scholarly journals Histone Deacetylase 11 (HDAC11) As a Novel Transcriptional Regulator of C/EBP-β, in Immature Myeloid Cell to Myeloid Derived Suppressor Cell Transition

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 225-225 ◽  
Author(s):  
Jie Chen ◽  
Eva Sahakian ◽  
John J. Powers ◽  
Maritza LienlafMoreno ◽  
Limin Xing ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Tumor Growth ◽  
Myeloid Cells ◽  
Transcriptional Regulator ◽  
Suppressor Cell ◽  
Epigenetic Mechanism ◽  
Regulatory Function ◽  
Pathological Conditions ◽  
Myeloid Derived Suppressor Cell

Abstract In normal myelopoiesis, immature myeloid cells (IMCs) differentiate into macrophages, dendritic cells, and neutrophils. However, in pathological conditions such as in cancer, these immature cells differentiate into myeloid derived suppressor cells (MDSCs). Transcription factor CCAAT-enhancer-binding protein beta (C/EBP-β) plays a crucial role in the accumulation of MDSCs in several pathological conditions. Of note, mice lacking C/EBP-β in the bone marrow compartment lose the ability to differentiate IMCs into pathologically active MDSCs2.In contrast, up-regulation of C/EBP-β can partly induce MDSC expansion through a mechanism involving the STAT3 pathway3. Epigenetic changes, such as histone acetylation status, have been recently shown to modulate the regulatory function of MDSCs4. However, the epigenetic mechanism(s) involved in regulation of C/EBP-β gene expression in MDSCs are poorly understood. Here we show for the first time that among all the HDACs known, HDAC11, the newest member of this family of enzymes, is recruited to the C/EBP-β gene promoter region of primary myeloid cells isolated from C57BL/6 mice. Such a finding led us to explore the functional consequences of disrupting HDAC11 in myeloid cells. First, we observed a markedly higher expression of C/EBP-β mRNA (194 fold difference) in the CD11b+/Ly6G+ granulocytic compartment and a 6.7 fold difference in the CD11b+/Ly6C+monocytic compartments of HDAC11KO mice relative to control wild type mice. Second, MDSCs from HDAC11 KO mice display a higher suppressive phenotype and mechanistically we have found that they have increased expression of the immunosuppressive STAT3/IL10 axis. Third, inoculation of EL4 tumor cells into HDAC11KO mice and controls resulted in a higher expansion capacity of splenic MDSCs in mice devoid of HDAC11. Such an effect was associated with a more rapid tumor growth in HDAC11KO mice as compared to WT mice. Similar aggressive tumor growth was also observed in HDAC11 myeloid conditional KO mice (LyZ-Cre-HDAC11KO). Taken together, we have uncovered a previously unknown role for HDAC11 as a transcriptional regulator of C/EBP-β in MDSCs. Indeed, in the absence of this epigenetic checkpoint of C/EBP-β gene expression, the fully suppressive potential of MDSCs was fully unleashed. A better understanding of this novel role of HDAC11 in myeloid biology will ultimately lead to targeted epigenetic therapies to manipulate the suppressive abilities of these immunoregulatory cells. 1. Hirai H, Zhang P, Dayaram T, et al. C/EBPbeta is required for 'emergency' granulopoiesis. Nat Immunol 2006; 7(7): 732-9. 2. Marigo I, Bosio E, Solito S, et al. Tumor-induced tolerance and immune suppression depend on the C/EBPbeta transcription factor. Immunity 2010; 32(6): 790-802. 3. Condamine T, Gabrilovich DI. Molecular mechanisms regulating myeloid-derived suppressor cell differentiation and function. Trends Immunol 2011; 32(1): 19-25. 4. Youn JI, Kumar V, Collazo M, et al. Epigenetic silencing of retinoblastoma gene regulates pathologic differentiation of myeloid cells in cancer. Nat Immunol 2013; 14(3): 211-20. Disclosures No relevant conflicts of interest to declare.

scholarly journals Functional effects of variation in transcription factor binding highlight long-range gene regulation by epromoters

2019 ◽  
Author(s):  
Joanna Mitchelmore ◽  
Nastasiya Grinberg ◽  
Chris Wallace ◽  
Mikhail Spivakov
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Statistical Power ◽  
Target Genes ◽  
Allelic Variation ◽  
Regulatory Function ◽  
Regulatory Sequences ◽  
Distal Enhancer ◽  
Association Testing ◽  
Gene Regulatory

