更新于：2024-05-01

GFI1B

growth factor independent 1B transcriptional repressor

更新于：2024-05-01

基本信息

别名

GFI1B、growth factor independent 1B transcriptional repressor、Growth factor independent protein 1B

+ [3]

简介

Essential proto-oncogenic transcriptional regulator necessary for development and differentiation of erythroid and megakaryocytic lineages. Component of a RCOR-GFI-KDM1A-HDAC complex that suppresses, via histone deacetylase (HDAC) recruitment, a number of genes implicated in multilineage blood cell development and controls hematopoietic differentiation. Transcriptional repressor or activator depending on both promoter and cell type context; represses promoter activity of SOCS1 and SOCS3 and thus, may regulate cytokine signaling pathways. Cooperates with GATA1 to repress target gene transcription, such as the apoptosis regulator BCL2L1; GFI1B silencing in leukemic cell lines markedly increase apoptosis rate. Inhibits down-regulation of MYC and MYB as well as the cyclin-dependent kinase inhibitor CDKN1A/P21WAF1 in IL6-treated myelomonocytic cells. Represses expression of GATA3 in T-cell lymphomas and inhibits GATA1-mediated transcription; as GATA1 also mediates erythroid GFI1B transcription, both GATA1 and GFI1B participate in a feedback regulatory pathway controlling the expression of GFI1B gene in erythroid cells. Suppresses GATA1-mediated stimulation of GFI1B promoter through protein interaction. Binds to gamma-satellite DNA and to its own promoter, auto-repressing its own expression. Alters histone methylation by recruiting histone methyltransferase to target genes promoters. Plays a role in heterochromatin formation.

关联

100 项与 GFI1B 相关的临床结果

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100 项与 GFI1B 相关的转化医学

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0 项与 GFI1B 相关的专利（医药）

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202

项与 GFI1B 相关的文献（医药）

2024-02-12·eLife

A methylation-phosphorylation switch controls EZH2 stability and hematopoiesis.

Article

作者: Pengfei Guo ; Rebecca C Lim ; Keshari Rajawasam ; Tiffany Trinh ; Hong Sun ; Hui Zhang

The Polycomb Repressive Complex 2 (PRC2) methylates H3K27 to regulate development and cell fate by transcriptional silencing. Alteration of PRC2 is associated with various cancers. Here, we show that mouse Kdm1a deletion causes dramatic reduction of PRC2 proteins, whereas mouse null mutation of L3mbtl3 or Dcaf5 results in PRC2 accumulation and increased H3K27 trimethylation. The catalytic subunit of PRC2, EZH2, is methylated at lysine 20 (K20), promoting EZH2 proteolysis by L3MBTL3 and the CLR4^DCAF5 ubiquitin ligase. KDM1A (LSD1) demethylates the methylated K20 to stabilize EZH2. K20 methylation is inhibited by AKT-mediated phosphorylation of serine 21 in EZH2. Mouse Ezh2^K20R/K20R mutants develop hepatosplenomegaly associated with high GFI1B expression, and Ezh2^K20R/K20R mutant bone marrows expand hematopoietic stem cells and downstream hematopoietic populations. Our studies reveal that EZH2 is regulated by methylation-dependent proteolysis, which is negatively controlled by AKT-mediated S21 phosphorylation to establish a methylation-phosphorylation switch to control the PRC2 activity and hematopoiesis.

2023-12-29·Thrombosis and haemostasis

Gaining Insights into Inherited Bleeding Disorders of Complex Etiology in Pediatric Patients: Whole-Exome Sequencing as First-Line Investigation Tool.

Article

作者: Perla Bandini ; Nina Borràs ; Ruben Berrueco ; Susanna Gassiot ; Laura Martin-Fernandez ; Edurne Sarrate ; Natàlia Comes ; Lorena Ramírez ; Carlos Hobeich ; Francisco Vidal ; Irene Corrales

INTRODUCTION:

Investigation of the molecular basis of inherited bleeding disorders (IBD) is mostly performed with gene panel sequencing. However, the continuous discovery of new related genes underlies the limitation of this approach. This study aimed to identify genetic variants responsible for IBD in pediatric patients using whole-exome sequencing (WES), and to provide a detailed description and reclassification of candidate variants.

