The Hedgehog Regulated Transcription Factor and Tumor Suppressor, Gli3, Regulates Hematopoietic Stem Cell Number, Self-Renewal and Differentiation

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2381-2381
Author(s):  
Parvesh Chaudhry ◽  
Mohan Singh ◽  
Amy R McManus ◽  
Aparna Jorapur ◽  
Stephen James Capone ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Tumor Suppressor ◽  
Hedgehog Signaling ◽  
Fine Tuning ◽  
Myeloid Differentiation ◽  
Self Renewal ◽  
Hematopoietic System ◽  
Hh Signaling

Abstract The Hedgehog (Hh) signaling pathway plays a critical role in embryonic development and adult tissue homeostasis and has emerged as an important therapeutic target in many cancers, including leukemia and myeloproliferative diseases. Our mechanistic understanding of Hh pathway signaling and regulation comes primarily from developmental studies in neural and limb development. Studies of Hedgehog signaling in the hematopoietic system have produced contradictory results, and no clear consensus regarding Hh signaling in normal hematopoiesis is available to inform the role of Hedgehog signaling in hematologic malignancies. In our work we have focused on understanding the downstream effectors of Hedgehog signaling, the Gli transcription factors. The three Gli proteins, Gli1, Gli2 and Gli3 have both transcriptional activator and repressor functions, which allow for regulation and fine-tuning of Hedgehog pathway output. Previous studies from our group have revealed that Gli1null HSCs had no defects in self-renewal, however myeloid differentiation and stress hematopoiesis were severely impaired (Merchant, et al., Blood 2010). In normal tissues, Hh pathway activation via Ptch/Smo causes an increase in the downstream activating transcription factor GLI1 and a decrease in the transcriptional repressor Gli3R. Our recent studies demonstrated that GLI3R has a tumor suppressor role in human acute myeloid leukemia by directly repressing AKT expression (Chaudhry et al., AACR Annual Meeting 2015). To date nothing is known about the role of Gli3 in normal hematopoiesis. In the present study, we crossed Vav-Cre transgenic mice to Gli3fl/fl mice to generate mice with a conditional loss of Gli3 (Gli3null) in the hematopoietic system. HSC self-renewal was analyzed by serial transplant. In comparison to HSCs from Gli3 wild type (Gli3WT) mice bone marrow (BM), HSCs from Gli3null BM showed decreased long-term engraftment and self-renewal. In addition, quantification of long-term HSC (LT-HSC, CD34neg Flt3neg KSL), short-term HSC (ST-HSC, CD34+ Flt3neg KSL), and multi-potent progenitor (MPP, CD34+ Flt3+ KSL) revealed that the frequency of LT-HSCs in Gli3null BM (0.004-0.007%) was lower compared to Gli3 WT BM (0.008-0.02%). In mice transplanted with Gli3null BM, myeloid expansion was observed with a block in T and B cell lineage differentiation. Analysis of the c-Kit+ Sca1neg Linneg (KL) myeloid progenitor compartment revealed a two-fold increase in the FcRγhigh CD34+ KL granulocyte-monocyte progenitors (GMPs) in Gli3null BM, suggesting an expansion of granulocytic compartment. Since Gli3R is a key negative regulator of Gli1, these are consistent with decrease in GMP and myeloid differentiation previously seen in Gli1null mice. In summary, our studies reveal a previously unknown function for Gli3 in regulating HSCs and myeloid differentiation, and help to elucidate the complex regulation of Hh signaling in the hematopoietic system. Disclosures No relevant conflicts of interest to declare.

ETO2 Controls Hematopoietic Stem Cell Expansion.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 396-396
Author(s):  
Stephane Barakat ◽  
Julie Lambert ◽  
Guy Sauvageau ◽  
Trang Hoang
Keyword(s):  
Stem Cells ◽  
Transcription Factor ◽  
Stem Cell ◽  
Hematopoietic Stem Cells ◽  
Short Term ◽  
Self Renewal ◽  
Hematopoietic Stem

