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Collateral lethality between HDAC1 and HDAC2 exploits cancer-specific NuRD complex vulnerabilities [ATAC-Seq]

ABSTRACT: Transcriptional coregulators have been widely pursued as targets for disrupting oncogenic gene regulatory programs. However, many proteins in this target class are universally essential for cell survival, which may limit the therapeutic window that can be achieved by drug candidates. By examining large collections of CRISPR/Cas9-based essentiality screens, we discovered a genetic interaction between histone deacetylase 1 (HDAC1) and HDAC2 wherein each paralog is synthetically lethal with hemizygous deletion of the other. This collateral synthetic lethality is caused by recurrent chromosomal translocations that occur in diverse solid and hematological malignancies, including neuroblastoma and multiple myeloma. Using genetic deletion or dTAG-mediated degradation, we show that HDAC2 disruption suppresses the growth of HDAC1-deficient neuroblastoma in vitro and in vivo. Mechanistically, we find that targeted degradation of HDAC2 in these cells prompts the degradation of several members of the nucleosome remodeling and deacetylase (NuRD) complex, leading to diminished chromatin accessibility at HDAC2/NuRD-bound sites of the genome and impaired control of enhancer-associated transcription. Furthermore, we reveal that several of the degraded NuRD complex subunits are dependencies in neuroblastoma and multiple myeloma, providing motivation to develop paralog-selective HDAC1 or HDAC2 degraders. Altogether, we identify HDAC1/2 collateral synthetic lethality as a new therapeutic target and reveal a novel mechanism for exploiting NuRD-associated cancer dependencies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE202702 | GEO | 2022/06/09

REPOSITORIES: GEO

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Collateral lethality between HDAC1 and HDAC2 exploits cancer-specific NuRD complex vulnerabilities

Project description:Histone deacetylases (HDACs) have been widely pursued as targets for anti-cancer therapeutics. However, many of these targets are universally essential for cell survival, which may limit the therapeutic window that can be achieved by drug candidates. By examining large collections of CRISPR/Cas9-based essentiality screens, we discovered a genetic interaction between HDAC1 and HDAC2 wherein each paralog is synthetically lethal with hemizygous deletion of the other. This collateral synthetic lethality is caused by recurrent chromosomal translocations that occur in diverse solid and hematological malignancies, including neuroblastoma and multiple myeloma. Using genetic deletion or dTAG-mediated degradation, we show that HDAC2 disruption suppresses the growth of HDAC1-deficient neuroblastoma in vitro and in vivo. Mechanistically, we find that targeted degradation of HDAC2 in these cells prompts the degradation of several members of the nucleosome remodeling and deacetylase (NuRD) complex, leading to diminished chromatin accessibility at HDAC2/NuRD-bound sites of the genome and impaired control of enhancer-associated transcription. Furthermore, we reveal that several of the degraded NuRD complex subunits are dependencies in neuroblastoma and multiple myeloma, providing motivation to develop paralog-selective HDAC1 or HDAC2 degraders. Altogether, we identify HDAC1/2 collateral synthetic lethality as a new therapeutic target and reveal a novel mechanism for exploiting NuRD-associated cancer dependencies.

2023-06-11 | PXD034444 | Pride

Collateral lethality between HDAC1 and HDAC2 exploits cancer-specific NuRD complex vulnerabilities [RNA-Seq]

Project description:Transcriptional coregulators have been widely pursued as targets for disrupting oncogenic gene regulatory programs. However, many proteins in this target class are universally essential for cell survival, which may limit the therapeutic window that can be achieved by drug candidates. By examining large collections of CRISPR/Cas9-based essentiality screens, we discovered a genetic interaction between histone deacetylase 1 (HDAC1) and HDAC2 wherein each paralog is synthetically lethal with hemizygous deletion of the other. This collateral synthetic lethality is caused by recurrent chromosomal translocations that occur in diverse solid and hematological malignancies, including neuroblastoma and multiple myeloma. Using genetic deletion or dTAG-mediated degradation, we show that HDAC2 disruption suppresses the growth of HDAC1-deficient neuroblastoma in vitro and in vivo. Mechanistically, we find that targeted degradation of HDAC2 in these cells prompts the degradation of several members of the nucleosome remodeling and deacetylase (NuRD) complex, leading to diminished chromatin accessibility at HDAC2/NuRD-bound sites of the genome and impaired control of enhancer-associated transcription. Furthermore, we reveal that several of the degraded NuRD complex subunits are dependencies in neuroblastoma and multiple myeloma, providing motivation to develop paralog-selective HDAC1 or HDAC2 degraders. Altogether, we identify HDAC1/2 collateral synthetic lethality as a new therapeutic target and reveal a novel mechanism for exploiting NuRD-associated cancer dependencies.

2022-06-09 | GSE202705 | GEO

Collateral lethality between HDAC1 and HDAC2 exploits cancer-specific NuRD complex vulnerabilities [Cut & Run]

Project description:Transcriptional coregulators have been widely pursued as targets for disrupting oncogenic gene regulatory programs. However, many proteins in this target class are universally essential for cell survival, which may limit the therapeutic window that can be achieved by drug candidates. By examining large collections of CRISPR/Cas9-based essentiality screens, we discovered a genetic interaction between histone deacetylase 1 (HDAC1) and HDAC2 wherein each paralog is synthetically lethal with hemizygous deletion of the other. This collateral synthetic lethality is caused by recurrent chromosomal translocations that occur in diverse solid and hematological malignancies, including neuroblastoma and lymphoid malignancies. Using genetic deletion or dTAG-mediated degradation, we show that HDAC2 disruption suppresses the growth of HDAC1-deficient neuroblastoma in vitro and in vivo. Mechanistically, we find that targeted degradation of HDAC2 in these cells prompts the turnover of several members of the nucleosome remodeling and deacetylase (NuRD) complex, leading to diminished chromatin accessibility at HDAC2/NuRD-bound sites of the genome and impaired control of enhancer-associated transcription. Several of the degraded NuRD complex subunits are themselves lineage-specific cancer dependencies, providing motivation to develop paralog-selective HDAC degraders. Altogether, we identify HDAC1/2 collateral synthetic lethality as a new therapeutic target and reveal a novel mechanism for exploiting NuRD-associated cancer dependencies.

