Temporal autoregulation during human PU.1 locus SubTAD formation

Schuetzmann, Daniel; Walter, Carolin; Riel, Boet van; Kruse, Sabrina; König, Thorsten; Erdmann, Tabea; Tönges, Alexander; Bindels, Eric; Weilemann, André; Gebhard, Claudia; Wethmar, Klaus; Perrod, Chiara; Minderjahn, Julia; Rehli, Michael; Delwel, Ruud; Lenz, Georg; Gröschel, Stefan; Dugas, Martin; Rosenbauer, Frank

doi:10.1182/blood-2018-02-834721

Cited by 15 publications

(15 citation statements)

References 59 publications

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“…Suspecting that this region might reside in close proximity to the proximal Ϫ60-bp region as a consequence of chromatin looping, we next investigated the contribution of LDB1. Since this factor has been shown to facilitate chromatin loop formation of the genes regulated by the GATA factors or PU.1 (27)(28)(29)(30), we speculate that the ϩ10.4-kbp and Ϫ60-bp regions were bound by LDB1. As expected, ChIP-qPCR analysis revealed that the ϩ10.4-kbp and Ϫ60-bp regions were bound by LDB1 in BMMCs and that PU.1 ablation significantly reduced the binding activity (Fig.…”

Section: Resultsmentioning

confidence: 93%

“…Furthermore, LDB1 appeared to be a novel positive regulator of Ms4a2 gene expression according to KD studies. Interestingly, a recent study reported that PU.1 plays an essential role in the formation of the chromosome architecture during SPI1 gene autoregulation by recruiting LDB1 in human monocytes (30). Recent Hi-C experiments revealed that eukaryote chromatin is organized into compartments composed of topologically associating domains (TADs) that are critical chromosome structural domains in the regulation of long-range gene expression (47)(48)(49).…”

Section: Discussionmentioning

confidence: 99%

“…In erythroid cells, LDB1 interacts with a LIM-only protein (LMO2), GATA1, and SCL/TAL (26), and this protein complex plays a critical role in the formation of the enhancer-promoter loop formation of the ␤-globin and Myb genes (27)(28)(29). More recently, LDB1 was shown to be required for the self-activation of the Spi1 gene in myeloid cells (30), while its role in mast cells has been unclear.…”

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confidence: 99%

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GATA2 and PU.1 Collaborate To Activate the Expression of the Mouse Ms4a2 Gene, Encoding FcεRIβ, through Distinct Mechanisms

Ohmori

Ishijima

Numata

et al. 2019

Molecular and Cellular Biology

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GATA factors GATA1 and GATA2 and ETS factor PU.1 are known to function antagonistically during hematopoietic development. In mouse mast cells, however, these factors are coexpressed and activate the expression of the Ms4a2 gene encoding the β chain of the high-affinity IgE receptor (FcεRI). The present study showed that these factors cooperatively regulate Ms4a2 gene expression through distinct mechanisms. Although GATA2 and PU.1 contributed almost equally to Ms4a2 gene expression, gene ablation experiments revealed that simultaneous knockdown of both factors showed neither a synergistic nor an additive effect. A chromatin immunoprecipitation analysis showed that they shared DNA binding to the +10.4-kbp region downstream of the Ms4a2 gene with chromatin looping factor LDB1, whereas the proximal −60-bp region was exclusively bound by GATA2 in a mast cell-specific manner. Ablation of PU.1 significantly reduced the level of GATA2 binding to both the +10.4-kbp and −60-bp regions. Surprisingly, the deletion of the +10.4-kbp region by genome editing completely abolished the Ms4a2 gene expression as well as the cell surface expression of FcεRI. These results suggest that PU.1 and LDB1 play central roles in the formation of active chromatin structure whereas GATA2 directly activates the Ms4a2 promoter.

