scholarly journals Logical modeling of lymphoid and myeloid cell specification and transdifferentiation

2017 ◽  
Vol 114 (23) ◽  
pp. 5792-5799 ◽  
Author(s):  
Samuel Collombet ◽  
Chris van Oevelen ◽  
Jose Luis Sardina Ortega ◽  
Wassim Abou-Jaoudé ◽  
Bruno Di Stefano ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Cell Fate ◽  
Regulatory Network ◽  
Developmental Process ◽  
Ectopic Expression ◽  
Myeloid Cell ◽  
Hematopoietic Stem ◽  
Chip Sequencing ◽  
Cell Fate Decisions ◽  
Public Data

Blood cells are derived from a common set of hematopoietic stem cells, which differentiate into more specific progenitors of the myeloid and lymphoid lineages, ultimately leading to differentiated cells. This developmental process is controlled by a complex regulatory network involving cytokines and their receptors, transcription factors, and chromatin remodelers. Using public data and data from our own molecular genetic experiments (quantitative PCR, Western blot, EMSA) or genome-wide assays (RNA-sequencing, ChIP-sequencing), we have assembled a comprehensive regulatory network encompassing the main transcription factors and signaling components involved in myeloid and lymphoid development. Focusing on B-cell and macrophage development, we defined a qualitative dynamical model recapitulating cytokine-induced differentiation of common progenitors, the effect of various reported gene knockdowns, and the reprogramming of pre-B cells into macrophages induced by the ectopic expression of specific transcription factors. The resulting network model can be used as a template for the integration of new hematopoietic differentiation and transdifferentiation data to foster our understanding of lymphoid/myeloid cell-fate decisions.

An erythroid to myeloid cell fate conversion is elicited by LSD1 inactivation

Blood ◽  
2021 ◽  
Author(s):  
Lei Yu ◽  
Greggory Myers ◽  
Chia-Jui Ku ◽  
Emily Schneider ◽  
Yu Wang ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Cell Fate ◽  
Myeloid Cell ◽  
Globin Genes ◽  
Erythroid Progenitors ◽  
Erythroid Progenitor ◽  
Differentiation Potential ◽  
Hematopoietic Stem ◽  
Cell Fate Conversion ◽  
Bac Transgene

Histone H3 lysine 4 methylation (H3K4Me) is most often associated with chromatin activation, and removing H3K4 methyl groups has been shown to be coincident with gene repression. H3K4Me demethylase KDM1a/LSD1 is a therapeutic target for multiple diseases, including for the potential treatment of b-globinopathies (sickle cell disease and b-thalassemia) since it is a component of g-globin repressor complexes, and LSD1 inactivation leads to robust induction of the fetal globin genes. The effects of LSD1 inhibition in definitive erythropoiesis are not well characterized, so we examined the consequences of conditional inactivation of Lsd1 in adult red blood cells using a new Gata1creERT2 BAC transgene. Erythroid-specific loss of Lsd1 activity in mice led to a block in erythroid progenitor differentiation and to the expansion of GMP-like cells, converting hematopoietic differentiation potential from an erythroid to a myeloid fate. The analogous phenotype was also observed in human hematopoietic stem and progenitor cells (HSPC), coincident with induction of myeloid transcription factors (e.g. PU.1 and CEBPa). Finally, blocking the activity of transcription factors PU.1 or RUNX1 at the same time as LSD1 inhibition rescued myeloid lineage conversion to an erythroid phenotype. These data show that LSD1 promotes erythropoiesis by repressing myeloid cell fate in adult erythroid progenitors, and that inhibition of the myeloid differentiation pathway reverses the lineage switch induced by LSD1 inactivation.

scholarly journals Stag1 and Stag2 regulate cell fate decisions in hematopoiesis through non-redundant topological control

2019 ◽  
Author(s):  
Aaron D. Viny ◽  
Robert L. Bowman ◽  
Yu Liu ◽  
Vincent-Philippe Lavallée ◽  
Shira E. Eisman ◽  
...  
Keyword(s):  
Cell Fate ◽  
Cell Lineage ◽  
Chromatin Accessibility ◽  
Lineage Specification ◽  
Hematopoietic Stem ◽  
Chip Sequencing ◽  
Cell Fate Decisions ◽  
Transcriptional Dysregulation ◽  
Topologically Associated Domains