2022-06-09 | GSE202703 | GEO

Collateral lethality between HDAC1 and HDAC2 exploits cancer-specific NuRD complex vulnerabilities

Project description:Collateral lethality between HDAC1 and HDAC2 exploits cancer-specific NuRD complex vulnerabilities

| PRJNA837075 | ENA

Collateral lethality between HDAC1 and HDAC2 exploits cancer-specific NuRD complex vulnerabilities [Cut & Run]

Project description:Collateral lethality between HDAC1 and HDAC2 exploits cancer-specific NuRD complex vulnerabilities [Cut & Run]

| PRJNA837078 | ENA

Collateral lethality between HDAC1 and HDAC2 exploits cancer-specific NuRD complex vulnerabilities [RNA-Seq]

Project description:Collateral lethality between HDAC1 and HDAC2 exploits cancer-specific NuRD complex vulnerabilities [RNA-Seq]

| PRJNA837077 | ENA

Collateral lethality between HDAC1 and HDAC2 exploits cancer-specific NuRD complex vulnerabilities [ATAC-Seq]

Project description:Collateral lethality between HDAC1 and HDAC2 exploits cancer-specific NuRD complex vulnerabilities [ATAC-Seq]

| PRJNA837079 | ENA

Comparative genomic hybridisation of gDNA from HDAC1-/-; HDAC2+/- diseased mouse thymocytes and sample matched wild-type tail

Project description:Histone deacetylase 1 and 2 (HDAC1/2) regulate chromatin structure as the catalytic core of the Sin3A, NuRD and CoREST co-repressor complexes. To better understand the key pathways regulated by HDAC1/2 in the adaptive immune system and inform their exploitation as drug targets, we have generated mice with a T cell specific deletion and performed comparative genomic hybridisation using genomic DNA from HDAC1-/-; HDAC2+/- diseased thymocytes and sample-matched, wild-type tail. A data set from a related transcription-profiling study comparing HDAC1-/-; HDAC2+/- mouse thymus tissue against thymus tissues from wild-type counterparts has also been deposited at ArrayExpress under accession E-MTAB-1432: http://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-1432

2013-01-08 | E-MTAB-1433 | biostudies-arrayexpress

A variant NuRD complex containing PWWP2A/B excludes MBD2/3 to regulate transcription at active genes

Project description:Transcriptional regulation by chromatin is a highly dynamic process directed through the recruitment and coordinated action of epigenetic modifiers and readers of these modifications. Using an unbiased proteomic approach to find interactors of H3K36me3, a modification enriched on active chromatin, we identify PWWP2A and HDAC2 among the top interactors. PWWP2A and its paralog PWWP2B form a stable complex with NuRD subunits MTA1/2/3:HDAC1/2:RBBP4/7, but not with MBD2/3, p66α/β, and CHD3/4. PWWP2A competes with MBD3 for binding to MTA1, thus defining a new variant NuRD complex that is mutually exclusive with the MBD2/3-containing NuRD. In mESCs, PWWP2A/B is most enriched at highly transcribed genes. Loss of PWWP2A/B leads to increases in histone acetylation predominantly at highly expressed genes, accompanied by decreases in Pol II elongation. Collectively, these findings suggest a role for PWWP2A/B in regulating transcription through the fine-tuning of histone acetylation dynamics at actively transcribed genes.

2018-07-19 | PXD010445 | Pride

Rapid degradation of Histone Deacetylase 1 (HDAC1) reveals essential roles in both gene repression and active transcription

Project description:Histone Deacetylase 1 (HDAC1) removes acetyl groups from lysine residues on the core histones, balancing histone acetyltransferase (HAT) activity. Despite this apparent repressive function, suppression of HDAC activity causes both up and downregulation of gene expression. Here we exploit the degradation tag (dTAG) system to rapidly degrade HDAC1 in embryonic stem cells (ESCs) lacking the paralog, HDAC2. Unlike HDAC inhibitors that lack isoform specificity the dTAG system allowed specific HDAC1 targeting and completely removed HDAC1 100x faster than genetic knockouts. HDAC1 degradation caused rapid increases in histone acetylation, with H2BK5 and H2BK11 most sensitive. The majority of differentially expressed genes following 2 hours of HDAC1 degradation were upregulated (275 genes up vs 15 down) with increased proportions of downregulated genes at 6 (1153 up vs 443 down) and 24 hours (1146 up vs 967 down). Upregulated genes showed increased H2BK5ac and H3K27ac around their transcriptional start site (TSS). In contrast, decreased acetylation of super-enhancers (SEs) was linked to the most strongly downregulated genes, leading to a collapse of the core pluripotency-associated gene network. These findings suggest that HDAC1 plays a crucial role in regulating the ESC gene expression network by maintaining the correct acetylation levels at key genomic sites.

2024-11-27 | PXD053032 | Pride

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