AbstractIdentifying DNA cis-regulatory modules (CRMs) that control the expression of specific genes is crucial for deciphering the logic of transcriptional control. Natural genetic variation can point to the possible gene regulatory function of specific sequences through their allelic associations with gene expression. However, comprehensive identification of causal regulatory sequences in brute-force association testing without incorporating prior knowledge is challenging due to limited statistical power and effects of linkage disequilibrium. Sequence variants affecting transcription factor (TF) binding at CRMs have a strong potential to influence gene regulatory function, which provides a motivation for prioritising such variants in association testing. Here, we generate an atlas of CRMs showing predicted allelic variation in TF binding affinity in human lymphoblastoid cell lines (LCLs) and test their association with the expression of their putative target genes inferred from Promoter Capture Hi-C and immediate linear proximity. We reveal over 1300 CRM TF-binding variants associated with target gene expression, the majority of them undetected with standard association testing. A large proportion of CRMs showing associations with the expression of genes they contact in 3D localise to the promoter regions of other genes, supporting the notion of ‘epromoters’: dual-action CRMs with promoter and distal enhancer activity.

scholarly journals Host miR155 Promotes Tumor Growth through a Myeloid-Derived Suppressor Cell–Dependent Mechanism

2014 ◽  
Vol 75 (3) ◽  
pp. 519-531 ◽  
Author(s):  
Siqi Chen ◽  
Long Wang ◽  
Jie Fan ◽  
Cong Ye ◽  
Donye Dominguez ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Suppressor Cell ◽  
Myeloid Derived Suppressor Cell ◽  
Dependent Mechanism

scholarly journals Pak2 regulates myeloid-derived suppressor cell development in mice

2017 ◽  
Vol 1 (22) ◽  
pp. 1923-1933 ◽  
Author(s):  
Yi Zeng ◽  
Seongmin Hahn ◽  
Jessica Stokes ◽  
Emely A. Hoffman ◽  
Monika Schmelz ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Suppressor Cell ◽  
Cell Development ◽  
Myeloid Derived Suppressor Cell ◽  
Key Points

Key Points Pak2 negatively regulates CD11bhighGr1high MDSC development in mice via both cell-intrinsic and extrinsic mechanisms. Pak2 disruption activates STAT5 while downregulating the expression of IRF8, a well-described myeloid transcription factor.

scholarly journals Functional effects of variation in transcription factor binding highlight long-range gene regulation by epromoters

2020 ◽  
Vol 48 (6) ◽  
pp. 2866-2879 ◽  
Author(s):  
Joanna Mitchelmore ◽  
Nastasiya F Grinberg ◽  
Chris Wallace ◽  
Mikhail Spivakov
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Statistical Power ◽  
Target Genes ◽  
Allelic Variation ◽  
Regulatory Function ◽  
Regulatory Sequences ◽  
Distal Enhancer ◽  
Association Testing ◽  
Gene Regulatory

Abstract Identifying DNA cis-regulatory modules (CRMs) that control the expression of specific genes is crucial for deciphering the logic of transcriptional control. Natural genetic variation can point to the possible gene regulatory function of specific sequences through their allelic associations with gene expression. However, comprehensive identification of causal regulatory sequences in brute-force association testing without incorporating prior knowledge is challenging due to limited statistical power and effects of linkage disequilibrium. Sequence variants affecting transcription factor (TF) binding at CRMs have a strong potential to influence gene regulatory function, which provides a motivation for prioritizing such variants in association testing. Here, we generate an atlas of CRMs showing predicted allelic variation in TF binding affinity in human lymphoblastoid cell lines and test their association with the expression of their putative target genes inferred from Promoter Capture Hi-C and immediate linear proximity. We reveal >1300 CRM TF-binding variants associated with target gene expression, the majority of them undetected with standard association testing. A large proportion of CRMs showing associations with the expression of genes they contact in 3D localize to the promoter regions of other genes, supporting the notion of ‘epromoters’: dual-action CRMs with promoter and distal enhancer activity.

scholarly journals Structural basis of hypoxic gene regulation by the Rv0081 transcription factor ofMycobacterium tuberculosis

2018 ◽  
Author(s):  
Ashwani Kumar ◽  
Swastik Phulera ◽  
Arshad Rizvi ◽  
Parshuram Sonawane ◽  
Hemendra Singh Panwar ◽  
...  
Keyword(s):  
Gene Expression ◽  
Crystal Structure ◽  
Gene Regulation ◽  
Transcription Factor ◽  
Dna Binding ◽  
Metal Binding ◽  
Transcriptional Regulator ◽  
Tuberculosis Infection ◽  
Structural Basis ◽  
Latent Phase

