Mutant NPM1 Directly Regulates Oncogenic Transcription in Acute Myeloid Leukemia DOI
Hannah J. Uckelmann, Elena Haarer, Reina Takeda

et al.

Cancer Discovery, Journal Year: 2022, Volume and Issue: 13(3), P. 746 - 765

Published: Dec. 1, 2022

The dysregulation of developmental and stem cell-associated genes is a common phenomenon during cancer development. Around half patients with acute myeloid leukemia (AML) express high levels HOXA cluster MEIS1. Most these AML cases harbor an NPM1 mutation (NPM1c), which encodes for oncoprotein mislocalized from the nucleolus to cytoplasm. How NPM1c expression in hematopoietic cells leads its characteristic gene-expression pattern remains unclear. Here, we show that directly binds specific chromatin targets, are co-occupied by histone methyltransferase KMT2A (MLL1). Targeted degradation rapid decrease gene loss RNA polymerase II, as well activating modifications at targets. We demonstrate regulates oncogenic collaboration MLL1 complex define mechanism MLL1-Menin small-molecule inhibitors produce clinical responses NPM1-mutated AML. uncovered important functional role mutant crucial direct driver can bind cooperate MLL complex, providing first insight into Menin-MLL inhibition leukemias. See related article Wang et al., p. 724. This highlighted In Issue feature, 517.

Language: Английский

RNA sequencing: the teenage years DOI
Rory Stark, Marta Grzelak, James Hadfield

et al.

Nature Reviews Genetics, Journal Year: 2019, Volume and Issue: 20(11), P. 631 - 656

Published: July 24, 2019

Language: Английский

Citations

1592
Eukaryotic core promoters and the functional basis of transcription initiation DOI
Vanja Haberle, Alexander Stark

Nature Reviews Molecular Cell Biology, Journal Year: 2018, Volume and Issue: 19(10), P. 621 - 637

Published: June 26, 2018

Language: Английский

Citations

634
Modulation of cellular processes by histone and non-histone protein acetylation DOI
Maria Shvedunova, Asifa Akhtar

Nature Reviews Molecular Cell Biology, Journal Year: 2022, Volume and Issue: 23(5), P. 329 - 349

Published: Jan. 18, 2022

Language: Английский

Citations

541
Targeting the epigenetic regulation of antitumour immunity DOI
Simon J. Hogg, Paul A. Beavis, Mark A. Dawson

et al.

Nature Reviews Drug Discovery, Journal Year: 2020, Volume and Issue: 19(11), P. 776 - 800

Published: Sept. 14, 2020

Language: Английский

Citations

466
Selective targeting of BD1 and BD2 of the BET proteins in cancer and immunoinflammation DOI Open Access
Omer Gilan, Inmaculada Rioja, Kathy Knezevic

et al.

Science, Journal Year: 2020, Volume and Issue: 368(6489), P. 387 - 394

Published: March 19, 2020

Bromodomain inhibitors revisited and extraterminal domain (BET) proteins contribute to the pathogenesis of cancer immune diseases through their effects on transcriptional regulation. BET contain two nearly identical bromodomains, BD1 BD2, structural modules that have attracted great interest as targets for drug development. First-generation drugs inhibited both BD2 showed promising therapeutic activity in preclinical models but proved be less efficacious clinical trials. Gilan et al. took a different approach designed selectively or (see Perspective by Filippakopoulos Knapp). They found altered gene expression ways had greater than inflammation autoimmune disease. Science , this issue p. 387 ; see also 367

Language: Английский

Citations

354
Target gene-independent functions of MYC oncoproteins DOI
Apoorva Baluapuri, Elmar Wolf, Martin Eilers

et al.

Nature Reviews Molecular Cell Biology, Journal Year: 2020, Volume and Issue: 21(5), P. 255 - 267

Published: Feb. 18, 2020

Language: Английский

Citations

256
Lisa: inferring transcriptional regulators through integrative modeling of public chromatin accessibility and ChIP-seq data DOI Creative Commons
Qian Qin, Jingyu Fan, Rongbin Zheng

et al.

Genome biology, Journal Year: 2020, Volume and Issue: 21(1)

Published: Feb. 7, 2020

Abstract We developed Lisa ( http://lisa.cistrome.org/ ) to predict the transcriptional regulators (TRs) of differentially expressed or co-expressed gene sets. Based on input sets, first uses histone mark ChIP-seq and chromatin accessibility profiles construct a model related regulation these genes. Using TR peaks imputed binding sites, probes models using in silico deletion find most relevant TRs. Applied sets derived from targeted TF perturbation experiments, boosted performance cistromes outperformed alternative methods identifying perturbed

Language: Английский

Citations

242
Rapid and accurate alignment of nucleotide conversion sequencing reads with HISAT-3N DOI Creative Commons
Yun Zhang, Chanhee Park, Christopher Bennett

et al.

Genome Research, Journal Year: 2021, Volume and Issue: 31(7), P. 1290 - 1295

Published: June 8, 2021

Sequencing technologies using nucleotide conversion techniques such as cytosine to thymine in bisulfite-seq and SLAM seq are powerful tools explore the chemical intricacies of cellular processes. To date, no one has developed a unified methodology for aligning converted sequences consolidating alignment these package. In this paper, we describe hierarchical indexing spliced transcripts-3 nucleotides (HISAT-3N), which can rapidly accurately align consisting any by leveraging index repeat algorithms originally HISAT software. Tests on real simulated data sets show that HISAT-3N is faster than other modern systems, with greater accuracy, higher scalability, smaller memory requirements. therefore becomes an ideal aligner when used sequence technologies.

Language: Английский

Citations

228
Nascent RNA analyses: tracking transcription and its regulation DOI
Erin M. Wissink, Anniina Vihervaara, Nathaniel D. Tippens

et al.

Nature Reviews Genetics, Journal Year: 2019, Volume and Issue: 20(12), P. 705 - 723

Published: Aug. 9, 2019

Language: Английский

Citations

225
H3K4me3 regulates RNA polymerase II promoter-proximal pause-release DOI Creative Commons
Hua Wang, Zheng Fan, Pavel V. Shliaha

et al.

Nature, Journal Year: 2023, Volume and Issue: 615(7951), P. 339 - 348

Published: March 1, 2023

Abstract Trimethylation of histone H3 lysine 4 (H3K4me3) is associated with transcriptional start sites and has been proposed to regulate transcription initiation 1,2 . However, redundant functions the H3K4 SET1/COMPASS methyltransferase complexes complicate elucidation specific role H3K4me3 in regulation 3,4 Here, using mouse embryonic stem cells as a model system, we show that acute ablation shared subunits leads complete loss all methylation. Turnover occurs more rapidly than H3K4me1 H3K4me2 dependent on KDM5 demethylases. Notably, does not have detectable effects but widespread decrease output, an increase RNA polymerase II (RNAPII) pausing slower elongation. We required for recruitment integrator complex subunit 11 (INTS11), which essential eviction paused RNAPII Thus, our study demonstrates distinct pause-release elongation rather initiation.

Language: Английский

Citations

216