A GWAS sequence variant for platelet volume marks an alternative DNM3 promoter in megakaryocytes near a MEIS1 binding site

Nürnberg, Sylvia; Rendon, Augusto; Smethurst, Peter A.; Paul, Dirk S.; Voß, Katrin; Thon, Jonathan N.; Lloyd-Jones, Heather; Sambrook, Jennifer; Tijssen, Marloes R.; Italiano, Joseph E.; Deloukas, Panos; Göttgens, Berthold; Soranzo, Nicole; Ouwehand, Willem H.

doi:10.1182/blood-2012-01-401893

Cited by 43 publications

(42 citation statements)

References 41 publications

(51 reference statements)

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“…4D). This is consistent with the notion that CHRF-288-11 cells are immature and therefore more closely related to MK-erythroid progenitor cells (Nürnberg et al 2012), and is in agreement with the extensive overlap we found between NDRs in CHRF-288-11 and K562 cells (Supplemental Fig. 2G-J).…”

Section: Functional Classification Of Ndrs Based On Signal Strengthsupporting

confidence: 92%

“…As a further example, we recently described the molecular mechanism underlying the DNM3 platelet count and volume locus (Nürnberg et al 2012). In brief, the SNP rs2038479 was located at intron 2 of DNM3, which encodes Dynamin 3, a mechanochemical enzyme involved in MK progenitor proliferation and maturation (Reems et al 2008;Wang et al 2011).…”

Section: Identification Of Candidate Functional Variants At Platelet mentioning

confidence: 99%

“…In brief, the SNP rs2038479 was located at intron 2 of DNM3, which encodes Dynamin 3, a mechanochemical enzyme involved in MK progenitor proliferation and maturation (Reems et al 2008;Wang et al 2011). The corresponding MK-restricted NDR (Table 1) was found to be bound by the MK-specific transcription factor MEIS1 and to mark an alternative promoter of a truncated DNM3 transcript, which is uniquely expressed in MKs and whose level depends on the rs2038479 genotype (Nürnberg et al 2012). …”

Section: Identification Of Candidate Functional Variants At Platelet mentioning

confidence: 99%

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Maps of open chromatin highlight cell type–restricted patterns of regulatory sequence variation at hematological trait loci

et al. 2013

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Nearly three-quarters of the 143 genetic signals associated with platelet and erythrocyte phenotypes identified by metaanalyses of genome-wide association (GWA) studies are located at non-protein-coding regions. Here, we assessed the role of candidate regulatory variants associated with cell type-restricted, closely related hematological quantitative traits in biologically relevant hematopoietic cell types. We used formaldehyde-assisted isolation of regulatory elements followed by next-generation sequencing (FAIRE-seq) to map regions of open chromatin in three primary human blood cells of the myeloid lineage. In the precursors of platelets and erythrocytes, as well as in monocytes, we found that open chromatin signatures reflect the corresponding hematopoietic lineages of the studied cell types and associate with the cell typespecific gene expression patterns. Dependent on their signal strength, open chromatin regions showed correlation with promoter and enhancer histone marks, distance to the transcription start site, and ontology classes of nearby genes. Cell type-restricted regions of open chromatin were enriched in sequence variants associated with hematological indices. The majority (63.6%) of such candidate functional variants at platelet quantitative trait loci (QTLs) coincided with binding sites of five transcription factors key in regulating megakaryopoiesis. We experimentally tested 13 candidate regulatory variants at 10 platelet QTLs and found that 10 (76.9%) affected protein binding, suggesting that this is a frequent mechanism by which regulatory variants influence quantitative trait levels. Our findings demonstrate that combining large-scale GWA data with open chromatin profiles of relevant cell types can be a powerful means of dissecting the genetic architecture of closely related quantitative traits.

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Section: Functional Classification Of Ndrs Based On Signal Strengthsupporting

confidence: 92%

Section: Identification Of Candidate Functional Variants At Platelet mentioning

confidence: 99%

Section: Identification Of Candidate Functional Variants At Platelet mentioning

confidence: 99%

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Maps of open chromatin highlight cell type–restricted patterns of regulatory sequence variation at hematological trait loci

et al. 2013

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“…17,18 However, individuals expressing a truncated and inactive DNM3 in MKs have normal blood platelet counts and minimally affected mean platelet volumes, indicating that DNM3 plays a redundant role in platelet formation in humans. 19 In contrast, mutations in the housekeeping DNM2 have been associated with thrombocytopenia and hematopoietic disorders such as neutropenia and early T-cell precursor acute lymphoblastic leukemia. [20][21][22][23] We investigated the role of DNM2 in MK maturation and platelet formation by generating Dnm2 fl/fl Pf4-Cre mice specifically lacking DNM2 in the MK lineage via Cre-loxP recombination.…”

