A TFIID-SAGA Perturbation that Targets MYB and Suppresses Acute Myeloid Leukemia

Xu, Yali; Milazzo, Joseph P.; Somerville, Tim D.D.; Tarumoto, Yusuke; Huang, Yuhan; Ostrander, Elizabeth L.; Wilkinson, John E.; Challen, Grant A.; Vakoc, Christopher R.

doi:10.1016/j.ccell.2017.12.002

Cited by 67 publications

(64 citation statements)

References 67 publications

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“…If c-Myb in fact acts as a pioneer factor and through its binding displaces nucleosomes and creates a nucleosome-free region, this drop is exactly what we should expect. Moreover, from published ChIP-seq data we know that c-Myb, like many other TFs, is found in “valleys” of the acetylation profile (exemplified in [ 29 ], specifically its Fig. 5 c).…”

Section: Resultsmentioning

confidence: 99%

The pioneer factor activity of c-Myb involves recruitment of p300 and induction of histone acetylation followed by acetylation-induced chromatin dissociation

Fuglerud

Ledsaak

Rogne

et al. 2018

Epigenetics & Chromatin

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BackgroundThe concept of pioneer transcription factors is emerging as an essential part of the epigenetic regulation, taking place during cell development and differentiation. However, the precise molecular mechanism underlying pioneer factor activity remains poorly understood. We recently reported that the transcription factor c-Myb acts as a pioneer factor in haematopoiesis, and a point mutation in its DNA binding domain, D152V, is able to abrogate this function.ResultsHere, we show that specific histone modifications, including H3K27ac, prevent binding of c-Myb to histone tails, representing a novel effect of histone modifications, namely restricting binding of a pioneer factor to chromatin. Furthermore, we have taken advantage of the pioneer-defect D152V mutant to investigate mechanisms of c-Myb’s pioneer factor activity. We show that c-Myb-dependent transcriptional activation of a gene in inaccessible chromatin relies on c-Myb binding to histones, as well as on c-Myb interacting with the histone acetyltransferase p300. ChIP assays show that both wild type and the D152V mutant of c-Myb bind to a selected target gene at its promoter and enhancer, but only wild-type c-Myb causes opening and activation of the locus. Enhancement of histone acetylation restores activation of the same gene in the absence of c-Myb, suggesting that facilitating histone acetylation is a crucial part of the pioneer factor function of c-Myb.ConclusionsWe suggest a pioneer factor model in which c-Myb binds to regions of closed chromatin and then recruits histone acetyltransferases. By binding to histones, c-Myb facilitates histone acetylation, acting as a cofactor for p300 at c-Myb bound sites. The resulting H3K27ac leads to chromatin opening and detachment of c-Myb from the acetylated chromatin. We propose that the latter phenomenon, acetylation-induced chromatin dissociation, represents a mechanism for controlling the dynamics of pioneer factor binding to chromatin.Electronic supplementary materialThe online version of this article (10.1186/s13072-018-0208-y) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

The pioneer factor activity of c-Myb involves recruitment of p300 and induction of histone acetylation followed by acetylation-induced chromatin dissociation

Fuglerud

Ledsaak

Rogne

et al. 2018

Epigenetics & Chromatin

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“…A yet to be resolved dynamic interaction network between TFIIA, TBP, subunits of the Twin lobe and the transcription activators Rap1 is functionally important to regulate the expression of ribosomal genes 48 . In humans, the transactivation domain of the oncogenic transcription factor MYB binds directly to the HFDs of Taf4/12 to drive the expression of genes involved in the development of Acute Myeloid Leukemia 49 suggesting an evolutionary conserved function.…”

Section: Discussionmentioning

confidence: 99%

Molecular structure of promoter-bound yeast TFIID

et al. 2018

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Transcription preinitiation complex assembly on the promoters of protein encoding genes is nucleated in vivo by TFIID composed of the TATA-box Binding Protein (TBP) and 13 TBP-associate factors (Tafs) providing regulatory and chromatin binding functions. Here we present the cryo-electron microscopy structure of promoter-bound yeast TFIID at a resolution better than 5 Å, except for a flexible domain. We position the crystal structures of several subunits and, in combination with cross-linking studies, describe the quaternary organization of TFIID. The compact tri lobed architecture is stabilized by a topologically closed Taf5-Taf6 tetramer. We confirm the unique subunit stoichiometry prevailing in TFIID and uncover a hexameric arrangement of Tafs containing a histone fold domain in the Twin lobe.

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“…examined the mRNA levels of MYC, MYB, TAL1 and LMO2, four key genes that are known to be regulated by super enhancers during leukemogenesis and disease progression [36][37][38] . We detected a marked reduction in the expression of all four super-enhancer regulated genes in K562 and murine BETi-resistant AF9 AML cells upon the combination treatment ( Fig.…”

Section: K562mentioning

confidence: 99%

A combination strategy targeting enhancer plasticity exerts synergistic lethality against BETi-resistant leukemia cells

Guo

Zeng

et al. 2020

Nat Commun

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Primary and acquired drug resistance imposes a major threat to achieving optimized clinical outcomes during cancer treatment. Aberrant changes in epigenetic modifications are closely involved in drug resistance of tumor cells. Using BET inhibitor (BETi) resistant leukemia cells as a model system, we demonstrated herein that genome-wide enhancer remodeling played a pivotal role in driving therapeutic resistance via compensational re-expression of pro-survival genes. Capitalizing on the CRISPR interference technology, we identified the second intron of IncRNA, PVT1, as a unique bona fide gained enhancer that restored MYC transcription independent of BRD4 recruitment in leukemia. A combined BETi and CDK7 inhibitor treatment abolished MYC transcription by impeding RNAPII loading without affecting PVT1-mediated chromatin looping at the MYC locus in BETi-resistant leukemia cells. Together, our findings have established the feasibility of targeting enhancer plasticity to overcome drug resistance associated with epigenetic therapies.

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A TFIID-SAGA Perturbation that Targets MYB and Suppresses Acute Myeloid Leukemia

Cited by 67 publications

References 67 publications

The pioneer factor activity of c-Myb involves recruitment of p300 and induction of histone acetylation followed by acetylation-induced chromatin dissociation

The pioneer factor activity of c-Myb involves recruitment of p300 and induction of histone acetylation followed by acetylation-induced chromatin dissociation

Molecular structure of promoter-bound yeast TFIID

A combination strategy targeting enhancer plasticity exerts synergistic lethality against BETi-resistant leukemia cells

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