ABSTRACTThe transcription factor Rv0081 ofM. tuberculosiscontrols the hypoxic gene expression and acts as a regulatory hub in the latent phase of tuberculosis infection. We report here the crystal structure of Rv0081 at 3.3 Å resolution revealing that it belongs to the well-known ArsR/SmtB family proteins. ArsR/SmtB family transcriptional repressors exert gene regulation by reversible metal binding. Hypoxia in general is sensed by bacterial transcriptional regulators via metals or Cys-mediated thiol switches. Oxygen sensing typically leads to transcriptional repressor changing its conformational state with altered DNA-binding property under different oxygen levels. Surprisingly Rv0081 neither has a metal binding domain nor does it possess Cys residues suggesting an alternate mechanism of gene regulation. Our structural analysis identified Ser 48, Ser 49, Ser 52 and Gln 53 as potential residues of Rv0081 involved in DNA binding. We probed DNA-binding of Rv0081 with electrophoretic mobility shift assay (EMSA) as well as surface plasmon resonance (SPR), where the Alanine mutants of these residues showed diminished DNA binding. Similarly, Aspartate mutants of these Ser residues was shown to fail to bind to DNA. Since, phosphorylation of various regulatory proteins is one of the important controlling mechanisms, we expected the role of Ser-phosphorylation of Rv0081 in hypoxic condition. Probing Rv0081 with anti-phosphoserine antibodies inM. tuberculosiscell lysate showed marked enhancement in the phosphorylation of Rv0081 protein under hypoxia. Overall, our structural and biochemical analysis provides the molecular basis for the regulation of Rv0081 in the latent phase of tuberculosis infection.IMPORTANCETuberculosis is one of the deadliest infectious diseases caused by the bacteriumMycobacterium tuberculosis. In about 90% of the infected people,M. tuberculosisexists in a dormant or a latent stage which can be reactivated in favorable conditions. Hypoxia (low oxygen pressure) is one of causes of dormancy. Understanding hypoxic gene regulation inM. tuberculosisis therefore an important step to understand latency. Rv0081 is a transcriptional regulator of genes expressed during hypoxia. In order to understand the mechanism by which Rv00081 regulates gene expression during hypoxia, we have solved the crystal structure of Rv0081 and identified amino acid residues which are critical in its transcriptional regulator activity. The crystal structure is suggestive of mechanism of gene regulation under hypoxia.

scholarly journals Myeloid-derived suppressor cell subsets drive glioblastoma growth in a sex-specific manner

2020 ◽  
Author(s):  
Defne Bayik ◽  
Yadi Zhou ◽  
Chihyun Park ◽  
Changjin Hong ◽  
Daniel Vail ◽  
...  
Keyword(s):  
Gene Expression ◽  
Suppressor Cells ◽  
Suppressor Cell ◽  
Gene Signature ◽  
Myeloid Derived Suppressor Cells ◽  
Myeloid Derived Suppressor Cell ◽  
Specific Manner ◽  
Therapeutic Opportunity ◽  
Clinical Models ◽  
Medicine Analysis

AbstractMyeloid-derived suppressor cells (MDSCs) that block anti-tumor immunity are elevated in glioblastoma (GBM) patients. However, the distinct contribution of monocytic (mMDSC) versus granulocytic (gMDSC) subsets has yet to be determined. We observed that mMDSCs were enriched in the male tumor microenvironment, while gMDSCs were elevated in the circulation of female GBM models. Depletion of peripheral gMDSCs extended the survival only in female mice. Using gene expression signatures coupled with network medicine analysis, we demonstrated in pre-clinical models that mMDSCs could be targeted with anti-proliferative agents in males, whereas gMDSC function in females could be inhibited by IL-1β blockade. Analysis of patient data confirmed that proliferating mMDSCs were the predominant population in male tumors, and that a high gMDSC/IL-1β gene signature correlated with poor prognosis of female patients. These findings demonstrate that MDSC subsets differentially drive immune suppression in a sex-specific manner and can be leveraged for therapeutic intervention in GBM.Statement of SignificanceSexual dimorphism at the level of MDSC subset prevalence, localization and gene expression profile comprises a therapeutic opportunity. Our results indicate that chemotherapy can be used to target mMDSC in males, while IL-1 pathway inhibitors can provide benefit to females through blockade of gMDSC function.

Do age-related changes in DNA methylation play a role in the development of age-related diseases?

