CBFβ-SMMHC Inhibition Triggers Apoptosis by Disrupting MYC Chromatin Dynamics in Acute Myeloid Leukemia

Pulikkan, John Anto; Hegde, Mahesh; Ahmad, Hafiz; Belaghzal, Houda; Illendula, Anuradha; Yu, Jun; O’Hagan, Kelsey; Ou, Jianhong; Müller‐Tidow, Carsten; Wolfe, Scot A.; Zhu, Lihua Julie; Dekker, Job; Bushweller, John H.; Castilla, Lucio H.

doi:10.1016/j.cell.2018.05.048

Cited by 79 publications

(78 citation statements)

References 88 publications

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“…Notably, emerging evidence has indicated that these ATF1 target genes, including MYC, BRAF, NRAS, BIRC2, and ID1, play important roles in cell apoptosis and proliferation in the progression of multiple cancers, including CRC. 39,43,44 Therefore, these findings suggest that ATF1 can facilitate CRC development, and most of that facilitation is due to the pathological activation of these oncogenic pathways.…”

Section: P Ro -G + E N H -G P Ro -G + E N H -T P Ro -T + E N H -G P Rmentioning

confidence: 88%

Systematic Functional Interrogation of Genes in GWAS Loci Identified ATF1 as a Key Driver in Colorectal Cancer Modulated by a Promoter-Enhancer Interaction

Tian

Chang

Gong

et al. 2019

The American Journal of Human Genetics

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Genome-wide association studies (GWASs) have identified approximately 100 colorectal cancer (CRC) risk loci. However, the causal genes in these loci have not been systematically interrogated. We conducted a high-throughput RNA-interference functional screen to identify the genes essential for proliferation in the CRC risk loci of Asian populations. We found that ATF1, located in the 12q13.12 region, functions as an oncogene that facilitates cell proliferation; ATF1 has the most significant effect of the identified genes and promotes CRC xenograft growth by affecting cell apoptosis. Next, by integrating a fine-mapping analysis, a two-stage affectedcontrol study consisting of 6,213 affected individuals and 10,388 controls, and multipronged experiments, we elucidated that two risk variants, dbSNP: rs61926301 and dbSNP: rs7959129, that located in the ATF1 promoter and first intron, respectively, facilitate a promoter-enhancer interaction, mediated by the synergy of SP1 and GATA3, to upregulate ATF1 expression, thus synergistically predisposing to CRC risk (OR ¼ 1.77, 95% CI ¼ 1.42-2.21, p ¼ 3.16 3 10 À7 ; P multiplicative-interaction ¼ 1.20 3 10 À22 ; P additive-interaction ¼ 6.50 3 10 À3 ). Finally, we performed RNA-seq and ChIP-seq assays in CRC cells treated with ATF1 overexpression in order to dissect the target programs of ATF1. Results showed that ATF1 activates a subset of genes, including BRAF, NRAS, MYC, BIRC2, DAAM1, MAML2, STAT1, ID1, and NKD2, related to apoptosis, Wnt, TGF-b, and MAPK pathways, and these effects could cooperatively increase the risk of CRC. These findings reveal the clinical potential of ATF1 in CRC development and illuminate a promoter-enhancer interaction module between the ATF1 regulatory elements dbSNP: rs61926301 and dbSNP: rs7959129, and they bring us closer to understanding the molecular drivers of cancer.We selected candidate genes on the basis of CRC GWASs, which identified 15 loci associated with CRC risk (2016.12, Table S1) in Asian (ASN) populations. To select candidate genes in each region for functional screening, we performed fine mapping by extending 1 Mb upstream and downstream of the tag SNPs. After we excluded microRNAs, noncoding RNAs, and pseudogenes on the basis of their functional annotation in the National Center for Biotechnology Information database, we ultimately selected a total of 157 protein-coding genes (Table S2) for a proliferation measurement of CRC cells by a large-scale RNAi interrogation. The siRNA library was provided by ViewSolid Biotech, and the repression efficiencies were guaranteed by the provider. Both p < 0.05 and an n-fold change >1.1 or <0.9 were selected as the threshold of significance.

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Section: P Ro -G + E N H -G P Ro -G + E N H -T P Ro -T + E N H -G P Rmentioning

confidence: 88%

Systematic Functional Interrogation of Genes in GWAS Loci Identified ATF1 as a Key Driver in Colorectal Cancer Modulated by a Promoter-Enhancer Interaction

Tian

Chang

Gong

et al. 2019

The American Journal of Human Genetics

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“…MYC is highly expressed in human pluripotent stem cells (Knoepfler, 2008). As MYC expression is regulated by long-range enhancers in various cell types, we thought that MYC expression in the stem cells should be also dependent on long-range enhancers (Bahr et al, 2018;Cho et al, 2018;Dave et al, 2017;Herranz et al, 2014;Hnisz et al, 2013;Lovén et al, 2013;Pulikkan et al, 2018;Shi et al, 2013;Sur et al, 2012;Uslu et al, 2014;Zhang et al, 2016). Hence we used the iPSC line 253G1, which was generated via retroviral transduction of OCT4, KLF4 and SOX2 but without MYC, to test the functionality of STITCH (Nakagawa et al, 2007).…”

