inhibitors. Proteolysis-targeting chimeras (PROTACs) can selectively degrade a target enzyme, abolishing both enzymatic and scaffolding function. Here, we report a novel HDAC3/8 dual degrader YX968 that induces highly potent, rapid, and selective degradation of both HDAC3/8 without triggering pan-HDAC inhibitory effects. Unbiased quantitative proteomic experiments confirmed its high selectivity. HDAC3/8 degradation by YX968 does not induce histone hyperacetylation and broad transcriptomic perturbation. Thus, histone hyperacetylation may be a major factor for altering transcription. YX968 promotes apoptosis and kills cancer cells with a high potency in vitro. YX968 thus represents a new probe for dissecting the complex biological functions of HDAC3/8.
| S-EPMC10802846 | biostudies-literature
Project description:Reversible acetylation of HDAC8 regulates cell cycle
| PRJNA1039808 | ENA
Project description:The development and severity of inflammatory bowel diseases (IBD) and other chronic inflammatory conditions can be influenced by host genetic and environmental factors, including signals derived from commensal bacteria. However, the mechanisms that integrate these diverse cues remain undefined. Here we demonstrate that intestinal epithelial cells (IECs) isolated from IBD patients exhibit decreased expression of the epigenome-modifying enzyme histone deacetylase 3 (HDAC3). Further, genome-wide analyses of murine IECs that lack HDAC3 (HDAC3ΔIEC) revealed that HDAC3 deficiency resulted in dysregulated gene expression coupled with alterations in histone acetylation. Critically, conventionally-housed HDAC3ΔIEC mice demonstrated loss of Paneth cells, impaired IEC function and alterations in the composition of intestinal commensal bacteria. In addition, HDAC3ΔIEC mice exhibited significantly increased susceptibility to intestinal damage and inflammation, indicating that epithelial expression of HDAC3 plays a central role in maintaining intestinal homeostasis. Strikingly, rederivation of HDAC3ΔIEC mice into germ-free conditions revealed that dysregulated IEC gene expression, Paneth cell homeostasis, and intestinal barrier function were largely restored in the absence of commensal bacteria. Collectively, these data indicate that the HDAC3 is a critical factor that integrates commensal bacteria-derived signals to calibrate epithelial cell responses required to establish normal host-commensal relationships and maintain intestinal homeostasis. Analyses of histone acetylation in primary IECs from HDAC3FF (3 biologic replicates) and HDAC3ΔIEC (3 biologic replicates) mice were conducted utilizing ChIP-seq for H3K9Ac.
2013-12-02 | E-GEOD-50453 | biostudies-arrayexpress
Project description:HDAC8, a member of class I HDACs, plays a pivotal role in cell cycle regulation by deacetylating the cohesin subunit SMC3. While cyclins and CDKs are well-established cell cycle regulators, our knowledge of other regulators remains limited. Here we reveal the acetylation of K202 in HDAC8 as a key cell cycle regulator responsive to stress. K202 acetylation in HDAC8, primarily catalyzed by Tip60, restricts HDAC8 activity, leading to increased SMC3 acetylation and cell cycle arrest. Furthermore, cells expressing the mutant form of HDAC8 mimicking K202 acetylation display significant alterations in gene expression, potentially linked to changes in 3D genome structure, including enhanced chromatid loop interactions. K202 acetylation impairs cell cycle progression by disrupting the expression of cell cycle-related genes and sister chromatid cohesion, resulting in G2/M phase arrest. These findings indicate the reversible acetylation of HDAC8 as a cell cycle regulator, expanding our understanding of stress-responsive cell cycle dynamics.
2024-05-24 | GSE247609 | GEO
Project description:HDAC8, a member of class I HDACs, plays a pivotal role in cell cycle regulation by deacetylating the cohesin subunit SMC3. While cyclins and CDKs are well-established cell cycle regulators, our knowledge of other regulators remains limited. Here we reveal acetylated K202 in HDAC8 as a key cell cycle regulator responsive to stress. K202 acetylation in HDAC8, primarily catalyzed by Tip60, negatively modulates HDAC8 activity, leading to increased SMC3 acetylation and cell cycle arrest. Furthermore, cells mimicking K202 acetylation display significant alterations in gene expression, potentially linked to changes in 3D genome structure, including enhanced chromatid loop interactions. K202 acetylation negatively impacts cell cycle progression by disrupting the expression of cell cycle-related genes and sister chromatid cohesion, resulting in G2/M phase arrest. These findings illuminate the reversible acetylation of HDAC8 as a novel cell cycle regulator, expanding our understanding of stress-responsive cell cycle dynamics.
2024-05-24 | GSE247610 | GEO