Section: Introductionmentioning

confidence: 99%

Dynamin 2–dependent endocytosis is required for normal megakaryocyte development in mice

Bender

Giannini

Grozovsky

et al. 2015

Blood

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Key Points• DNM2-dependent endocytosis in MKs regulates megakaryopoiesis, thrombopoiesis, and bone marrow homeostasis.Dynamins are highly conserved large GTPases (enzymes that hydrolyze guanosine triphosphate) involved in endocytosis and vesicle transport, and mutations in the ubiquitous and housekeeping dynamin 2 (DNM2) have been associated with thrombocytopenia in humans. To determine the role of DNM2 in thrombopoiesis, we generated Dnm2 fl/fl Pf4-Cre mice specifically lacking DNM2 in the megakaryocyte (MK) lineage. Dnm2fl/fl Pf4-Cre mice had severe macrothrombocytopenia with moderately accelerated platelet clearance. Dnm2-null bone marrow MKs had altered demarcation membrane system formation in vivo due to defective endocytic pathway, and fetal liver-derived Dnm2-null MKs formed proplatelets poorly in vitro, showing that DNM2-dependent endocytosis plays a major role in MK membrane formation and thrombopoiesis. Endocytosis of the thrombopoietin receptor Mpl was impaired in Dnm2-null platelets, causing constitutive phosphorylation of the tyrosine kinase JAK2 and elevated circulating thrombopoietin levels. MK-specific DNM2 deletion severely disrupted bone marrow homeostasis, as reflected by marked expansion of hematopoietic stem and progenitor cells, MK hyperplasia, myelofibrosis, and consequent extramedullary hematopoiesis and splenomegaly. Taken together, our data demonstrate that unrestrained MK growth and proliferation results in rapid myelofibrosis and establishes a previously unrecognized role for DNM2-dependent endocytosis in megakaryopoiesis, thrombopoiesis, and bone marrow homeostasis. (Blood. 2015;125(6):1014-1024

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“…This MEIS1 binding site falls within a region acting as an alternative promoter for DNM3 solely used in MKs [185]. DNM3 has since been confirmed as a key regulator of proplatelet formation [186].…”

Section: Meis1 and Its Regulator Gfi1bmentioning

confidence: 95%

Transcriptional Regulation of Platelet Formation: Harnessing the Complexity for Efficient Platelet Production In Vitro

Tijssen

Moreau

Ghevaert

2016

Molecular and Cellular Biology of Platelet Formation

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It is now common knowledge that specific repertoires of transcription factors (TFs) determine a cell's protein content and thereby its phenotype. The expression of a given TF is not necessarily cell specific, and many TFs play a pivotal role in several different cell types. For example, TAL1, FLI1, RUNX1, ERG and GATA2 are important regulators of stem cells, but also play a vital role in megakaryopoiesis. Although the megakaryocyte (MK) and its closest relative, the red blood cell, share key TFs like GATA1 and NFE2, the bifurcation between the two lineages has been associated with pairs of TFs that act as a toggle switch (such as FLI1 and KLF1). This chapter will summarise the current knowledge of key transcriptional regulators of MK differentiation and how some of these TFs, despite being expressed in several cell types, can impose MK cell identity. Since the discovery of TPO in 1994, our knowledge of MK biology and differentiation has increased exponentially, but we still lack a deep understanding of what triggers the transition from MK growth and maturation to proplatelet formation. We describe how some well-known TFs control the expression of proteins that play a pivotal role in the dramatic cytoplasmic and cytoskeletal events that accompany proplatelet formation. Finally, we show how TFs can be harnessed in a powerful way to produce MKs and, potentially, platelets in vitro for future clinical applications.

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A GWAS sequence variant for platelet volume marks an alternative DNM3 promoter in megakaryocytes near a MEIS1 binding site

Cited by 43 publications

References 41 publications

Maps of open chromatin highlight cell type–restricted patterns of regulatory sequence variation at hematological trait loci

Maps of open chromatin highlight cell type–restricted patterns of regulatory sequence variation at hematological trait loci

Dynamin 2–dependent endocytosis is required for normal megakaryocyte development in mice

Transcriptional Regulation of Platelet Formation: Harnessing the Complexity for Efficient Platelet Production In Vitro

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