Phc2 controls hematopoietic stem and progenitor cell mobilization from bone marrow by repressing Vcam1 expression.

Published on Aug 2, 2019in Nature Communications14.919
路 DOI :10.1038/S41467-019-11386-4
Joonbeom Bae7
Estimated H-index: 7
(KU: Korea University),
Sang Pil Choi4
Estimated H-index: 4
(KU: Korea University)
+ 13 AuthorsTaehoon Chun22
Estimated H-index: 22
(KU: Korea University)
Sources
Abstract
The timely mobilization of hematopoietic stem and progenitor cells (HSPCs) is essential for maintaining hematopoietic and tissue leukocyte homeostasis. Understanding how HSPCs migrate between bone marrow (BM) and peripheral tissues is of great significance in the clinical setting, where therapeutic strategies for modulating their migration capacity determine the clinical outcome. Here, we identify an epigenetic regulator, Phc2, as a critical modulator of HSPC trafficking. The genetic ablation of Phc2 in mice causes a severe defect in HSPC mobilization through the derepression of Vcam1 in bone marrow stromal cells (BMSCs), ultimately leading to a systemic immunodeficiency. Moreover, the pharmacological inhibition of VCAM-1 in Phc2-deficient mice reverses the symptoms. We further determine that Phc2-dependent Vcam1 repression in BMSCs is mediated by the epigenetic regulation of H3K27me3 and H2AK119ub. Together, our data demonstrate a cell-extrinsic role for Phc2 in controlling the mobilization of HSPCs by finely tuning their bone marrow niche. Mobilization of hematopoietic stem and progenitor cells (HSPCs) into the circulation is essential for maintaining homeostasis. Here, the authors show that Phc2 in bone marrow stromal cells represses the cell adhesion molecule Vcam1 and facilitates mobilization of HSPCs through regulation of epigenetic marks.
Figures & Tables
Download
馃摉 Papers frequently viewed together
201423.63Blood
17 Authors (Lin Chen)
References70
Newest
#1Miguel Vidal (CSIC: Spanish National Research Council)H-Index: 48
#2Katarzina Starowicz (CSIC: Spanish National Research Council)H-Index: 1
Hematopoiesis, the process by which blood cells are continuously produced, is one of the best studied differentiation pathways. Hematological diseases are associated with reiterated mutations in genes encoding important gene expression regulators, including chromatin regulators. Among them, the Polycomb group (PcG) of proteins is an essential system of gene silencing involved in the maintenance of cell identities during differentiation. PcG proteins assemble into two major types of Polycomb repr...
Source
#1Felicia Gray (UM: University of Michigan)H-Index: 4
#2Hyo Je Cho (UM: University of Michigan)H-Index: 14
Last. Tomasz Cierpicki (UM: University of Michigan)H-Index: 28
view all 12 authors...
BMI1, a core element of the polycomb repressive complex 1, is suggested to have oncogenic activity in a variety of cancers. Here, the authors report the structure of BMI1 bound to the protein PHC2, identify BMI1 homo-oligomerization interfaces, and analyse the role of BMI1 protein-protein interactions in PRC1 function.
Source
#1Jihye Han (KU: Korea University)H-Index: 5
#2Joonbeom Bae (KU: Korea University)H-Index: 7
Last. Taehoon Chun (KU: Korea University)H-Index: 22
view all 12 authors...
ABSTRACTSevere hepatic inflammation is a common cause of acute or chronic liver disease. Macrophages are one of the key mediators which regulate the progress of hepatic inflammation. Increasing evidence shows that the TAM (TYRO3, AXL and MERTK) family of RTKs (receptor tyrosine kinases), which is expressed in macrophages, alleviates inflammatory responses through a negative feedback loop. However, the functional contribution of each TAM family member to the progression of hepatic inflammation re...
Source
#1Deqing HuH-Index: 20
#2Ali Shilatifard (NU: Northwestern University)H-Index: 93
: Hematological malignancies comprise a diverse set of lymphoid and myeloid neoplasms in which normal hematopoiesis has gone awry and together account for 鈭10% of all new cancer cases diagnosed in the United States in 2016. Recent intensive genomic sequencing of hematopoietic malignancies has identified recurrent mutations in genes that encode regulators of chromatin structure and function, highlighting the central role that aberrant epigenetic regulation plays in the pathogenesis of these neopl...
Source
#1Mihaela Pertea (Johns Hopkins University)H-Index: 38
#2Daehwan Kim (Johns Hopkins University)H-Index: 10
Last. Steven L. SalzbergH-Index: 154
view all 5 authors...
Pertea et al. describe a protocol to analyze RNA-seq data using HISAT, StringTie and Ballgown (the 鈥榥ew Tuxedo鈥 package). The protocol can be used for assembly of transcripts, quantification of gene expression levels and differential expression analysis.
Source
#1Milica Vukovic (Edin.: University of Edinburgh)H-Index: 12
#2Catarina Sepulveda (Edin.: University of Edinburgh)H-Index: 7
Last. Kamil R. Kranc (Edin.: University of Edinburgh)H-Index: 22
view all 15 authors...
The hematopoietic stem cell (HSC) pool is maintained under hypoxic conditions within the bone marrow microenvironment. Cellular responses to hypoxia are largely mediated by the hypoxia-inducible factors, Hif-1 and Hif-2. The oxygen-regulated 伪 subunits of Hif-1 and Hif-2 (namely, Hif-1伪 and Hif-2伪) form dimers with their stably expressed 尾 subunits and control the transcription of downstream hypoxia-responsive genes to facilitate adaptation to low oxygen tension. An initial study concluded that ...