AbstractTranscriptional regulators, including the cohesin complex member STAG2, are recurrently mutated in cancer. The role of STAG2 in gene regulation, hematopoiesis, and tumor suppression remains unresolved. We show Stag2 deletion in hematopoietic stem/progenitor cells (HSPC) results in altered hematopoietic function, increased self-renewal, and impaired differentiation. ChIP-sequencing revealed that while Stag2 and Stag1 can bind the same loci, a component of Stag2 binding sites are unoccupied by Stag1 even in Stag2-deficient HSPCs. While concurrent loss of Stag2 and Stag1 abrogated hematopoiesis, Stag2 loss alone decreased chromatin accessibility and transcription of lineage-specification genes, including Ebf1 and Pax5, leading to blunted HSPC commitment to the B-cell lineage. Our data illustrate a role for Stag2 in transformation and transcriptional dysregulation distinct from its shared role with Stag1 in chromosomal segregation.One Sentence SummaryStag1 rescues topologically associated domains in the absence of Stag2, but cannot restore chromatin architecture required for hematopoietic lineage commitment

Regulation of Hematopoietic Stem and Progenitor Cell Differentiation By Mirn23a/b Micrornas

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3880-3880
Author(s):  
Jeffrey Kurkewich ◽  
Justin Hansen ◽  
Nathan Klopfenstein ◽  
Helen Zhang ◽  
Christian Wood ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Transcription Factors ◽  
Cell Fate ◽  
Negative Regulation ◽  
Mirna Cluster ◽  
Hematopoietic Stem ◽  
Smad Pathway ◽  
Cell Fate Decisions ◽  
Regulatory Feedback Loop ◽  
Marrow Cellularity

Abstract Differentiation from hematopoietic stem and progenitor cells (HSPCs) to committed blood lineages is dependent on lineage specific transcription factors that simultaneously promote gene expression that commits progenitors to specific lineages while repressing genes associated with alternative lineages. In addition to transcription factors, small non-coding microRNAs (miRNAs) also have the potential to influence cell fate decisions through negative regulation of lineage specific genes. We previously observed that germline knockout of the mirn23a miRNA cluster (which codes for mature miRNAs miR-23a, miR-27a, and miR-24-2) resulted in increased common lymphoid progenitors (CLPs) and B cells with a concomitant decrease in granulocyte/monocyte progenitors (GMPs) and their progeny. This was the first evidence of a miRNA being able to influence a lymphoid/myeloid cell fate decision using a genetic knockout model. To follow up these results, we sought to identify a detailed molecular mechanism of the mirn23a-/- mouse phenotype. Evaluation of HSPC populations by flow cytometry revealed that while mirn23a-/- mice have no difference s in their LT-HSC populations, they show imbalanced levels of MPP3 and MPP4 populations, suggesting that bifurcation from the MPP2 to the MPP3/MPP4 is the earliest cell type regulated by mirn23a to influence hematopoietic cell fate decisions. RNA and protein analysis of multipotent EML cell lines generated from wildtype and mirn23a-/- mice revealed that mirn23a negatively regulated critical HSPC genes Runx1, Satb1, Ikzf1, Mef2c, Bach1, and Bach2 that are involved in committing MPPs to CLPs. Additionally, genes associated with the commitment of CLPs to B cells, EBF1 and Pax5, were also increased. We observed that miR-24-2 target, Trib3, antagonizes PI3K/AKT signaling to promote EBF1 and Pax5 expression through nuclear accumulation of FoxO1. Trib3 also agonizes the BMP/Smad pathway through negative regulation of E3-ubiquitinase Smurf1. Ex vivo OP9 cultures with primary mirn23a-/- cells cultured with FoxO1 and BMP inhibitors revealed that both the PI3K/Akt and BMP/Smad pathway are critical for mirn23a-/- phenotypes. Consistent with mirn23a being a critical gene for myeloid commitment of hematopoietic progenitors, we observe that B Cell factor EBF1 represses transcription of mirn23a, creating a regulatory feedback loop between mirn23a and EBF1. In addition to mirn23a, there is a homologous mirn23b miRNA cluster that is expressed at lower levels in hematopoietic cells. To investigate compound loss of mirn23a and mirn23b in adult hematopoiesis, we generated mirn23a-/-mirn23bf/f Mx-1 cre mice to circumvent variable embryonic/ neonatal lethality. These mice showed a further increase in B lymphopoiesis and decrease in myelopoiesis compared to mirn23a-/- mice. Interestingly, these mice also exhibited decreased bone marrow cellularity at 3 weeks post mirn23b excision. As judged by overall numbers and percent of bone marrow, LT-HSC, MPP, and LSK populations were decreased. We are currently investigating the underlying mechanism for the decreased stem cells and overall cellularity. Overall, these results show that mirn23a/b miRNAs bias cell fate decisions at the MPP through negative regulation of critical lymphoid transcription factors. Sustained commitment to the B cell lineage is dependent on both the PI3K/Akt and BMP/Smad signaling pathways, both of which are regulated by mirn23a target Trib3. In turn, EBF1 negatively regulates mirn23a, creating a regulatory feedback loop between EBF1 and mirn23a. Compound loss of mirn23a/mirn23b results in decreased bone marrow cellularity and stem cell loss. Disclosures No relevant conflicts of interest to declare.