MATERIAL AND METHODS:

WES was performed for 18 pediatric patients, and variants were filtered using a first-line list of 290 genes. Variant prioritization was discussed in a multidisciplinary team based on genotype-phenotype correlation, and segregation studies were performed with available family members.

RESULTS:

The study identified 22 candidate variants in 17 out of 18 patients (94%). Eleven patients had complete genotype-phenotype correlation, resulting in a diagnostic yield of 61%, 5 (28%) were classified as partially solved, and 2 (11%) remained unsolved. Variants were identified in platelet (ACTN1, ANKRD26, CYCS, GATA1, GFI1B, ITGA2, NBEAL2, RUNX1, SRC, TUBB1), bleeding (APOLD1), and coagulation (F7, F8, F11, VWF) genes. Notably, 9 out of 22 (41%) variants were previously unreported. Variant pathogenicity was assessed according to the American College of Medical Genetics and Genomics guidelines and reclassification of three variants based on family segregation evidence, resulting in the identification of 10 pathogenic or likely pathogenic variants, 6 variants of uncertain significance, and 6 benign or likely benign variants.

CONCLUSION:

This study demonstrated the high potential of WES in identifying rare molecular defects causing IBD in pediatric patients, improving their management, prognosis, and treatment, particularly for patients at risk of malignancy and/or bleeding due to invasive procedures.

2023-12-14·Journal of thrombosis and haemostasis : JTH

Aggregates of non-muscular myosin IIA in erythrocytes associate with GATA1- and GFI1B-related thrombocytopenia.

Article

作者: Carlo Zaninetti ; Jose' Rivera ; Leonard Vater ; Sandra Ohlenforst ; Eva Leinøe ; Doris Böckelmann ; Kathleen Freson ; Thomas Thiele ; Houssain Makhloufi ; Matthias Rath ; Wolfgang Eberl ; Martina Wolff ; Carmen Freyer ; Jan Wesche ; Barbara Zieger ; Ute Felbor ; Florian H Heidel ; Andreas Greinacher

BACKGROUND:

The transcription factor GATA1 is an essential regulator of erythroid cell gene expression and maturation, and is also relevant for platelet biogenesis. GATA1-related thrombocytopenia (GATA1-RT) is a rare X-linked inherited platelet disorder (IPD) characterized by macrothrombocytopenia and dyserythropoiesis. Enlarged platelet size, reduced platelet granularity and noticeable red blood cell (RBC) anisopoikilocytosis are characteristic but unspecific morphological findings in GATA1-RT.

OBJECTIVES:

To expand the investigation of platelet phenotype of GATA1-RT patients by light- and immunofluorescence microscopy on the blood smear.

METHODS:

We assessed blood smears by light- and immunofluorescence microscopy upon May-Grünwald-Giemsa staining and using a set of 13 primary antibodies against markers belonging to different platelet structures. Antibody binding was visualized by fluorescence-labelled secondary antibodies.

RESULTS:

We investigated 12 genetically-confirmed GATA1-RT individuals from 8, unrelated families. While confirming the already known characteristic of platelet morphology (platelet macrocytosis and reduced expression of markers for alpha granules), we also found aggregates of non-muscular myosin heavy chain II A (NMMIIA) in the erythrocytes in all individuals (1-3 aggregates/cell, 1-3 μm diameter). By systematic re-analysis of blood smears from a cohort of patients with 19 different forms of IPD, we found similar NMMIIA aggregates in the RBC only in subjects with GFI1B-related thrombocytopenia (GFI1B-RT), the other major IPD featured by dyserythropoiesis.

CONCLUSIONS:

Aggregates of NMMIIA in the erythrocytes associate with GATA1-RT and GFI1B-RT and can facilitate their diagnosis on the blood smears. This hitherto unreported finding might represent a novel marker of dyserythropoiesis assessable in peripheral blood.