Source
#1Andrea Piunti (NU: Northwestern University)H-Index: 18
#2Ali Shilatifard (NU: Northwestern University)H-Index: 93
BACKGROUND Multicellular organisms depend on the precise orchestration of gene expression to direct embryonic development and to maintain tissue homeostasis through their life spans. Exactly how such cell type鈥搒pecific patterns of gene expression are established, maintained, and passed on to the next generation is one of the most fundamental questions of biology. Eukaryotes package their DNA into nucleosomes to form chromatin fibers. Chromatin plays a central role in regulating accessibility to ...
Source
Polycomb group (PcG) proteins are epigenetic regulatory factors that maintain the repression of target gene expression through histone modification. PcG proteins control the repression of genes that regulate differentiation and the cell cycle in the maintenance of hematopoietic stem cells (HSC). Moreover, abnormalities in expression level and mutations in PcG genes have been reported in various types of cancer, including hematological malignancies. In this review, we present an overview of the r...
Source
#1Martin Schlesinger (University of Bonn)H-Index: 14
#2Gerd Bendas (University of Bonn)H-Index: 28
Vascular cell adhesion molecule-1 (VCAM-1) first attracted attention more than two decades ago as endothelial adhesion receptor with key function for leukocyte recruitment in term of cellular immune response. The early finding of VCAM-1 binding to melanoma cells, and thus a suggested mechanistic contribution to metastatic spread, was the first and for a long time the only link of VCAM-1 to cancer sciences. In the last few years, hallmarked by a growing insight into the molecular understanding of...
Source
#4Hu Wang (Hangzhou Normal University)H-Index: 3
#8K. Lenhard Rudolph (Leibniz Association)H-Index: 46
Aging leads to impaired differentiation and increased pool size of hematopoietic stem cells (HSCs). Here, the authors show that wild-type p53-induced phosphatase 1 (Wip1), a negative regulator of DNA damage response pathways, regulates aging-associated HSC differentiation and expansion via p53 and mTORC1 pathways, respectively.
Source
Cited By5
Newest
#1Ping WangH-Index: 1
#2Jun WangH-Index: 1
Last. Jian-xun WangH-Index: 1
view all 6 authors...
Background: Sepsis is life-threatening organ dysfunction associated with high risk of death. The immune response of sepsis is complex and varies over time. The immune cells are derived from hematopoietic stem and progenitor cells (HSPC) which can respond to many infections. Our previous study found that sepsis causes HSPC dysregulation in mouse. But few studies have previously investigated the kinetics of HSPC and its contribution to immune system in sepsis patients. Purpose: We aimed to identif...
Source
#1Junchul Kim (SNU: Seoul National University)H-Index: 3
#2Sang-Woo Lee (SNU: Seoul National University)H-Index: 6
Last. Kyungpyo Park (SNU: Seoul National University)H-Index: 26
view all 3 authors...
CXC-chemokine receptor type 4 (CXCR4), a 7-transmembrane receptor family member, displays multifaceted roles, participating in immune cell migration, angiogenesis, and even adipocyte metabolism. However, the activity of such a ubiquitously expressed receptor in epithelial gland organogenesis has not yet been fully explored. To investigate the relationship between CXCL12/CXCR4 signaling and embryonic glandular organogenesis, we used an ex vivo culture system with live imaging and RNA sequencing t...
Source
#1Seok Jin Kang (KU: Korea University)H-Index: 3
#2Taehoon Chun (KU: Korea University)H-Index: 22
Epigenetic regulation is mainly mediated by enzymes that can modify the structure of chromatin by altering the structure of DNA or histones. Proteins involved in epigenetic processes have been identified to study the detailed molecular mechanisms involved in the regulation of specific mRNA expression. Evolutionarily well-conserved polycomb group (PcG) proteins can function as transcriptional repressors by the trimethylation of histone H3 at the lysine 27 residue (H3K27me3) and the monoubiquitina...
Source
#1Sanguo Zhang (THU: Tsinghua University)H-Index: 2
#2Huanhuan Joyce Wang (THU: Tsinghua University)H-Index: 1
Last. Qin Shen (Tongji University)H-Index: 20
view all 5 authors...
Angiogenesis in the developing cerebral cortex accompanies cortical neurogenesis. However, the precise mechanisms underlying cortical angiogenesis at the embryonic stage remain largely unknown. Here, we show that radial glia-derived vascular cell adhesion molecule 1 (VCAM1) coordinates cortical vascularization through different enrichments in the proximal and distal radial glial processes. We found that VCAM1 was highly enriched around the blood vessels in the inner ventricular zone (VZ), preven...
Source
#1Yu QiuH-Index: 1
#2Chao Pu (North Sichuan Medical College)H-Index: 1
Last. Baochuang QiH-Index: 1
view all 4 authors...
Background Osteosarcoma (OS) is a common primary malignant bone tumour. Growing evidence suggests that circular RNAs (circRNAs) are closely related to the development of tumours. However, the function of circRNAs in OS remains unknown. Here, we aimed to determine the regulatory mechanisms of circRNAs in OS.
Source
This website uses cookies.
We use cookies to improve your online experience. By continuing to use our website we assume you agree to the placement of these cookies.
To learn more, you can find in our Privacy Policy.