Section: Stitch Blocks the Interaction Of Myc With The Enhancer When mentioning

confidence: 99%

“…Further our transcriptome analysis revealed that down-regulation of MYC leads to decrease of genes involved in cholesterol synthesis and ribosomal assembly ( Figure 2). Genes related to ribosomes have been well known targets of MYC in various cell types, and are thought to contribute to increasing cell proliferation (Hofmann et al, 2015;Pulikkan et al, 2018;Uslu et al, 2014;van Riggelen et al, 2010;Zeller et al, 2006). Also MYC haploinsufficient mice showed reduction of cholesterol synthesis through down-regulation of genes involved in the process (Hofmann et al, 2015).…”

Section: The Myc Regulationmentioning

confidence: 99%

“…Tight regulation by enhancers should be critical for organismal development and homeostasis considering the roles of MYC in the cellular processes. So far, many enhancers have been identified around the locus in different cell types including cancer cells(Bahr et al, 2018;Cho et al, 2018;Dave et al, 2017;Herranz et al, 2014;Hnisz et al, 2013;Lovén et al, 2013;Pulikkan et al, 2018;Shi et al, 2013;Sur et al, 2012;Zhang et al, 2016). Their locations vary much.…”

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confidence: 99%

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Controlling gene activation by enhancers through a drug-inducible topological insulator

Tsujimura

Takase

Yoshikawa

et al. 2019

Preprint

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AbstractWhile regulation of gene-enhancer interaction is better understood, its application remains limited. Here, we reconstituted arrays of CTCF binding sites and devised a synthetic topological insulator with tetO for chromatin-engineering (STITCH). By coupling STITCH with tetR linked to the KRAB domain to induce heterochromatin and disable the insulation, we developed a drug-inducible system to control gene activation by enhancers. We applied this to dissect MYC regulation in human pluripotent stem cells. Insertion of STITCH between MYC and the enhancer down-regulated MYC and affected its target transcriptome. Progressive mutagenesis of STITCH led to preferential escalation of the gene-enhancer interaction, corroborating the strong insulation ability of STITCH. The STITCH insertion altered epigenetic states around MYC. Time-course analysis by drug induction uncovered deposition and removal of H3K27me3 repressive marks follows and reflects, but does not precede and determine, the expression change. Thus the tool provided important insights in gene regulation, demonstrating its potency.

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“…For example, the syncytins, a family of mammalian genes required for successful placentation, derive from genes encoding retrovirus envelope proteins, now conserved for other purposes [10]. Similarly, the neuronal protein Arc, which assembles into capsid-like structures that mediate communication between mammalian nerve cells, derives from the retroviral polyprotein Gag [11,12]. Exaptation of genes from non-retroviruses is also documented.…”

Section: Introductionmentioning

confidence: 99%

RNA interference identifies domesticated viral genes involved in assembly and trafficking of virus-derived particles in ichneumonid wasps

et al. 2019

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There are many documented examples of viral genes retained in the genomes of multicellular organisms that may in some cases bring new beneficial functions to the receivers. The ability of certain ichneumonid parasitic wasps to produce virus-derived particles, the socalled ichnoviruses (IVs), not only results from the capture and domestication of single viral genes but of almost entire ancestral virus genome(s). Indeed, following integration into wasp chromosomal DNA, the putative and still undetermined IV ancestor(s) evolved into encoding a 'virulence gene delivery vehicle' that is now required for successful infestation of wasp hosts. Several putative viral genes, which are clustered in distinct regions of wasp genomes referred to as IVSPERs (Ichnovirus Structural Protein Encoding Regions), have been assumed to be involved in virus-derived particles morphogenesis, but this question has not been previously functionally addressed. In the present study, we have successfully combined RNA interference and transmission electron microscopy to specifically identify IVSPER genes that are responsible for the morphogenesis and trafficking of the virusderived particles in ovarian cells of the ichneumonid wasp Hyposoter didymator. We suggest that ancestral viral genes retained within the genomes of certain ichneumonid parasitoids possess conserved functions which were domesticated for the purpose of assembling viral vectors for the delivery of virulence genes to parasitized host animals. Author summaryThousands of parasitic wasp from the ichneumonid family rely on virus-derived particles, named Ichnoviruses (Polydnavirus family), to ensure their successful development. The particles are produced in a specialized ovarian tissue of the female wasp named calyx. Virions are assembled in the calyx cell nuclei and stored in the oviduct before being transferred to the parasitoid host upon female wasp oviposition. Genes encoding proteins PLOS Pathogens | https://doi.

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CBFβ-SMMHC Inhibition Triggers Apoptosis by Disrupting MYC Chromatin Dynamics in Acute Myeloid Leukemia

Cited by 79 publications

References 88 publications

Systematic Functional Interrogation of Genes in GWAS Loci Identified ATF1 as a Key Driver in Colorectal Cancer Modulated by a Promoter-Enhancer Interaction

Systematic Functional Interrogation of Genes in GWAS Loci Identified ATF1 as a Key Driver in Colorectal Cancer Modulated by a Promoter-Enhancer Interaction

Controlling gene activation by enhancers through a drug-inducible topological insulator

RNA interference identifies domesticated viral genes involved in assembly and trafficking of virus-derived particles in ichneumonid wasps

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