The MADS transcription factor Mef2c is a pivotal modulator of myeloid cell fate

Blood ◽  
2008 ◽  
Vol 111 (9) ◽  
pp. 4532-4541 ◽  
Author(s):  
Andrea Schüler ◽  
Maike Schwieger ◽  
Afra Engelmann ◽  
Kristoffer Weber ◽  
Stefan Horn ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Cell Fate ◽  
Serum Response Factor ◽  
Myeloid Cell ◽  
Cardiovascular Development ◽  
Monocytic Differentiation ◽  
Cell Fate Decisions ◽  
Extracellular Stimuli ◽  
Interfering Rna

AbstractMef2c is a MADS (MCM1-agamous–deficient serum response factor) transcription factor best known for its role in muscle and cardiovascular development. A causal role of up-regulated MEF2C expression in myelomonocytic acute myeloid leukemia (AML) has recently been demonstrated. Due to the pronounced monocytic component observed in Mef2c-induced AML, this study was designed to assess the importance of Mef2c in normal myeloid differentiation. Analysis of bone marrow (BM) cells manipulated to constitutively express Mef2c demonstrated increased monopoiesis at the expense of granulopoiesis, whereas BM isolated from Mef2cΔ/− mice showed reduced levels of monocytic differentiation in response to cytokines. Mechanistic studies showed that loss of Mef2c expression correlated with reduced levels of transcripts encoding c-Jun, but not PU.1, C/EBPα, or JunB transcription factors. Inhibiting Jun expression by short-interfering RNA impaired Mef2c-mediated inhibition of granulocyte development. Moreover, retroviral expression of c-Jun in BM cells promoted monocytic differentiation. The ability of Mef2c to modulate cell-fate decisions between monocyte and granulocyte differentiation, coupled with its functional sensitivity to extracellular stimuli, demonstrate an important role in immunity—and, consistent with findings of other myeloid transcription factors, a target of oncogenic lesions in AML.

scholarly journals E2A Antagonizes PU.1 Activity through Inhibition of DNA Binding

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Jason H. Rogers ◽  
Kristin S. Owens ◽  
Jeffrey Kurkewich ◽  
Nathan Klopfenstein ◽  
Sangeeta R. Iyer ◽  
...  
Keyword(s):  
Transcription Factors ◽  
B Cell ◽  
Cell Fate ◽  
Myeloid Cell ◽  
Myeloid Differentiation ◽  
B Cell Differentiation ◽  
Hematopoietic Progenitors ◽  
Hematopoietic Progenitor ◽  
Cell Fate Decisions ◽  
Cell Commitment

Antagonistic interactions between transcription factors contribute to cell fate decisions made by multipotent hematopoietic progenitor cells. Concentration of the transcription factor PU.1 affects myeloid/lymphoid development with high levels of PU.1 directing myeloid cell fate acquisition at the expense of B cell differentiation. High levels of PU.1 may be required for myelopoiesis in order to overcome inhibition of its activity by transcription factors that promote B cell development. The B cell transcription factors, E2A and EBF, are necessary for commitment of multipotential progenitors and lymphoid primed multipotential progenitors to lymphocytes. In this report we hypothesized that factors required for early B cell commitment would bind to PU.1 and antagonize its ability to induce myeloid differentiation. We investigated whether E2A and/or EBF associate with PU.1. We observed that the E2A component, E47, but not EBF, directly binds to PU.1. Additionally E47 represses PU.1-dependent transactivation of theMCSFRpromoter through antagonizing PU.1’s ability to bind to DNA. Exogenous E47 expression in hematopoietic cells inhibits myeloid differentiation. Our data suggest that E2A antagonism of PU.1 activity contributes to its ability to commit multipotential hematopoietic progenitors to the lymphoid lineages.

