Runx1 regulates embryonic myeloid fate choice in zebrafish through a negative feedback loop inhibiting Pu.1 expression

Abstract Proper cell fate choice in myelopoiesis is essential for generating correct numbers of distinct myeloid subsets manifesting a wide spectrum of subset-specific activities during development and adulthood. Studies have suggested that myeloid fate choice is primarily regulated by transcription factors; however, new intrinsic regulators and their underlying mechanisms remain to be elucidated. Zebrafish embryonic myelopoiesis gives rise to neutrophils and macrophages and represents a promising system to derive new regulatory mechanisms for myeloid fate decision in vertebrates. Here we present an in vivo study of cell fate specification during zebrafish embryonic myelopoiesis through characterization of the embryos with altered Pu.1, Runx1 activity alone, or their combinations. Genetic analysis shows that low and high Pu.1 activities determine embryonic neutrophilic granulocyte and macrophage fate, respectively. Inactivation and overexpression of Runx1 in zebrafish uncover Runx1 as a key embryonic myeloid fate determinant that favors neutrophil over macrophage fate. Runx1 is induced by high Pu.1 level and in turn transrepresses pu.1 expression, thus constituting a negative feedback loop that fashions a favorable Pu.1 level required for balanced fate commitment to neutrophils versus macrophages. Our findings define a Pu.1-Runx1 regulatory loop that governs the equilibrium between distinct myeloid fates by assuring an appropriate Pu.1 dosage.

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MicroRNAs acting in a double-negative feedback loop to control a neuronal cell fate decision

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.0505530102 ◽

2005 ◽

Vol 102 (35) ◽

pp. 12449-12454 ◽

Cited By ~ 182

Author(s):

R. J. Johnston ◽

S. Chang ◽

J. F. Etchberger ◽

C. O. Ortiz ◽

O. Hobert

Keyword(s):

Cell Fate ◽

Negative Feedback ◽

Feedback Loop ◽

Neuronal Cell ◽

Negative Feedback Loop ◽

Double Negative ◽

Cell Fate Decision ◽

Fate Decision

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Highly Selective Cleavage of TH2-Promoting Cytokines by the Human and the Mouse Mast Cell Tryptases, Indicating a Potent Negative Feedback Loop on TH2 Immunity

International Journal of Molecular Sciences ◽

10.3390/ijms20205147 ◽

2019 ◽

Vol 20 (20) ◽

pp. 5147 ◽

Cited By ~ 9

Author(s):

Zhirong Fu ◽

Srinivas Akula ◽

Michael Thorpe ◽

Lars Hellman

Keyword(s):

Negative Feedback ◽

Feedback Loop ◽

Regulatory Function ◽

Negative Feedback Loop ◽

Cytokines And Chemokines ◽

Th2 Immunity ◽

Strict Specificity ◽

Mouse Mast Cell ◽

Regulatory Functions

Mast cells (MC) are resident tissue cells found primarily at the interphase between tissues and the environment. These evolutionary old cells store large amounts of proteases within cytoplasmic granules, and one of the most abundant of these proteases is tryptase. To look deeper into the question of their in vivo targets, we have analyzed the activity of the human MC tryptase on 69 different human cytokines and chemokines, and the activity of the mouse tryptase (mMCP-6) on 56 mouse cytokines and chemokines. These enzymes were found to be remarkably restrictive in their cleavage of these potential targets. Only five were efficiently cleaved by the human tryptase: TSLP, IL-21, MCP3, MIP-3b, and eotaxin. This strict specificity indicates a regulatory function of these proteases and not primarily as unspecific degrading enzymes. We recently showed that the human MC chymase also had a relatively strict specificity, indicating that both of these proteases have regulatory functions. One of the most interesting regulatory functions may involve controlling excessive TH2-mediated inflammation by cleaving several of the most important TH2-promoting inflammatory cytokines, including IL-18, IL-33, TSLP, IL-15, and IL-21, indicating a potent negative feedback loop on TH2 immunity.

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Estrogen-regulated feedback loop limits the efficacy of estrogen receptor–targeted breast cancer therapy

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1722617115 ◽

2018 ◽

Vol 115 (31) ◽

pp. 7869-7878 ◽

Cited By ~ 19

Author(s):

Tengfei Xiao ◽

Wei Li ◽

Xiaoqing Wang ◽

Han Xu ◽

Jixin Yang ◽

...

