Identification of AML-1 and the (8;21) Translocation Protein (AML-1/ETO) as Sequence-Specific DNA-Binding Proteins: the<i>runt</i>Homology Domain is Required for DNA Binding and Protein-Protein Interactions

Meyers, Samuel P.; Downing, James R.; Hiebert, Scott W.

doi:10.1128/mcb.13.10.6336-6345.1993

Cited by 39 publications

(10 citation statements)

References 41 publications

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“…It is also worth mentioning that a normal allele of RUNX1 is retained alongside RUNX1-ETO fusion gene in t(8;21) AML cells, 50 and that RUNX1-ETO is implicated in exerting opposing effects by competing with RUNX1 for binding to protein partners and to RUNX1-binding sites, but not affecting URE-PrPr interaction. 42,51,52 Collectively, our findings uncover heretoforeunknown cross-regulation and molecular interactions of lncRNAs with transcription factors and their oncogenic derivatives, providing mechanistic understanding underlying their molecular functions.…”

Section: Discussionmentioning

confidence: 71%

Myeloid lncRNA LOUP mediates opposing regulatory effects of RUNX1 and RUNX1-ETO in t(8;21) AML

Trinh

Ummarino

Zhang

et al. 2021

Blood

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The mechanism underlying cell type-specific gene induction conferred by ubiquitous transcription factors as well as disruptions caused by their chimeric derivatives in leukemia is not well understood. Here we investigate whether RNAs coordinate with transcription factors to drive myeloid gene transcription. In an integrated genome-wide approach surveying for gene loci exhibiting concurrent RNA- and DNA-interactions with the broadly expressed transcription factor RUNX1, we identified the long noncoding RNA LOUP. This myeloid-specific and polyadenylated lncRNA induces myeloid differentiation and inhibits cell growth, acting as a transcriptional inducer of the myeloid master regulator PU.1. Mechanistically, LOUP recruits RUNX1 to both the PU.1 enhancer and the promoter, leading to the formation of an active chromatin loop. In t(8;21) acute myeloid leukemia, wherein RUNX1 is fused to ETO, the resulting oncogenic fusion protein RUNX1-ETO limits chromatin accessibility at the LOUP locus, causing inhibition of LOUP and PU.1 expression. These findings highlight the important role of the interplay between cell type-specific RNAs and transcription factors as well as their oncogenic derivatives in modulating lineage-gene activation and raise the possibility that RNA regulators of transcription factors represent alternative targets for therapeutic development.

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Section: Discussionmentioning

confidence: 71%

Myeloid lncRNA LOUP mediates opposing regulatory effects of RUNX1 and RUNX1-ETO in t(8;21) AML

Trinh

Ummarino

Zhang

et al. 2021

Blood

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“…To investigate the molecular mechanism of NLRP12 transcriptional regulation, potential transcriptional binding sites were screened within 800 bp on the NLRP12 promoter region using the JASPAR database for eukaryotic transcription factor (TF) binding profiles ( https://jaspar.genereg.net/ ). A conserved sequence motif (5′-TGTGGT/ACCACA-3′), recognized by a TF known as runt-related transcription factor 1 (RUNX1) ( 22 ) was found to have occurred 4 times ( Figure 2A ). Therefore, we evaluated the role of RUNX1 in the regulation of NLRP12 expression by generating luciferase reporter plasmid driven by 830 bp (pGL4: –830 to +90 NLRP12 ) of the NLRP12 promoter region containing 4 RUNX1-binding sites (NLRP12-Luc#1).…”

Section: Resultsmentioning

confidence: 99%

NLRP12 is an innate immune checkpoint for repressing IFN signatures and attenuating lupus nephritis progression

Tsao¹,

Tseng²,

Chao³

et al. 2023

Journal of Clinical Investigation

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Signaling driven by nucleic acid sensors participates in interferonopathy-mediated autoimmune diseases. NLRP12, a pyrin-containing NLR protein, is a negative regulator of innate immune activation and type I interferon (IFN-I) production. Peripheral blood mononuclear cells (PBMCs) derived from systemic lupus erythematosus (SLE) patients expressed lower levels of NLRP12 , with an inverse correlation with IFNA expression and high disease activity. NLRP12 expression was transcriptionally suppressed by runt-related transcription factor 1–dependent (RUNX1-dependent) epigenetic regulation under IFN-I treatment, which enhanced a negative feedback loop between low NLRP12 expression and IFN-I production. Reduced NLRP12 protein levels in SLE monocytes was linked to spontaneous activation of innate immune signaling and hyperresponsiveness to nucleic acid stimulations. Pristane-treated Nlrp12 –/– mice exhibited augmented inflammation and immune responses; and substantial lymphoid hypertrophy was characterized in NLRP12-deficient lupus-prone mice. NLRP12 deficiency mediated the increase of autoantibody production, intensive glomerular IgG deposition, monocyte recruitment, and the deterioration of kidney function. These were bound in an IFN-I signature–dependent manner in the mouse models. Collectively, we reveal a remarkable link between low NLRP12 expression and lupus progression, which suggests the impact of NLRP12 on homeostasis and immune resilience.

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“…Runx2 response element in OC promoter was first identified in rat as an osteogenic tissue specific nuclear matrix protein binding site [Merriman et al, 1995] and in mouse as a osteoblast specific factor 2 binding site [Geoffroy et al, 1995], respectively. The binding sites of Runx2 and Runx1 have an identical core binding sequence [Bae et al, 1993, 1994; Meyers et al, 1993, 1995; Ogawa et al, 1993a,b]. However, it has not been reported that Runx3 binds directly to OSE2.…”

Section: Discussionmentioning

confidence: 99%

Establishment and characterization of a stable cell line to evaluate cellular Runx2 activity

Kim¹,

Park²,

Kim³

et al. 2004

J of Cellular Biochemistry

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Runx2 is an essential transcription factor for osteoblast differentiation from early commitment step to final differentiation. Based on its crucial role in osteoblast differentiation, the transcriptional activity of Runx2 protein implies more valuable information for osteoblast differentiation than any other parameters, such as Runx2 mRNA or protein level. Thus, a sensitive, specific, and consistent method to determine the Runx2 transcriptional activity has long been expected. Here we suggest a stable cell line that carries 6xOSE2-Luciferase reporter vector would be a good evaluation system to determine biological Runx2 transcriptional activity. The proliferation rate, cell shape, and the myogenic differentiation potential of the cloned cell line were similar to those of parental premyoblastic C2C12 cells. The cells specifically responded to Runx2 modulating agent such as FGF2. The stable cell line responded 5-6 folds more sensitively than the transiently transfected cells with Runx2. Though overexpression of any Runx gene stimulated the luciferase activity, Runx2 enhanced the reporter activity the highest. Collectively, the 6xOSE2-luc stable cells would be a good biological evaluation system to assess the activity of extracellular Runx2 modulating stimulations as well as the signal transduction pathways involved in the stimulations.

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Identification of AML-1 and the (8;21) Translocation Protein (AML-1/ETO) as Sequence-Specific DNA-Binding Proteins: theruntHomology Domain is Required for DNA Binding and Protein-Protein Interactions

Cited by 39 publications

References 41 publications

Myeloid lncRNA LOUP mediates opposing regulatory effects of RUNX1 and RUNX1-ETO in t(8;21) AML

Myeloid lncRNA LOUP mediates opposing regulatory effects of RUNX1 and RUNX1-ETO in t(8;21) AML

NLRP12 is an innate immune checkpoint for repressing IFN signatures and attenuating lupus nephritis progression

Establishment and characterization of a stable cell line to evaluate cellular Runx2 activity

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