Dot(1L) on the spot

Blood ◽  
2010 ◽  
Vol 116 (22) ◽  
pp. 4385-4386
Author(s):  
Jörg Bungert
Keyword(s):  
Transcription Factors ◽  
Cell Fate ◽  
Histone H3 ◽  
Myeloid Cell ◽  
Specific Gene ◽  
Erythroid Progenitor ◽  
Cell Fate Decisions ◽  
Erythroid Progenitor Cells ◽  
Early Embryonic Lethality ◽  
Lineage Specific Gene

Hematopoietic cell fate decisions are regulated primarily by transcription factors that activate or repress lineage-specific gene expression programs.1 The transcription factors GATA-1/2 and Pu.1 are critical regulators of erythroid and myeloid cell differentiation. In this issue of Blood, Feng et al demonstrate that the histone methyltransferase disruptor of telomeric silencing (Dot1L), which catalyzes the methylation of histone H3 at lysine residue 79 (H3K79), is required for the proper activation of GATA-2 and for the repression of Pu.1 during erythropoiesis.2 Disruption of Dot1L activity in mice leads to early embryonic lethality in part due to a decrease in the expansion of erythroid progenitor cells and a defect in angiogenesis.

scholarly journals Depletion of L3MBTL1 promotes the erythroid differentiation of human hematopoietic progenitor cells: possible role in 20q− polycythemia vera

Blood ◽  
2010 ◽  
Vol 116 (15) ◽  
pp. 2812-2821 ◽  
Author(s):  
Fabiana Perna ◽  
Nadia Gurvich ◽  
Ruben Hoya-Arias ◽  
Omar Abdel-Wahab ◽  
Ross L. Levine ◽  
...  
Keyword(s):  
Polycythemia Vera ◽  
Progenitor Cells ◽  
Cell Fate ◽  
Myeloproliferative Neoplasms ◽  
Erythroid Differentiation ◽  
Polycomb Group ◽  
Human Cord Blood ◽  
Hematopoietic Stem ◽  
Cell Fate Decisions ◽  
Cd34 Cells

Abstract L3MBTL1, the human homolog of the Drosophila L(3)MBT polycomb group tumor suppressor gene, is located on chromosome 20q12, within the common deleted region identified in patients with 20q deletion-associated polycythemia vera, myelodysplastic syndrome, and acute myeloid leukemia. L3MBTL1 is expressed within hematopoietic CD34+ cells; thus, it may contribute to the pathogenesis of these disorders. To define its role in hematopoiesis, we knocked down L3MBTL1 expression in primary hematopoietic stem/progenitor (ie, CD34+) cells isolated from human cord blood (using short hairpin RNAs) and observed an enhanced commitment to and acceleration of erythroid differentiation. Consistent with this effect, overexpression of L3MBTL1 in primary hematopoietic CD34+ cells as well as in 20q− cell lines restricted erythroid differentiation. Furthermore, L3MBTL1 levels decrease during hemin-induced erythroid differentiation or erythropoietin exposure, suggesting a specific role for L3MBTL1 down-regulation in enforcing cell fate decisions toward the erythroid lineage. Indeed, L3MBTL1 knockdown enhanced the sensitivity of hematopoietic stem/progenitor cells to erythropoietin (Epo), with increased Epo-induced phosphorylation of STAT5, AKT, and MAPK as well as detectable phosphorylation in the absence of Epo. Our data suggest that haploinsufficiency of L3MBTL1 contributes to some (20q−) myeloproliferative neoplasms, especially polycythemia vera, by promoting erythroid differentiation.

Post-transcriptional regulation in hematopoiesis: RNA binding proteins take control

2019 ◽  
Vol 97 (1) ◽  
pp. 10-20 ◽  
Author(s):  
Laura P.M.H. de Rooij ◽  
Derek C.H. Chan ◽  
Ava Keyvani Chahi ◽  
Kristin J. Hope
Keyword(s):  
Transcriptional Regulation ◽  
Stem Cell ◽  
Cell Fate ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Control Of Gene Expression ◽  
Hematopoietic Stem ◽  
Cell Fate Decisions ◽  
Post Transcriptional Regulation