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

Endocrine Therapy ◽

Negative Feedback ◽

Feedback Loop ◽

Therapy Resistance ◽

Negative Feedback Loop ◽

Endocrine Therapy Resistance ◽

Estrogen Receptor Positive ◽

Underlying Mechanisms

Endocrine therapy resistance invariably develops in advanced estrogen receptor-positive (ER+) breast cancer, but the underlying mechanisms are largely unknown. We have identified C-terminal SRC kinase (CSK) as a critical node in a previously unappreciated negative feedback loop that limits the efficacy of current ER-targeted therapies. Estrogen directly drives CSK expression in ER+ breast cancer. At low CSK levels, as is the case in patients with ER+ breast cancer resistant to endocrine therapy and with the poorest outcomes, the p21 protein-activated kinase 2 (PAK2) becomes activated and drives estrogen-independent growth. PAK2 overexpression is also associated with endocrine therapy resistance and worse clinical outcome, and the combination of a PAK2 inhibitor with an ER antagonist synergistically suppressed breast tumor growth. Clinical approaches to endocrine therapy-resistant breast cancer must overcome the loss of this estrogen-induced negative feedback loop that normally constrains the growth of ER+ tumors.

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Molecular mechanism regulating transcriptional control of the hig toxin-antitoxin locus of antibiotic-resistance plasmid Rts1 from Proteus vulgaris

10.1101/2021.03.04.434028 ◽

2021 ◽

Author(s):

Ian J. Pavelich ◽

Marc A. Schureck ◽

Dongxue Wang ◽

Eric D. Hoffer ◽

Michelle Boamah ◽

...

Keyword(s):

Negative Feedback ◽

Transcriptional Repression ◽

Feedback Loop ◽

Negative Feedback Loop ◽

Transcriptional Level ◽

Type Ii ◽

Proteus Vulgaris ◽

Dynamic Simulations ◽

Molecular Rheostat

Regulation of ubiquitous bacterial type II toxin-antitoxin (TA) gene pairs occurs via a negative feedback loop whereby their expression is typically responsive to changing levels of toxins at the transcriptional level similar to a molecular rheostat. While this mechanism can explain how certain TA complexes are regulated, accumulating evidence suggests diversity in this regulation. One system for which the negative feedback loop is not well defined is the plasmid-encoded HigBHigA TA pair originally identified in a post-operative infection with antibiotic resistant Proteus vulgaris. In contrast to other type II TA modules, each hig operator functions independently and excess toxin does not contribute to increased transcription in vivo. Structures of two different oligomeric complexes of HigBHigA bound to its operator DNA reveal similar interactions are maintained suggesting plasticity in how hig is repressed. Consistent with this result, molecular dynamic simulations reveal both oligomeric states exhibit similar dynamics. Further, engineering a dedicated trimeric HigBHigA complex does not regulate transcriptional repression. We propose that HigBHigA functions via a simple on/off transcriptional switch regulated by antitoxin proteolysis rather than a molecular rheostat. The present studies thus expand the known diversity of how these abundant bacterial protein pairs are regulated.

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RAC1/miR-3613/RAC1 feedback loop contributes to ovarian cancer progression

10.21203/rs.3.rs-380396/v1 ◽

2021 ◽

Author(s):

Changzhong Li ◽

Ruobing Leng ◽

Yunfang Meng ◽

Na Li ◽

Feifei Li ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Progression ◽

Negative Feedback ◽

Feedback Loop ◽

Inhibitory Effect ◽

Ovarian Cancer Cells ◽

Negative Feedback Loop

Abstract The RAC1 signal pathway is involved in various tumor cell biological processes. Here, the role of RAC1-miR-3613-RAC1 negative feedback loop in ovarian cancer was explored. Results showed that RAC1 knockdown up-regulated miR-3613, which in turn inhibited RAC1 expression. RAC1 counteracted the inhibitory effect of miR-3613 on the proliferation and invasion of ovarian cancer cells in vitro and on the tumor growth in vivo. In ovarian cancer, miR-3613 expression was negatively correlated with RAC1, and patients with low miR-3613 expression had poor prognosis. These findings indicate the role of RAC1-miR-3613-RAC1 negative feedback loop in the malignant progression of ovarian cancer and its possible therapeutic values.

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Polarized endosome dynamics engage cytosolic Par-3 and dynein during asymmetric division

10.1101/2020.05.15.098012 ◽

2020 ◽

Cited By ~ 2

Author(s):

Xiang Zhao ◽

Kai Tong ◽

Xingye Chen ◽

Bin Yang ◽

Qi Li ◽

...

