Mechanism of c-MYC repression by IRF8 in myeloid lineages
Mechanism of c-MYC repression by IRF8 in myeloid lineages
批准号:
10493389
负责人:
Kenneth M Murphy
金额:
$23.63万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
已结题
起止时间:
2021-09-22 至 2023-08-31
关键词:
AgeBindingBinding SitesCD8-Positive T-LymphocytesCRISPR/Cas technologyCell LineageCellsChromatinCodeCommon Lymphoid ProgenitorDataDefectDendritic CellsDevelopmentEnhancersFailureFamilyFamily memberGene ExpressionGene Expression RegulationGenesGeneticGenetic TranscriptionGerm-Line MutationGrowthHelix-Turn-Helix MotifsHematopoiesisHematopoieticHematopoietic stem cellsHomologous GeneHumanHyperplasiaImmuneImmunoprecipitationKnock-outLeftLymphocyteLymphoidMYC Family GenesMYC geneMediatingMethodsModelingMolecularMusMyelogenousMyeloid CellsPatternPopulationPublishingRegulationRegulatory ElementReportingRepressionResponse ElementsSiteSolidStructureSupporting CellT-LymphocyteTestingTranscriptional ActivationType I Epithelial Receptor CellUntranslated RNAWeightactivating transcription factorbasec-myc Genesgene repressiongenetic elementgenomic locusin vivomacrophagemembermetabolic fitnessmetabolic phenotypemonocytemouse modelnovelpreventprogenitorprototypeself-renewalstem cell populationstem cellstranscription factortumorigenesis
中文摘要
摘要
免疫细胞的生长、分化和存活是MYC基因家族的调控成员。这个家庭是
是碱性螺旋-环-螺旋(BHLH)转录因子家族的成员,包含三个成员,即
原型c-myc(由Myc编码)、N-myc(Mycn)和L-myc(myc1,mycl1)。C-MYC是使用最广泛的
在许多类型的免疫谱系中,但N-MYC在早期造血干细胞(HSCs)中表达,
而我们几年前发现的L-MYC表达于树突状细胞(DC)的髓系亚群。
我们报道了L-MYC向表达的转变发生在普通树突状细胞的前体细胞阶段。
Tor(CDP),当c-myc被切断而诱发L-myc时。我们还发现L-MYC在
DC支持强健的代谢表型,是树突状细胞最佳T细胞启动所必需的。
对这些不同的MYC家族成员的监管受到严格控制,但潜在的机制
它们表达的协调尚不清楚。特别是,c-myc被抑制的机制是
未知,但在基本层面上显然很重要。在我们的研究中,我们发现了一个事实,即代表-
C-myc在CDP阶段依赖于转录因子IRF8,IRF8缺陷小鼠失败
抑制c-myc并在包括经典树突状细胞和浆细胞样树突状细胞在内的髓系细胞中继续表达
(PDC)。这一观察结果令人费解,因为证据的份量表明,IRF8是一种激活的反式反应。
转录因子,目前尚无直接分子抑制基因表达的例子。要理解
IRF8是如何抑制c-myc的,我们用染色质免疫方法检测了Myc基因的IRF8结合位点。
髓系和树突状细胞系一系列祖细胞阶段的沉淀(CHIP)。我们确定了几个具体的
IRF8结合区,提出了一个具体的假设来解释c-myc的抑制。这些绑定
这些位点位于c-myc编码区和已知Myc增强子之间,称为Benc
Myc基因下游近两百万个碱基。IRF8介导的非编码RNA激活转录
位于Myc基因及其增强子Benc之间的基因有可能改变染色体
该基因的环状结构,并形成一种功能障碍,阻止Myc基因及其编码基因的进入。
因此会导致丧失表达能力。此R21应用程序将通过删除
用我们已有的CRISPR/Cas9方法,在原代细胞和体内特异地结合IRF8结合位点。
已经建立起来了,我们已经公布了一些结果。
英文摘要
ABSTRACT
Growth, differentiation and survival of immune cells are regulated members of MYC gene family. This family is
a member of the basic helix-loop-helix (bHLH) family of transcription factors, and contains three members, the
prototype c-MYC (encoded by Myc), N-MYC (Mycn) and L-Myc (Mycl, Mycl1). c-MYC is the most widely used
among the many types of immune lineages, but N-MYC is expressed in early hematopoietic stem cells (HSCs),
while L-MYC, we discovered several years ago, is expressed in the myeloid subsets of dendritic cells (DCs).
We reported that the switch to expression of L-MYC occurs at the stage of the common dendritic cell progeni-
tor (CDP), when c-MYC is shut off and L-MYC is induced. We also discovered that L-MYC serves a function in
DCs of supporting a robust metabolic phenotype and is required for optimal T cell priming by dendritic cells.
The regulation of these various MYC family members is under tight control, but the mechanisms underlying the
coordination of their expression is not known. In particular, the mechanism by which c-MYC is repressed is
unknown but obviously important at a basic level. In our studies, we have uncovered the fact that the repres-
sion of c-MYC at the CDP stage is dependent on the transcription factor IRF8 and that IRF8-deficient mice fail
to repress c-MYC and continue to express it in myeloid lineages including classical DCs and plasmacytoid DCs
(pDCs). This observation is puzzling because the weight of evidence indicates that IRF8 is an activating tran-
scription factor, and no example of direct molecular repression of gene expression is known. To understand
how IRF8 can repress c-MYC, we examined the Myc gene locus for IRF8 binding sites by chromatin immune
precipitation (ChIP) in a set of progenitor stages of myeloid and DC lineages. We identified several specific
regions of IRF8 binding that suggest a concrete hypothesis to explain suppression of c-MYC. These binding
sites are located between the c-MYC coding locus and the known Myc enhancer, called BENC, that is located
nearly 2 megabases downstream of the Myc gene. IRF8-mediated activation transcription of non-coding RNA
that are located between the Myc gene and its enhancer BENC have the potential to alter the chromosomal
loop structure of the locus and create a functional blockade preventing access of the Myc gene with its en-
hancer, thus causing loss of expression. This R21 application will test this hypothesis directly by deleting the
specific IRF8 binding sites specific in primary cells and in vivo using CRISPR/Cas9 methods that we have al-
ready established and for which we have a number of published results.
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