2013 ◽  
Vol 41 (3) ◽  
pp. 803-807 ◽  
Author(s):  
Sanne D. van Otterdijk ◽  
John C. Mathers ◽  
Gordon Strathdee
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Cpg Islands ◽  
Large Body ◽  
Epigenetic Mechanism ◽  
Aberrant Methylation ◽  
Gene Promoters ◽  
Cpg Sites ◽  
Pathological Conditions ◽  
Age Related

DNA methylation is an important epigenetic mechanism in mammalian cells. It occurs almost exclusively at CpG sites and has a key role in a number of biological processes. It plays an important part in regulating chromatin structure and has been best studied for its role in controlling gene expression. In particular, hypermethylation of gene promoters which have high levels of CpG sites, known as CpG islands, leads to gene inactivation. In healthy cells, however, it appears that only a small number of genes are controlled through promoter hypermethylation, such as genes on the inactivated X-chromosome or at imprinted loci, and most promoter-associated CpG islands remain methylation-free regardless of gene expression status. However, a large body of evidence has now shown that this protection from methylation not only breaks down in a number of pathological conditions (e.g. cancer), but also already occurs during the normal process of aging. The present review focuses on the methylation changes that occur during healthy aging and during disease development, and the potential links between them. We focus especially on the extent to which the acquisition of aberrant methylation changes during aging could underlie the development of a number of important age-related pathological conditions.

scholarly journals Tunable Transcription Factor Library for Robust Quantification of Gene Expression Dynamics in E. coli

2021 ◽  
Author(s):  
Vinuselvi Parisutham ◽  
Shivani Chhabra ◽  
Zulfikar Ali ◽  
Robert C Brewster
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Binding Affinity ◽  
Gene Networks ◽  
Regulatory Function ◽  
Precise Control ◽  
E Coli ◽  
Gene Expression Dynamics ◽  
Binding Sequence

Predicting the quantitative regulatory function of a TF based on factors such as binding sequence, binding location and promoter type is not possible. The interconnected nature of gene networks and the difficulty in tuning individual TF concentrations makes the isolated study of TF function challenging. Here we present a library of E. coli strains designed to allow for precise control of the concentration of individual TFs enabling the study of the role of TF concentration on physiology and regulation. We demonstrate the usefulness of this resource by measuring the regulatory function of the zinc responsive TF, ZntR and the paralogous TF pair, GalR/GalS. For ZntR, we find that zinc alters ZntR regulatory function in a way that enables activation of the regulated gene to be robust with respect to ZntR concentration. For GalR and GalS, we are able to demonstrate that these parlogous TFs have fundamentally distinct regulatory roles beyond differences in binding affinity.

scholarly journals Neutrophil elastase from myeloid cells promotes TSC2-null tumor growth

2020 ◽  
Vol 27 (4) ◽  
pp. 261-274 ◽  
Author(s):  
Manisha Taya ◽  
Maria de la Luz Garcia-Hernandez ◽  
Javier Rangel-Moreno ◽  
Briaunna Minor ◽  
Erin Gibbons ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Tumor Cell ◽  
Neutrophil Elastase ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Suppressor Cell ◽  
Migration And Invasion ◽  
Mouse Uterus ◽  
Estrogen Sensitivity

Chronic inflammation promotes progression of many cancers, with circulating myeloid-derived suppressor cell (MDSC) levels correlating with poor prognosis. Here we examine effects of MDSCs on lymphangioleiomyomatosis (LAM), a rare disease occurring almost exclusively in women whereby estrogen-sensitive metastatic TSC2-null tumors grow throughout the lungs, markedly reducing pulmonary function. The LAM cell origin remains unknown; however, previous work demonstrated that Tsc2 inactivation in the mouse uterus induced estrogen-dependent myometrial tumors with nearly all features of LAM. Half of these animals developed metastatic myometrial tumors in the lungs, suggesting that LAM cells might originate from the myometrium, possibly explaining its overwhelming female prevalence and estrogen-sensitivity. Here we report that MDSC levels, and in particular granulocytic myeloid cell levels, are elevated in the periphery and in tumors of uterine-specific Tsc2-null mice. Importantly, MDSC depletion or inhibition of their recruitment impairs myometrial tumor growth. RNA and protein analysis of Tsc2-null myometrial tumors and xenografts demonstrate high expression and activity of the serine protease neutrophil elastase (NE), with selective qPCR studies indicating a stromal origin of the NE. Notably, treatment with sivelestat, a known NE inhibitor already approved for human use in some countries, reduces tumor growth similar to MDSC depletion. Furthermore, NE promotes Tsc2-null tumor cell growth, migration, and invasion in vitro. Finally, NE-expressing myeloid cells are present throughout the lungs of LAM patients but not controls. These data suggest that NE derived from granulocytic myeloid cells might directly promote LAM tumor cell progression and could be a novel therapeutic target for LAM.

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