Keyword(s):

Notch Signaling ◽

Cell Fate ◽

Radial Glia ◽

Asymmetric Cell Division ◽

Time Lapse ◽

Cell Fate Decisions ◽

Dynein Motor ◽

Fate Decision ◽

Underlying Mechanisms

AbstractAsymmetric cell division (ACD), which produces two daughters with different fates, is fundamental for generating cellular diversity. In the developing embryos of both invertebrates and vertebrates, asymmetrically dividing progenitors generate daughter cells with differential activity of Notch signaling1–7, a key regulator of cell fate decisions8,9. The cell polarity regulator Par-3 is critical for establishing this Notch asymmetry1,4,6, but the underlying mechanisms are not understood. Here, employing in vivo time-lapse imaging in the developing zebrafish forebrain during the mitotic cycle of radial glia, the principal vertebrate neural stem cells10,11, we show that during ACD, endosomes containing the Notch ligand Delta D (Dld) undergo convergent movement toward the cleavage plane, followed by preferential segregation into the posterior (and subsequently basal) Notchhi daughter. This asymmetric segregation requires the activity of Par-3 and the dynein motor complex. Employing label-retention expansion microscopy, we further detect Par-3 in the cytosol in association with the dynein light intermediate chain 1 (DLIC1) on Dld endosomes, suggesting a direct involvement of Par-3 in dynein-mediated polarized transport of Notch signaling endosomes. Our data reveal an unanticipated mechanism by which Par-3 regulates cell fate decision by directly polarizing Notch signaling components during ACD.

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Long noncoding RNA LINC00518 induces radioresistance by regulating glycolysis through an miR-33a-3p/HIF-1α negative feedback loop in melanoma

Cell Death and Disease ◽

10.1038/s41419-021-03523-z ◽

2021 ◽

Vol 12 (3) ◽

Author(s):

Yan Liu ◽

Dong He ◽

Mengqing Xiao ◽

Yuxing Zhu ◽

Jianda Zhou ◽

...

Keyword(s):

Histone Deacetylase ◽

Cancer Progression ◽

Negative Feedback ◽

Long Noncoding Rna ◽

Noncoding Rna ◽

Feedback Loop ◽

Negative Feedback Loop ◽

Histone Deacetylase 2

AbstractThe long noncoding RNA, LINC00518, is highly expressed in various types of cancers and is involved in cancer progression. Although LINC00518 promotes the metastasis of cutaneous malignant melanoma (CMM), the mechanism underlaying its effects on CMM radiosensitivity remains unclear. In this study, LINC00518 expression was significantly upregulated in CMM samples, and LINC00518 levels were associated with poor prognosis of patients with CMM. Knockdown of LINC00518 in CMM cells significantly inhibited cell invasion, migration, proliferation, and clonogenicity. LINC00518-mediated invasion, migration, proliferation, and clonogenicity were negatively regulated by the microRNA, miR-33a-3p, in vitro, which increased sensitivity to radiotherapy via inhibition of the hypoxia-inducible factor 1α (HIF-1α)/lactate dehydrogenase A glycolysis axis. Additionally, HIF-1α recognized the miR-33a-3p promoter region and recruited histone deacetylase 2, which decreased the expression of miR-33a-3p and formed an LINC00518/miR-33a-3p/HIF-1α negative feedback loop. Furthermore, signaling with initially activated glycolysis and radioresistance in CMM cells was impaired by Santacruzamate A, a histone deacetylase inhibitor, and 2-deoxy-D-glucose, a glycolytic inhibitor. Lastly, knockdown of LINC00518 expression sensitized CMM cancer cells to radiotherapy in an in vivo subcutaneously implanted tumor model. In conclusion, LINC00518 was confirmed to be an oncogene in CMM, which induces radioresistance by regulating glycolysis through an miR-33a-3p/HIF-1α negative feedback loop. Our study, may provide a potential strategy to improve the treatment outcome of radiotherapy in CMM.

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Regulation of HDAC9 Gene Expression by MEF2 Establishes a Negative-Feedback Loop in the Transcriptional Circuitry of Muscle Differentiation

Molecular and Cellular Biology ◽

10.1128/mcb.01415-06 ◽

2006 ◽

Vol 27 (2) ◽

pp. 518-525 ◽

Cited By ~ 81

Author(s):

Michael Haberland ◽

Michael A. Arnold ◽

John McAnally ◽

Dillon Phan ◽

Yuri Kim ◽

...

Keyword(s):

Gene Expression ◽

Negative Feedback ◽

Feedback Loop ◽

Muscle Development ◽

Transcriptional Repressor ◽

Muscle Differentiation ◽

Negative Feedback Loop ◽

Bhlh Genes

ABSTRACT Skeletal muscle development is controlled by the myocyte enhancer factor (MEF2) and myogenic basic helix-loop-helix (bHLH) families of transcription factors, which associate and synergistically activate muscle gene expression. Muscle differentiation is further reinforced by positive-feedback loops in which myogenic bHLH proteins activate their own expression and the expression of MEF2, while MEF2 stimulates expression of myogenic bHLH genes and the Mef2c gene. Here we describe a myogenic negative-feedback loop that consists of MEF2 proteins and the transcriptional repressor histone deacetylase 9 (HDAC9). We show that the HDAC9 gene is a direct transcriptional target of MEF2 in vitro and in vivo. HDAC9 can associate with MEF2 proteins and suppress their transcriptional activity. The transcriptional repressor HDAC9 thus forms a negative-feedback loop in the transcriptional circuitry of muscle differentiation.

