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The effect of PROTAC-mediated depletion of TAF1 on gene expression

ABSTRACT: The effect of PROTAC-mediated depletion of TAF1 on gene expression

PROVIDER: PRJNA1223918 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR32345721_1.fastq.gz	Fastqsanger.gz
	SRR32345721_2.fastq.gz	Fastqsanger.gz
	SRR32345722_1.fastq.gz	Fastqsanger.gz
	SRR32345722_2.fastq.gz	Fastqsanger.gz
	SRR32345723_1.fastq.gz	Fastqsanger.gz

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The effect of PROTAC-mediated depletion of TAF1 on gene expression

Project description:The goal of this experiment was to determine the change in gene expression after transient depletion of the TAF1 transcription factor (aka TFII-250) using a PROTAC molecule (ZS3-046) containing GNE371 as TAF1 ligand and pomalidomide as CRBN ligand.

2025-04-01 | GSE289670 | GEO

PROTAC-mediated degradation of TAF1 induces apoptosis in AML cells and inhibits tumor growth in vivo

Project description:The bromodomain-containing protein, TAF1 (TFII-250), is the largest component of the multiprotein assembly TFIID, a dynamic complex that serves as a general factor for transcription initiation. CRISPR and RNAi screens of pan cancer cell lines revealed TAF1 is broadly required for optimal cell growth and survival, but a subset of cell lines showed enhanced TAF1 dependence. These observations suggest that TAF1 has the potential to serve as a therapeutic target in sensitive tumors. Current approaches employed to target TAF1 are limited to monovalent small molecule inhibitors of the bromodomain. However, recent studies showed that such inhibitors lack cancer cell kill potential. We applied a structure-guided approach to generate cereblon (CRBN) recruiting PROTAC degraders of TAF1 using the chemical scaffolds of ceralasertib and GNE371. We present evidence that GNE371-based PROTACs are effective in degradation of TAF1 at concentrations as low as 1 nM. TAF1 depletion activated p53 and induced apoptosis in AML cell lines and certain solid tumor cells. An in vivo active TAF1 PROTAC inhibited the growth of AML tumor xenograft. The results showed that inhibition of bromodomain is not sufficient to inactivate TAF1 functions, while a PROTAC approach induces strong biological effects. Furthermore, TAF1 PROTACs have therapeutic potential against AML and other sensitive tumors.

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Effect of PROTAC-mediated BRD4 degradation in acute myeloid leukemia

Project description:Effect of PROTAC-mediated BRD4 degradation in acute myeloid leukemia

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TAF1 is critical for AE driven leukemogenesis [RNA-seq]

Project description:TAF1 is essential for AE driven leukemogenesis. Depletion of TAF1 impairs the recruitment of AE to its target genes, interfering with its control of gene expression. The bromodomains of TAF1 associate with K43 acetylated AE and this association plays a role in the proliferation of AE expressing AML cells.

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TAF1 is critical for AE driven leukemogenesis [ATAC-seq]

Project description:TAF1 is essential for AE driven leukemogenesis. Depletion of TAF1 impairs the recruitment of AE to its target genes, interfereing with its control of gene expression. The bromodomains of TAF1 associate with K43 acetylated AE and this association plays a role in the proliferationof AE expressing AML cells.

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Genome-wide transcriptional dependencies on TAF1 functional domains

Project description:TFIID plays a central role in regulating the expression of most eukaryotic genes. Of the 14 TAF subunits that compose TFIID, TAF1 is one of the largest and most functionally diverse. Yeast (Saccharomyces cerevisiae) TAF1 reportedly possesses at least four distinct activities including a histone acetyltransferase, and TBP, TAF, and promoter binding. Establishing the importance of each region in gene expression through deletion analysis has been hampered by the cellular requirement of TAF1 for viability. To circumvent this limitation we introduced galactose-inducible deletion derivatives of previously defined functional regions of TAF1 into a temperature sensitive taf1ts2 yeast strain. After galactose-induction and temperature inactivation of the temperature-sensitive allele, we examined the properties and phenotypes of the mutants, including their impact on genome-wide transcription. Virtually all TAF1-dependent genes, which comprise ~90% of the yeast genome, displayed a strong dependency upon all regions of TAF1 that were tested. This might reflect the need for each region of TAF1 to stabilize TAF1 against degradation or that all TAF1-dependent genes require the many activities of TAF1. Paradoxically, deletion of the region of TAF1 that is important for promoter binding interfered with the expression of many genes that are normally TFIID-independent/SAGA-dominated, suggesting that this region normally prevents TAF1 (TFIID) from interfering with the expression of SAGA-regulated genes. Keywords: genetic modification

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Effect of PROTAC-mediated BRD4 degradation on bone marrow-derived mesenchymal stromal cells [BM-MSCs]

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Effect of PROTAC-mediated BRD4 degradation in acute myeloid leukemia [OCI-AML3]

Project description:BRD4, a member of the BET family of histone readers, binds to acetylated lysine of histone H3 and promotes assembly of super-enhancer complexes that drive expression of key oncogenes in acute myeloid leukemia (AML) and other cancers. ARV-825 is a proteolysis-targeting chimera (PROTAC) that targets BRD4 for CRBN-mediated ubiquitination and degradation. We treated the AML cell line OCI-AML3, as well as primary tumor cells from a case of AML, with ARV-825 in vitro. At low concentrations, ARV-825 caused profound and sustained reduction in BRD4 protein levels. This caused reduction in transcription of key genes including MYC, anti-apoptotic BCL2 and BCLXL, PIM1, and CD44. Downstream effects included loss of CXCR4 surface expression and mitochondrial respiration; increased reactive oxygen species; toxicity to AML cells in vitro; and efficacy vs. OCI-AML3 cells in a mouse model of AML.

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