Abstract Abstract 396 Hematopoietic stem cells that provide short term reconstitution (ST-HSCs) as well as hematopoietic progenitors expand from a small population of long term hematopoietic stem cells (LT-HSCs) that are mostly dormant cells. The mechanisms underlying this expansion remain to be clarified. SCL (stem cell leukemia), is a bHLH transcription factor that controls HSC quiescence and long term competence. Using a proteomics approach to identify components of the SCL complex in erythroid cells, we and others recently showed that the ETO2 co-repressor limits the activity of the SCL complex via direct interaction with the E2A transcription factor. ETO2/CBF2T3 is highly homologous to ETO/CBFA2T1 and both are translocation partners for AML1. We took several approaches to identify ETO2 function in HSCs. We initially found by Q-PCR that ETO2 is highly expressed in populations of cells enriched in short-term HSC (CD34+Flt3-Kit+Sca+Lin-) and lympho-myeloid progenitors (CD34+Flt3+Kit+Sca+Lin-) and at lower levels in LT-HSCs (CD34-Kit+Sca+Lin- or CD150+CD48-Kit+Sca+Lin-). Next, the role of ETO2 was studied by overexpression or downregulation combined with transplantation in mice. Ectopic ETO2 expression induces a 100 fold expansion of LT-HSCs in vivo in transplanted mice associated with differentiation blockade in all lineages, suggesting that ETO2 overexpression overcomes the mechanisms that limit HSC expansion in vivo. We are currently testing the role of the NHR1 domain of ETO2 in this expansion. Conversely, shRNAs directed against ETO2 knock down ET02 levels in Kit+Sca+Lin- cells, causing a ten-fold decrease in this population after transplantation, associated with reduced short-term reconstitution in mice. Finally, proliferation assays using Hoechst and CFSE indicate that ETO2 downregulation affects cell division (CFSE) and leads to an accumulation of Kit+Sca+Lin-cells in G0/G1 state (Hoescht). In conclusion, we show that ETO2 is highly expressed in ST-HSCs and lymphoid progenitors, and controls their expansion by regulating cell cycle entry at the G1-S checkpoint. In addition, ETO2 overexpression converts the self-renewal of maintenance into self-renewal of expansion in LT-HSCs. Disclosures: No relevant conflicts of interest to declare.

scholarly journals MAPK15 Controls Hedgehog Signaling in Medulloblastoma Cells by Regulating Primary Ciliogenesis

Cancers ◽  
2021 ◽  
Vol 13 (19) ◽  
pp. 4903
Author(s):  
Silvia Pietrobono ◽  
Lorenzo Franci ◽  
Francesco Imperatore ◽  
Cristina Zanini ◽  
Barbara Stecca ◽  
...  
Keyword(s):  
Hedgehog Signaling ◽  
In Vitro Model ◽  
Cellular Transformation ◽  
Genetic Alterations ◽  
Self Renewal ◽  
Promising Target ◽  
Hh Signaling ◽  
Vitro Model

In medulloblastomas, genetic alterations resulting in over-activation and/or deregulation of proteins involved in Hedgehog (HH) signaling lead to cellular transformation, which can be prevented by inhibition of primary ciliogenesis. Here, we investigated the role of MAPK15 in HH signaling and, in turn, in HH-mediated cellular transformation. We first demonstrated, in NIH3T3 mouse fibroblasts, the ability of this kinase of controlling primary ciliogenesis and canonical HH signaling. Next, we took advantage of transformed human medulloblastoma cells belonging to the SHH-driven subtype, i.e., DAOY and ONS-76 cells, to ascertain the role for MAPK15 in HH-mediated cellular transformation. Specifically, medullo-spheres derived from these cells, an established in vitro model for evaluating progression and malignancy of putative tumor-initiating medulloblastoma cells, were used to demonstrate that MAPK15 regulates self-renewal of these cancer stem cell-like cells. Interestingly, by using the HH-related oncogenes SMO-M2 and GLI2-DN, we provided evidences that disruption of MAPK15 signaling inhibits oncogenic HH overactivation in a specific cilia-dependent fashion. Ultimately, we show that pharmacological inhibition of MAPK15 prevents cell proliferation of SHH-driven medulloblastoma cells, overall suggesting that oncogenic HH signaling can be counteracted by targeting the ciliary gene MAPK15, which could therefore be considered a promising target for innovative “smart” therapies in medulloblastomas.