Normal hematopoiesis is sustained through a carefully orchestrated balance between hematopoietic stem cell (HSC) self-renewal and differentiation. The functional importance of this axis is underscored by the severity of disease phenotypes initiated by abnormal HSC function, including myelodysplastic syndromes and hematopoietic malignancies. Major advances in the understanding of transcriptional regulation of primitive hematopoietic cells have been achieved; however, the post-transcriptional regulatory layer that may impinge on their behavior remains underexplored by comparison. Key players at this level include RNA-binding proteins (RBPs), which execute precise and highly coordinated control of gene expression through modulation of RNA properties that include its splicing, polyadenylation, localization, degradation, or translation. With the recent identification of RBPs having essential roles in regulating proliferation and cell fate decisions in other systems, there has been an increasing appreciation of the importance of post-transcriptional control at the stem cell level. Here we discuss our current understanding of RBP-driven post-transcriptional regulation in HSCs, its implications for normal, perturbed, and malignant hematopoiesis, and the most recent technological innovations aimed at RBP–RNA network characterization at the systems level. Emerging evidence highlights RBP-driven control as an underappreciated feature of primitive hematopoiesis, the greater understanding of which has important clinical implications.

scholarly journals Maximal STAT5-Induced Proliferation and Self-Renewal at Intermediate STAT5 Activity Levels

2008 ◽  
Vol 28 (21) ◽  
pp. 6668-6680 ◽  
Author(s):  
Albertus T. J. Wierenga ◽  
Edo Vellenga ◽  
Jan Jacob Schuringa
Keyword(s):  
Gene Expression ◽  
Cell Fate ◽  
Target Genes ◽  
Expression Patterns ◽  
Activity Levels ◽  
Dependent Manner ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Cell Fate Decisions

ABSTRACT The level of transcription factor activity critically regulates cell fate decisions, such as hematopoietic stem cell (HSC) self-renewal and differentiation. We introduced STAT5A transcriptional activity into human HSCs/progenitor cells in a dose-dependent manner by overexpression of a tamoxifen-inducible STAT5A(1*6)-estrogen receptor fusion protein. Induction of STAT5A activity in CD34+ cells resulted in impaired myelopoiesis and induction of erythropoiesis, which was most pronounced at the highest STAT5A transactivation levels. In contrast, intermediate STAT5A activity levels resulted in the most pronounced proliferative advantage of CD34+ cells. This coincided with increased cobblestone area-forming cell and long-term-culture-initiating cell frequencies, which were predominantly elevated at intermediate STAT5A activity levels but not at high STAT5A levels. Self-renewal of progenitors was addressed by serial replating of CFU, and only progenitors containing intermediate STAT5A activity levels contained self-renewal capacity. By extensive gene expression profiling we could identify gene expression patterns of STAT5 target genes that predominantly associated with a self-renewal and long-term expansion phenotype versus those that identified a predominant differentiation phenotype.

scholarly journals Dynamic epigenetic enhancer signatures reveal key transcription factors associated with monocytic differentiation states

Blood ◽  
2012 ◽  
Vol 119 (24) ◽  
pp. e161-e171 ◽  
Author(s):  
Thu-Hang Pham ◽  
Christopher Benner ◽  
Monika Lichtinger ◽  
Lucia Schwarzfischer ◽  
Yuhui Hu ◽  
...  
Keyword(s):  
Transcription Factors ◽  
De Novo ◽  
Histone H3 ◽  
Human Macrophage ◽  
Cell Type ◽  
Monocytic Differentiation ◽  
Hematopoietic Stem ◽  
Chip Sequencing ◽  
Monocytes And Macrophages ◽  
Cell Type Specific

Abstract Cellular differentiation is orchestrated by lineage-specific transcription factors and associated with cell type–specific epigenetic signatures. In the present study, we used stage-specific, epigenetic “fingerprints” to deduce key transcriptional regulators of the human monocytic differentiation process. We globally mapped the distribution of epigenetic enhancer marks (histone H3 lysine 4 monomethylation, histone H3 lysine 27 acetylation, and the histone variant H2AZ), describe general properties of marked regions, and show that cell type–specific epigenetic “fingerprints” are correlated with specific, de novo–derived motif signatures at all of the differentiation stages studied (ie, hematopoietic stem cells, monocytes, and macrophages). We validated the novel, de novo–derived, macrophage-specific enhancer signature, which included ETS, CEBP, bZIP, EGR, E-Box and NF-κB motifs, by ChIP sequencing for a subset of motif corresponding transcription factors (PU.1, C/EBPβ, and EGR2), confirming their association with differentiation-associated epigenetic changes. We describe herein the dynamic enhancer landscape of human macrophage differentiation, highlight the power of genome-wide epigenetic profiling studies to reveal novel functional insights, and provide a unique resource for macrophage biologists.

Sign in / Sign up

Export Citation Format

Share Document