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Section: Resultsmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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GATA2 and PU.1 Collaborate To Activate the Expression of the Mouse Ms4a2 Gene, Encoding FcεRIβ, through Distinct Mechanisms

Ohmori

Ishijima

Numata

et al. 2019

Molecular and Cellular Biology

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“…In some cases, overexpression or ablation of key TFs results in cell fate changes [46]. Once established, lineage choice is often reinforced by autoregulatory circuits [47,48].…”

Section: Transcription Factors In Mds and Amlmentioning

confidence: 99%

Transcription Factors, R-Loops and Deubiquitinating Enzymes: Emerging Targets in Myelodysplastic Syndromes and Acute Myeloid Leukemia

Barabino

Citterio

2021

Cancers

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Myeloid neoplasms encompass a very heterogeneous family of diseases characterized by the failure of the molecular mechanisms that ensure a balanced equilibrium between hematopoietic stem cells (HSCs) self-renewal and the proper production of differentiated cells. The origin of the driver mutations leading to preleukemia can be traced back to HSC/progenitor cells. Many properties typical to normal HSCs are exploited by leukemic stem cells (LSCs) to their advantage, leading to the emergence of a clonal population that can eventually progress to leukemia with variable latency and evolution. In fact, different subclones might in turn develop from the original malignant clone through accumulation of additional mutations, increasing their competitive fitness. This process ultimately leads to a complex cancer architecture where a mosaic of cellular clones—each carrying a unique set of mutations—coexists. The repertoire of genes whose mutations contribute to the progression toward leukemogenesis is broad. It encompasses genes involved in different cellular processes, including transcriptional regulation, epigenetics (DNA and histones modifications), DNA damage signaling and repair, chromosome segregation and replication (cohesin complex), RNA splicing, and signal transduction. Among these many players, transcription factors, RNA splicing proteins, and deubiquitinating enzymes are emerging as potential targets for therapeutic intervention.

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“…It is orchestrated by precise spatiotemporal expression of the hematopoietic master regulator PU.1 [1][2][3][4] . PU.1 gene expression is regulated through enhancer-promoter interactions within a topologically associated domain (TAD) 5,6 . PU.1 levels increase during myeloid differentiation while failure to do so results in myeloid leukemia 7 .…”

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confidence: 99%

Core binding factor leukemia hijacks T-cell prone PU.1 antisense promoter

Kouwe¹,

Castilla²,

Tenen³

et al. 2020

Preprint

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Summary paragraphThe blood system serves as a key model for cell differentiation and cancer. It is orchestrated by precise spatiotemporal expression of the hematopoietic master regulator PU.11–4. PU.1 gene expression is regulated through enhancer-promoter interactions within a topologically associated domain (TAD)5,6. PU.1 levels increase during myeloid differentiation while failure to do so results in myeloid leukemia7. In contrast, T-cell differentiation requires PU.1 to be completely switched off8–10. Little is known about the precise mechanisms of PU.1 repression, physiological as in T-cell differentiation, or pathological as in leukemia. Here we demonstrate that the down-regulation of PU.1 mRNA is a dynamic process involving an alternative promoter11 in intron 3 that is induced by RUNX transcription factors driving noncoding antisense transcription. Core binding factor (CBF) fusions, RUNX1-ETO and CBFβ-MYH11 in t(8;21) and inv(16) acute myeloid leukemia (AML)12, activate the PU.1 antisense promoter, thus shifting from sense towards antisense transcription and blocking myeloid differentiation. In patients with CBF-AML, we found that an elevated antisense/sense ratio represents a hallmark compared to normal karyotype AML or healthy CD34+ cells. Competitive interaction of the enhancer with the proximal or the antisense promoter are at the heart of differential PU.1 expression during myeloid and T-cell development. Leukemic CBF fusions thus utilize a physiologic mechanism employed by T-cells to decrease sense PU.1 transcription. Our results identify the first example of a sense/antisense promoter competition as a crucial functional switch for gene expression perturbation by oncogenes. This novel basic disease mechanism reveals a previously unknown Achilles heel for future precise therapeutic targeting of oncogene-induced chromatin remodeling.

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Temporal autoregulation during human PU.1 locus SubTAD formation

Cited by 15 publications

References 59 publications

GATA2 and PU.1 Collaborate To Activate the Expression of the Mouse Ms4a2 Gene, Encoding FcεRIβ, through Distinct Mechanisms

GATA2 and PU.1 Collaborate To Activate the Expression of the Mouse Ms4a2 Gene, Encoding FcεRIβ, through Distinct Mechanisms

Transcription Factors, R-Loops and Deubiquitinating Enzymes: Emerging Targets in Myelodysplastic Syndromes and Acute Myeloid Leukemia

Core binding factor leukemia hijacks T-cell prone PU.1 antisense promoter

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