scholarly journals BRN2 is a non-canonical melanoma tumor-suppressor

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Michael Hamm ◽  
Pierre Sohier ◽  
Valérie Petit ◽  
Jérémy H. Raymond ◽  
Véronique Delmas ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Tumor Suppressor ◽  
The Other ◽  
Pi3k Signaling ◽  
Melanoma Tumor ◽  
Temporal Regulation ◽  
Metastatic Colonization ◽  
Pou Domain

AbstractWhile the major drivers of melanoma initiation, including activation of NRAS/BRAF and loss of PTEN or CDKN2A, have been identified, the role of key transcription factors that impose altered transcriptional states in response to deregulated signaling is not well understood. The POU domain transcription factor BRN2 is a key regulator of melanoma invasion, yet its role in melanoma initiation remains unknown. Here, in a BrafV600EPtenF/+ context, we show that BRN2 haplo-insufficiency promotes melanoma initiation and metastasis. However, metastatic colonization is less efficient in the absence of Brn2. Mechanistically, BRN2 directly induces PTEN expression and in consequence represses PI3K signaling. Moreover, MITF, a BRN2 target, represses PTEN transcription. Collectively, our results suggest that on a PTEN heterozygous background somatic deletion of one BRN2 allele and temporal regulation of the other allele elicits melanoma initiation and progression.

Role of knot (kn) in Wing Patterning in Drosophila

Genetics ◽  
1997 ◽  
Vol 147 (3) ◽  
pp. 1203-1212 ◽  
Author(s):  
Katerina Nestoras ◽  
Helena Lee ◽  
Jym Mohler
Keyword(s):  
Hedgehog Signaling ◽  
Imaginal Disc ◽  
Hedgehog Signaling Pathway ◽  
Posterior Compartment ◽  
Drosophila Wing ◽  
Compartment Boundary ◽  
Hh Signaling ◽  
Embryonic Segmentation ◽  
Anterior Posterior

We have undertaken a genetic analysis of new strong alleles of knot (kn). The original kn1 mutation causes an alteration of wing patterning similar to that associated with mutations of fused (fu), an apparent fusion of veins 3 and 4 in the wing. However, unlike fu, strong kn mutations do not affect embryonic segmentation and indicate that kn is not a component of a general Hh (Hedgehog)-signaling pathway. Instead we find that kn has a specific role in those cells of the wing imaginal disc that are subject to ptc-mediated Hh-signaling. Our results suggest a model for patterning the medial portion of the Drosophila wing, whereby the separation of veins 3 and 4 is maintained by kn activation in the intervening region in response to Hh-signaling across the adjacent anterior-posterior compartment boundary.

scholarly journals Protein Carbonylation in Patients with Myelodysplastic Syndrome: An Opportunity for Deferasirox Therapy

Antioxidants ◽  
2019 ◽  
Vol 8 (11) ◽  
pp. 508 ◽  
Author(s):  
Alba Rodríguez-García ◽  
María Luz Morales ◽  
Vanesa Garrido-García ◽  
Irene García-Baquero ◽  
Alejandra Leivas ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Target Gene ◽  
Iron Chelator ◽  
Protein Carbonylation ◽  
Fine Tuning ◽  
Self Renewal ◽  
Proliferation And Differentiation ◽  
P53 Target Gene ◽  
And Control

Control of oxidative stress in the bone marrow (BM) is key for maintaining the interplay between self-renewal, proliferation, and differentiation of hematopoietic cells. Breakdown of this regulation can lead to diseases characterized by BM failure such as the myelodysplastic syndromes (MDS). To better understand the role of oxidative stress in MDS development, we compared protein carbonylation as an indicator of oxidative stress in the BM of patients with MDS and control subjects, and also patients with MDS under treatment with the iron chelator deferasirox (DFX). As expected, differences in the pattern of protein carbonylation were observed in BM samples between MDS patients and controls, with an increase in protein carbonylation in the former. Strikingly, patients under DFX treatment had lower levels of protein carbonylation in BM with respect to untreated patients. Proteomic analysis identified four proteins with high carbonylation levels in MDS BM cells. Finally, as oxidative stress-related signaling pathways can modulate the cell cycle through p53, we analyzed the expression of the p53 target gene p21 in BM cells, finding that it was significantly upregulated in patients with MDS and was significantly downregulated after DFX treatment. Overall, our results suggest that the fine-tuning of oxidative stress levels in the BM of patients with MDS might control malignant progression.