项与 GFI1B 相关的新闻（医药）

2024-01-21

·生物谷

研究发现髓系恶性血液肿瘤重要家族风险因素

鉴于SEC在多种血液肿瘤发生中的重要作用，以PAF1复合体亚基与SEC结合的蛋白为靶点或成为某些类型的髓系白血病药物发展的新思路。深圳理工大学（筹）药学院教授、中国科学院深圳先进技术研究院生物医药与技术研究所癌症免疫研究中心研究员赵佳伟，联合美国哈佛大学医学院附属波士顿儿童医院教授Vijay Sankaran团队，运用群体遗传学的方法，发现了髓系恶性血液肿瘤易感性的重要家族风险因素，并揭示了转录延伸在其中的重要作用机制。相关研究成果发表在《细胞》（Cell）上。血液肿瘤是一类常见的恶性肿瘤。与其他实体恶性肿瘤不同，髓系血液恶性肿瘤几乎常见于各个年龄段，具有明显的可遗传性。尽管近几十年关于血液恶性肿瘤发生的体细胞驱动突变的发现以及相关致病机理已有较完整的研究，但关于可遗传的胚系突变在血液肿瘤发生中的作用的认知仍然有限。作为群体遗传学的研究手段，全基因组相关联研究（GWAS）在识别和寻找可遗传性胚系突变的致病作用中具有重要意义。例如，胎儿向成人血红蛋白素表达转换的重要调控因子BCL11A的发现，归功于GWAS技术。然而，GWAS技术在某些方面上却有劣势。这种劣势主要表现在GWAS技术高度依赖基因组测序技术和大量样本，但过去的几十年全基因组测序的高额费用使得GWAS技术仅可应用于以微阵列技术为主体的发生频率超过5%的常见突变体。从孟德尔经典遗传学以及宏观进化中可知，有害突变体的发生频率通常较低，而常见突变体的外显率通常较低。因此，通过GWAS技术找到的常见突变体，对恶性肿瘤形成的实际意义在遗传学和癌症生物学中存在争议。随着全基因组测序技术日趋成熟，测序的费用显著下降。越来越多的全基因组测序数据的释放使得群体遗传学进入了新纪元，也即是说，我们可以通过全基因组测序找到的罕见突变体来进行罕见突变体相关联研究（RVAS）。通过RVAS找到的髓系恶性血液肿瘤易感性的重要家族风险因素（CTR9突变体），相比于传统GWAS找到的风险因素致病可能性有显著提高（1000% v.s. 25%）。 CTR9是PAF1蛋白质复合体的重要支架蛋白，在结构上具有粘合PAF1蛋白质复合体其余亚基CDC73、PAF1、LEO1、WDR61的重要作用，而PAF1复合体通常被认为在RNA聚合酶进行转录延展时起到关键作用。后续研究发现，当且仅当CTR9部分缺失时，人长期和短期造血干细胞显著扩增，且扩增的造血干细胞具备干细胞功能。从机制上，当CTR9部分缺失时，一部分PAF1复合体亚基将完全解离成为游离的蛋白质。在这部分游离的蛋白质中，CDC73和PAF1可通过MLLT3加入另一个蛋白质复合体——超级延展复合体（SEC）。加入CDC73和PAF1的SEC，可以特异性地提升与造血干细胞自我更新相关的转录因子，即其他相关蛋白质的mRNA延展效率，从而提高造血干细胞的扩增。该成果展现了群体遗传学特别是全基因组相关联研究在复杂疾病致病机理中的作用，为家族性髓系恶性血液肿瘤发生的机理提供了新思路。同时，上述研究揭示了以往尚未被解释的PAF1复合体亚基与SEC的潜在关联性。鉴于SEC在多种血液肿瘤发生中的重要作用，以PAF1复合体亚基与SEC结合的蛋白为靶点或成为某些类型的髓系白血病药物发展的新思路。突变体/单碱基多样性随着发生频率的下降造成更高的外显率。当等位基因频率小于0.005且概率比例（odds ratio）大于5时，该突变体基本遵循孟德尔遗传，而常见单碱基多样性（发生频率大于0.05）通常难以产生较大的概率比例，只有在捕捉到罕见单碱基多样性时该等位基因才可能会对目标性状具有有较大影响。相对于常见单碱基多样性的GWAS（CVAS），罕见单碱基多样性（RVAS）的概率比例显著提高，其造成的外显率比例也显著上升。部分CTR9的缺失使得一部分PAF1复合体被拆解，释放出的部分亚基，如PAF1和CDC73被超级延展复合体募集，从而增强与造血干细胞稳态与自我更新有关的基因如MECOM、GFI1B、LMO2等的转录延展，从而调高这部分基因的表达，导致造血干细胞扩增的后果。而CTR9/PAF1复合体作为一类管家基因对于细胞的存活是不可或缺的，因此CTR9完全缺失的造血干细胞无法长期维持稳态。