HDAC inhibition results in widespread alteration of the histone acetylation landscape and BRD4 targeting to gene bodies

Slaughter, Mariesa J.; Shanle, Erin K.; Khan, Abid; Chua, Katrin F.; Hong, Tao; Boxer, Lisa D.; Allis, C. David; Josefowicz, Steven Z.; García, Benjamin A.; Rothbart, Scott B.; Strahl, Brian D.; Davis, Ian J.

doi:10.1016/j.celrep.2020.108638

Cited by 71 publications

(71 citation statements)

References 54 publications

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“…These results showed a loss of H4 acetylation distributed across the genome, particularly at gene bodies. This finding mirrors what has been recently described for H4 acetylation in cells treated with an HDAC inhibitor, causing an overall elevation in H4 acetylation with some of the most significant increases occurring in gene bodies (Slaughter et al, 2021). Despite the global loss of H4 acetylation in germ-free mice, we find that this histone modification becomes more pronounced at transcription start sites.…”

Section: Discussionsupporting

confidence: 90%

Stable Isotope Tracing In Vivo Reveals A Metabolic Bridge Linking The Microbiota To Host Histone Acetylation

Leboeuf

et al. 2021

Preprint

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The gut microbiota influences host epigenetics by fermenting dietary fiber into butyrate. Although butyrate could promote histone acetylation by inhibiting histone deacetylases, it may also undergo oxidation to acetyl-CoA, a necessary cofactor for histone acetyltransferases. Here, we find that epithelial cells from germ-free mice harbor a loss of histone H4 acetylation across the genome except at promoter regions. Using stable isotope tracing in vivo with 13C-labeled fiber, we demonstrate that the microbiota supplies carbon for histone acetylation. Subsequent metabolomic profiling revealed hundreds of labeled molecules and supported a microbial contribution to host fatty acid metabolism, which declined in response to colitis and correlated with reduced expression of genes involved in fatty acid oxidation. These results illuminate the flow of carbon from the diet to the host via the microbiota, disruptions to which may affect energy homeostasis in the distal gut and contribute to the development of colitis.

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Section: Discussionsupporting

confidence: 90%

Stable Isotope Tracing In Vivo Reveals A Metabolic Bridge Linking The Microbiota To Host Histone Acetylation

Leboeuf

et al. 2021

Preprint

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“…For example, in colon cancer cells, TSA and sodium butyrate cause a global increase in histone acetylation but loss of H3ac and H4ac at transcription start sites [ 76 ]. In a study where the authors evaluated the genomic distribution of H4 acetylation after vorinostat treatment, they observed a preferential increase in gene bodies [ 77 ]. Notably, this could be due to the preferential localization of the chemical probe, which has been shown to happen in the case of vorinostat [ 78 ].…”

Section: Effects Of Hdac Inhibitors and Therapeutic Implications For Tumor Heterogeneitymentioning

confidence: 99%

“…Notably, this could be due to the preferential localization of the chemical probe, which has been shown to happen in the case of vorinostat [ 78 ]. In addition, several studies have noted that the pre-existing state of chromatin influences local response of chromatin to HDACi [ 77 , 79 ].…”

Section: Effects Of Hdac Inhibitors and Therapeutic Implications For Tumor Heterogeneitymentioning

confidence: 99%

“…In glioma, several HDAC inhibitors were found to reduce H3K27ac in super-enhancers of oncogenes such as MYC and PIK3C2B [ 85 , 86 ]. One study suggests that this is due to the redistribution of BRD4, an acetylation-binding protein that mediates super-enhancer assembly [ 87 ], to gene bodies [ 77 ]. In line with this, Kim and colleagues used global run-on sequencing (GRO-seq), a method of high-throughput analysis of nascent transcription, and showed that HDACi represses transcription elongation, thereby selectively inhibiting transcription of highly-expressed genes [ 88 ].…”

Section: Effects Of Hdac Inhibitors and Therapeutic Implications For Tumor Heterogeneitymentioning

confidence: 99%

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HDAC Inhibitors: Dissecting Mechanisms of Action to Counter Tumor Heterogeneity

Karagiannis

Ράμπιας

2021

Cancers

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Intra-tumoral heterogeneity presents a major obstacle to cancer therapeutics, including conventional chemotherapy, immunotherapy, and targeted therapies. Stochastic events such as mutations, chromosomal aberrations, and epigenetic dysregulation, as well as micro-environmental selection pressures related to nutrient and oxygen availability, immune infiltration, and immunoediting processes can drive immense phenotypic variability in tumor cells. Here, we discuss how histone deacetylase inhibitors, a prominent class of epigenetic drugs, can be leveraged to counter tumor heterogeneity. We examine their effects on cellular processes that contribute to heterogeneity and provide insights on their mechanisms of action that could assist in the development of future therapeutic approaches.

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“…Next, we investigated whether Bdf1 binding correlates to histone H4 acetylation levels. We measured the genome-wide acetylation of H4 lysine 12 (H4K12ac), which was shown to be a preferred target for Bdf1 (Slaughter et al, 2021) (Figure S3H). Importantly, for both classes of genes, the normalized H4K12ac level at promoters significantly differs depending on the presence of a Bdf1 peak (Figure 2D and Table S4).…”

Section: A B C D Fmentioning

confidence: 99%

BET family members Bdf1/2 modulate global transcription initiation and elongation inSaccharomyces cerevisiae

Donczew

Hahn

2021

Preprint

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Human bromodomain-containing BET family members are promising targets for therapy of cancer and immunoinflammatory diseases, but their mechanisms of action and functional redundancies are poorly understood. Bdf1/2, yeast homologues of the human BET factors, were previously proposed to target transcription factor TFIID to acetylated histone H4, analogous to bromodomains that are present within the largest subunit of metazoan TFIID. We investigated the genome-wide roles of Bdf1/2 and found that their important contributions to transcription extend beyond TFIID function, as transcription of many genes is more sensitive to Bdf1/2 than to TFIID depletion. Bdf1/2 co-occupy the majority of yeast promoters and affect preinitiation complex formation through recruitment of TFIID, Mediator and basal transcription factors to chromatin. Surprisingly, we discovered that hypersensitivity of genes to Bdf1/2 depletion results from combined defects in transcription initiation and processive elongation, a striking functional similarity to human BET proteins, most notably Brd4. Our results establish Bdf1/2 as critical for yeast transcription and provide important mechanistic insights into the function of BET proteins in all eukaryotes.

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HDAC inhibition results in widespread alteration of the histone acetylation landscape and BRD4 targeting to gene bodies

Cited by 71 publications

References 54 publications

Stable Isotope Tracing In Vivo Reveals A Metabolic Bridge Linking The Microbiota To Host Histone Acetylation

Stable Isotope Tracing In Vivo Reveals A Metabolic Bridge Linking The Microbiota To Host Histone Acetylation

HDAC Inhibitors: Dissecting Mechanisms of Action to Counter Tumor Heterogeneity

BET family members Bdf1/2 modulate global transcription initiation and elongation inSaccharomyces cerevisiae

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