scholarly journals Role of the Hedgehog Signaling Pathway in Regulating the Behavior of Germline Stem Cells

2017 ◽  
Vol 2017 ◽  
pp. 1-9 ◽  
Author(s):  
Shiqin Li ◽  
Meng Wang ◽  
Yanghui Chen ◽  
Wei Wang ◽  
Junying Wu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Signaling Pathway ◽  
Hedgehog Signaling ◽  
Adult Stem Cells ◽  
Reproductive Function ◽  
Future Research ◽  
Germline Stem Cells ◽  
Proliferation And Differentiation ◽  
Hh Signaling

Germline stem cells (GSCs) are adult stem cells that are responsible for the production of gametes and include spermatogonial stem cells (SSCs) and ovarian germline stem cells (OGSCs). GSCs are located in a specialized microenvironment in the gonads called the niche. Many recent studies have demonstrated that multiple signals in the niche jointly regulate the proliferation and differentiation of GSCs, which is of significance for reproductive function. Previous studies have demonstrated that the hedgehog (Hh) signaling pathway participates in the proliferation and differentiation of various stem cells, including GSCs in Drosophila and male mammals. Furthermore, the discovery of mammalian OGSCs challenged the traditional opinion that the number of primary follicles is fixed in postnatal mammals, which is of significance for the reproductive ability of female mammals and the treatment of diseases related to germ cells. Meanwhile, it still remains to be determined whether the Hh signaling pathway participates in the regulation of the behavior of OGSCs. Herein, we review the current research on the role of the Hh signaling pathway in mediating the behavior of GSCs. In addition, some suggestions for future research are proposed.

Absence of the Rho GTPase Activating Protein p190-B Enhances Long Term Hematopoietic Stem Cell Engraftment

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 614-614 ◽  
Author(s):  
Haiming Xu ◽  
Hartmut Geiger ◽  
Kathleen Szczur ◽  
Deidra Deira ◽  
Yi Zheng ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Ex Vivo ◽  
Gtpase Activating Protein ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Proliferation And Differentiation ◽  
Serial Transplantation

Abstract Hematopoietic stem cell (HSC) engraftment is a multistep process involving HSC homing to bone marrow (BM), self-renewal, proliferation and differentiation to mature blood cells. However, the molecular regulation of HSC engraftment is still poorly defined. Small Rho GTPases are critical regulator of cell migration, proliferation and differentiation in multiple cell types. While their role in HSC functions has begun to be understood, the role of their regulator in vivo has been understudied. P190-B GTPase Activating Protein (GAP), a negative regulator of Rho activity, has been implicated in regulating cell size and adipogenesis-myogenesis cell fate determination during fetal development (Sordella, Dev Cell, 2002; Cell 2003). Here, we investigated the role of p190-B in HSC/P engraftment. Since mice lacking p190-B die before birth, serial competitive repopulation assay was performed using fetal liver (FL) tissues from day E14.5 WT and p190-B−/− embryos. WT and p190-B−/− FL cells exhibited similar levels of engraftment in primary recipients. However, the level of contribution of p190-B−/− cells to peripheral blood and bone marrow was maintained between the primary and secondary recipients and still easily detectable in tertiary recipients, while the level of contribution of FL WT cells dramatically decreased with successive serial transplantion and was barely detectable in tertiary recipients. The contribution to T cell, B cell and myeloid cell reconstitution was similar between the genotypes. A pool of HSC was maintained in serially transplanted p190-B−/− animals, since LinnegScaposKitpos (LSK) cells were still present in the BM of p190-B−/− secondary engrafted mice while this population disappeared in WT controls. Importantly, this enhanced long term engraftment was due to a difference in the functional capacity of p190-B−/− HSC compared to WT HSC since highly enriched p190-B−/− HSC (LSK) demonstrated similar enhanced serial transplantation potential. Because previous studies have suggested that the loss of long term function of HSC during serial transplantation can depend, at least in part, on the upregulation of the cyclin dependent kinase inhibitor p16Ink4a (Ito et al, Nat Med 2006), the expression of p16Ink4a was examined during serial transplantation. While expression of p16Ink4a increased in WT HSC in primary and secondary recipients, p16Ink4a remained low in p190-B−/− HSC, which indicated that p190-B-deficiency represses the upregulation of p16Ink4a in HSC in primary and secondary transplant recipients. This provides a possible mechanism of p190-B-mediated HSC functions. We next examined whether p190-B-deficiency may preserve the repopulating capacity of HSC/P during ex vivo cytokine-induced culture. While freshly isolated LSK cells from WT and p190-B−/− mice exhibited comparable intrinsic clonogenic capacity, the frequency of colony-forming unit after 7 days in culture was 2 fold-higher in p190-B−/− compared with WT cultures, resulting in a net CFU expansion. Furthermore, competitive repopulation assays showed significantly higher repopulating activity in mice that received p190-B−/− cultured cells compared with WT cells equivalent to a 4.4-fold increase in the estimated frequency of repopulating units. Interestingly, p190-deficiency did not alter cell cycling rate or survival both in vivo and in vitro. Therefore, p190-B-deficiency maintains key HSC functions either in vivo or in ex vivo culture without altering cycling rate and survival of these cells. These findings define p190-B as a critical regulator of HSC functions regulating self renewal activity while maintaining a balance between proliferation and differentiation.