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An autoregulatory negative feedback loop controls thermomorphogenesis in Arabidopsis

10.1101/2021.01.04.425188 ◽

2021 ◽

Author(s):

Sanghwa Lee ◽

Ling Zhu ◽

Enamul Huq

Keyword(s):

Ambient Temperature ◽

Negative Feedback ◽

Feedback Loop ◽

Target Gene ◽

High Ambient Temperature ◽

Negative Feedback Loop ◽

Gene Promoters ◽

Plant Growth And Development ◽

Helix Loop Helix

AbstractPlant growth and development are acutely sensitive to high ambient temperature ascribable in part to climate change. However, the mechanism of high ambient temperature signaling is not well defined. Here, we show that HECATEs (HEC1 and HEC2), two helix-loop-helix transcription factors, inhibit thermomorphogenesis. While the expression of HEC1 and HEC2 is increased and HEC2 protein is stabilized at high ambient temperature, hec1hec2 double mutant showed exaggerated thermomorphogenesis. Analyses of the four major PIF (PIF1, PIF3, PIF4 and PIF5) mutants and overexpression lines showed that they all contribute to promote thermomorphogenesis. Furthermore, genetic analysis showed that pifQ is epistatic to hec1hec2. HECs and PIFs oppositely control the expression of many genes in response to high ambient temperature. HEC2 interacts with PIF4 both in yeast and in vivo. In the absence of HECs, PIF4 binding to its own promoter as well as the target gene promoters was enhanced, indicating that HECs control PIF4 activity via heterodimerization. Overall, these data suggest that PIF4-HEC forms an autoregulatory composite negative feedback loop that controls growth genes to modulate thermomorphogenesis.

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Long Non-Coding RNA LINC00518 Induces Radioresistance by Regulating Glycolysis Through An miR-33a-3p/HIF-1α Negative Feedback Loop in Melanoma

10.21203/rs.3.rs-37465/v1 ◽

2020 ◽

Author(s):

Ke Cao ◽

Liu yan ◽

He Dong ◽

Xiao Mengqin ◽

Xiang Liang ◽

...

Keyword(s):

Cancer Progression ◽

Negative Feedback ◽

Feedback Loop ◽

Luciferase Reporter ◽

Negative Feedback Loop ◽

Reporter System ◽

Non Coding Rna ◽

Long Non Coding Rna

Abstract Background: The long non-coding RNA (lncRNA),LINC00518, is highly expressed in many human cancers and is involved in cancer progression. However, the potential function and regulatory mechanism of LINC00518 in cutaneous malignant melanoma (CMM) remain unclear. Methods:Short hairpin RNA (shRNA) was used to silence LINC00518 and HIF-1α, and real-time PCR was performed to determine mRNA expression. Then, cell proliferation, colony formation, flow cytometric, scratch, and transwell assays were to examine the influence of LINC00518 silencing on cellular radiosensitivity. Dual luciferase reporter system,CHIP and COIP was used to verify the target relationship between LINC00518,miR‐33a-5b and HIF-1α,.Glycolysis assays were conducted to exam cell glycolysis process. Western blotting was performed to explore the expression of HIF-1α and LDHA. Finally, animal experiments were performed to demonstrate the effect of LINC00518 silencing on the radiosensitivity of melanoma in vivo.Results: LINC00518 expression was significantly upregulated in CMM samples, and LINC00518 levels were associated with poor prognosis of patients with CMM. Knockdown of LINC00518 in CMM cells significantly inhibited cell invasion, migration, proliferation, and clonogenicity. LINC00518-mediated invasion, migration, proliferation, and clonogenicity were negatively regulated by the microRNA, miR-33a-3p, in vitro, which intensified sensitivity to radiotherapy via inhibition of the hypoxia-induced factor 1α (HIF-1α)/lactate dehydrogenase A (LDHA)-glycolysis axis. Additionally, HIF-1α recognized the miR-33a-3p promoter region and recruited histone deacetylase2 (HDAC2), which decreased the expression of miR-33a-3p and formed an LINC00518/miR-33a-3p/HIF-1α negative feedback loop. Furthermore, signalling initially activated glycolysis and radioresistance in CMM cells was recovered by Santacruzamate A (a histone deacetylase inhibitor) and 2-deoxy-D-glucose (a glycolytic inhibitor). Lastly, knockdown of LINC00518 expression sensitized CMM cancer cells to radiotherapy in an in vivo subcutaneously implanted tumour model. Conclusion: LINC00518 was confirmed to be an oncogene in CMM, which induces radioresistance by regulating glycolysis through an miR-33a-3p/HIF-1α negative feedback loop. Our research may provide a potential strategy to improve the treatment outcome of radiotherapy in CMM.

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