Functional Role of BAALC In Leukemogenesis

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4194-4194
Author(s):  
Tobias Berg ◽  
Michael Heuser ◽  
Florian Kuchenbauer ◽  
Gyeongsin Park ◽  
Stephen Fung ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Cells ◽  
Myeloid Differentiation ◽  
Self Renewal ◽  
Murine Bone Marrow ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Marrow Cells

Abstract Abstract 4194 Cytogenetically normal acute myeloid leukemia (CN-AML) patients with high BAALC or MN1 expression have a poor prognosis. Whereas the oncogenic function of MN1 is well established, the functional role of BAALC in hematopoiesis is not known. We therefore compared the expression of BAALC and MN1 in 140 CN-AML patients by quantitative PCR. To further assess the impact of BAALC on leukemogenesis we used retroviral gene transfer into primary murine bone marrow cells and cells immortalized with NUP98-HOXD13 (ND13) and HOXA9. Transduced cells were assessed in vitro by colony forming assays and for their sensitivity to treatment with all-trans retinoic acid (ATRA). They were also evaluated by in vivo transplantation into lethally-irradiated mice. In the 140 CN-AML patients analyzed, the expression of BAALC and MN1 was highly correlated (R=0.71). Retroviral overexpression of MN1 or BAALC in the Hox gene-immortalized bone marrow cells did not cause upregulation of the other gene, suggesting that these genes do not regulate each other. In murine bone marrow cells BAALC did not immortalize the cells in vitro as assessed by serial replating of transduced cells in methylcellulose assays. Transplantation of transduced cells resulted in negligible engraftment of approximately 1 percent at 4 weeks after transplantation. However, co-transduction of BAALC into NUP98-HOXD13 cells (which are very sensitive to the treatment with all-trans retinoic acid) increased the 50 percent inhibitory concentration (IC50) of ATRA by 4.3-fold, suggesting a negative impact of BAALC on myeloid differentiation. We next evaluated whether the differentiation inhibiting effects of BAALC may cooperate with the self renewal-promoting effects of HOXA9 to induce leukemia in mice. Mice receiving transplants of murine bone marrow cells transduced with BAALC and HOXA9 developed myeloid leukemias with a median latency of 139.5 days that were characterized by leukocytosis, massively enlarged spleens (up to 1.02 g), anemia and thrombocytopenia. Infiltrations of myeloid cells were also found in liver, spleen, and kidney. The disease was transplantable into secondary animals. By Southern blot analysis we found one to two BAALC viral integrations per mouse, suggesting that clonal disease had developed from BAALC-transduced cells. We demonstrate for the first time that BAALC blocks myeloid differentiation and promotes leukemogenesis when combined with the self-renewal promoting oncogene HOXA9. Due to its prognostic and functional effects BAALC may become a valuable therapeutic target in leukemia patients. Disclosures: No relevant conflicts of interest to declare.

Regulation of Fetal Liver Hematopoietic Stem Cell Function By the Dpy30 Subunit of Set1/Mll Complexes

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5055-5055
Author(s):  
Zhenhua Yang ◽  
Hao Jiang
Keyword(s):  
Stem Cells ◽  
Cell Function ◽  
Fetal Liver ◽  
H3k4 Methylation ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Term Maintenance ◽  
Time Point

Abstract While stem cells undergo phenotypic and functional changes in development, the capacity of self-renewal and differentiation remains the defining property of stem cells throughout life, indicating certain fundamental regulatory mechanisms underlying these cardinal features of stem cells. A profound transition occurs to hematopoietic stem cells (HSCs) from embryonic to adult hematopoiesis, resulting in pronounced distinctions between fetal liver (FL) and adult bone marrow (BM) HSCs in many aspects. While many studies have documented a different dependence of fetal versus adult HSC function on epigenetic modulators including several Polycomb proteins, little is known about if Trithorax proteins play a similar or different role in fetal versus adult HSC function. More specifically, despite being a prominent epigenetic mark associated with gene activation, the role of H3K4 methylation (an activity of many Trithorax proteins) in different stages of HSCs remains unclear. As the major H3K4 methylases in mammals, the Set1/Mll family complexes play important roles in development and stem cell function, and are extensively associated with diseases including blood cancers. We have previously established a direct role of Dpy30, a core subunit in all Set1/Mll complexes, in facilitating genome-wide H3K4 methylation, and this allows an effective interrogation of the functional role of efficient H3K4 methylation through genetic studies of Dpy30. While dispensable for the self-renewal of embryonic stem cells (ESCs), Dpy30 is crucial for efficient differentiation of ESCs by facilitating the induction of many bivalently marked developmental genes (Jiang et al., Cell, 2011). We have then generated a Dpy30 conditional knockout mouse, and shown that Dpy30 plays a crucial role in the long term maintenance and differentiation of adult BM HSCs, and preferentially controls H3K4 methylation and expression of many hematopoiesis-associated genes in adult BM cells (Yang et al., J Exp Med, accepted). However, the role of Dpy30 and efficient H3K4 methylation in fetal HSCs is still unknown. To study the role of efficient H3K4 methylation in fetal HSCs, we deleted Dpy30 in fetal hematopoietic cells using VavCre line. VavCre; Dpy30F/- fetuses are anemic at E14.5 and E15.5, with reduced H3K4 methylation but significantly increased numbers of FL HSCs. However, these FL HSCs were functionally defective in colony formation and blood reconstitution following transplantation. Proliferation of the progenitors, but not HSCs, was significantly (but modestly) reduced. These results suggest a role of Dpy30 in differentiation of HSCs and progenitor proliferation in FL. We also competitively transplanted Mx1Cre; Dpy30F/- FL and deleted Dpy30 after stable engraftment. Our analysis at an early time point after deletion showed little effect on donor contribution to HSCs, but significant reduction of oligopotent progenitors. Analysis at a later time point after deletion, however, showed marked reduction of all hematopoietic cells including HSCs. These results support a cell-autonomous role of Dpy30 in the differentiation and long term maintenance of FL HSCs. The phenotypes of FL HSCs are largely similar to those of BM HSCs following Dpy30 loss, suggesting that Dpy30 and certain Dpy30 targets are fundamentally important in regulating HSCs regardless of the developmental stages. To identify these targets, we performed RNA-seq analyses for purified FL HSCs from VavCre; Dpy30F/- versus VavCre; Dpy30F/+ littermates. Among hundreds of genes that were significantly changed in FL HSCs, however, only a handful of genes were found to be co-downregulated in both FL and BM HSCs following Dpy30 loss, suggesting that Dpy30 may have different functional targets in different stages of HSCs. To identify Dpy30 targets fundamentally important to HSC regulation, we are now selectively investigating the function of a few common Dpy30 targets in HSCs by colony formation and potentially transplantation assays following their stable knockdown. The similar requirement of Dpy30 in both fetal and adult HSC differentiation as well as long-term maintenance underscores the fundamental importance of this epigenetic modulator in the central properties of stem cells, and studies of the common Dpy30 targets may identify new regulatory genes controlled by this modulator in fetal and adult HSC function. Disclosures No relevant conflicts of interest to declare.

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