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Negative regulation of lymphoid specification by the transcription factor Tal1

ABSTRACT: Lymphoid primed multipotent progenitors are a subset of MPPs that are undergoing specification to the lymphoid and myeloid cell fates. The transcription factors Lyl1 and E2A are both essential for the development LMPPs and can form a heterodimeric complex. We examined the consequences of E2A- or Lyl1-deficiency on development of LMPPs and on their gene expression program in comparison with wild-type LMPPs We used microarray data to examine the differences in gene expression between control, E2A-/- and Lyl1-/- CD138+ LSK cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE126148 | GEO | 2019/02/07

REPOSITORIES: GEO

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Negative regulation of lymphoid specification by the transcription factor TAL1

Project description:Lymphoid primed multipotent progenitors are a subset of MPPs that are undergoing specification to the lymphoid and myeloid cell fates. The transcription factors Lyl1 and E2A are both essential for the development LMPPs and can form a heterodimeric complex. We examined the consequences of E2A- or Lyl1-deficiency on development of LMPPs and on their gene expression program in comparison with wild-type LMPPs

2019-02-12 | GSE126402 | GEO

Lyl-1 knockout vs wildtype Lymphoid Primed Multipotent Progenitors (LMPPs)

Project description:We compared gene expression differences in Lyl-1 knockout vs wildtype LMPPs KO allele described in Pub Med ID: 21387538 LMPPS were purified as Lineage-negative, Sca-1+ c-Kit+ (LSK) and Flt3-high from both Lyl1-null and WT mice on C57Bl/6 background

2012-06-13 | E-GEOD-38681 | biostudies-arrayexpress

PU.1 is required for the developmental progression of multipotent progenitors to common lymphoid progenitors.

Project description:The transcription factor PU.1 is a central regulator of hematopoiesis, required for the normal differentiation of the myeloid and lymphoid lineages. Due to its essential role in early development and the importance of PU.1 in regulating several defining markers of lymphoid progenitors, its precise function in early lymphopoiesis has remained unclear. Using conditional mutagenesis and alternative lineage identification strategies, we demonstrate the developmental stage restricted function for PU.1 in early lymphopoiesis. PU.1 was required for efficient generation of “lymphoid primed multipotent progenitors (LMPPs)” from hematopoietic stem cells and was essential for the subsequent formation of “common lymphoid progenitors (CLPs)”. In contrast, further differentiation into the B cell lineage was independent of PU.1. The function of PU.1 was dosage sensitive as loss of one allele decreased all stages of early lymphopoiesis. PU.1 expression mirrored its functional role during lineage differentiation. PU.1 peaked at LMPPs and was maintained in CLPs, before being down regulated in committed pro-B cells. Examination of the transcriptional changes in PU.1 conditionally deficient LSK cells revealed that PU.1 activates lymphoid and dendritic cell associated genes in LMPPs, while repressing genes normally expressed in neutrophils. These data identify PU.1 as a critical regulator of lymphoid priming and the transition between LMPPs and CLPs.

2017-08-14 | GSE89642 | GEO

Gfi1 regulates survival and lineage commitment of hematopoietic precursors and prevents myeloproliferative diseases

Project description:Hematopoietic stem cells (HSCs) and lymphoid-primed multi-potential progenitors (LMPPs) are able to initiate both lymphoid and myeloid differentiation. We show here that the transcriptional repressor Gfi1 (growth factor independence 1) implements a specific gene expression program in HSCs and LMPPs that is critical for their survival and lymphoid differentiation potential. We present evidence that Gfi1 is required to maintain expression of genes involved in lymphoid development such as Flt-3, IL7R, Ebf1, Rag1, CCR9 and Notch1 and controls myeloid lineage commitment by regulating expression of genes such as Hoxa9 or M-CSFR. Gfi1 also inhibits apoptosis in HSCs by repressing pro-apoptotic genes such as Bax or Bak. As a consequence, Gfi1-/- mice show defects in self renewal, survival and both myeloid and lymphoid development of HSCs and LMPPs. Co-expression of a Bcl-2 transgene can partially restore the function of HSCs in Gfi1-/- mice, but not the defects in early lymphoid development. Of interest, Gfi1-/- x Bcl-2 transgenic mice show an accelerated expansion of myeloid cells and succumb to a fatal myeloproliferative disease resembling chronic myelomonocytic leukemia (CMML). Our data show that Gfi1 protects HSCs against apoptosis, ensures the proper development of LMPPs and plays a role in the development of myeloid leukemia. We used microarrays to detail the global gene expression changes following knockout of Gfi1 in mouse LSK cells We compared LSK cells isolated from Gfi1 knockout mice with wildtype cells to determine global gene expression changes by microarray analysis

2011-02-02 | E-GEOD-20282 | biostudies-arrayexpress

Regulation of lymphoid versus myeloid fate choice by Mef2c

Project description:Despite recent advances in the identification of lymphoid-restricted progenitors, the transcription factors essential for their generation remain to be identified. Here we describe an unexpected role for the myeloid oncogene Mef2c in multipotent progenitors (MPPs), where it is required for pan-lymphoid differentiation. Mef2c deficiency was associated with profound defects in B, T, NK cell and common lymphoid progenitor production and an enhanced myeloid output. Mef2c deficiency in MPPs leads to downregulation of several key lymphoid regulators and the upregulation of the myeloid factor C/EBPa. Our studies also show that Mef2c is a critical transcriptional target of PU.1 during lymphopoiesis. Thus, Mef2c is a crucial component of the transcriptional network that regulates lymphoid specification and cell fate choice in MPPs.

2008-11-21 | GSE13686 | GEO

Dach1 downregulation marks a lymphoid-primed progenitor in early haematopoiesis (2X96 cells)

Project description:A classical view of blood cell development is that multipotent haematopoietic stem and progenitor cells (HSPCs) become lineage-restricted at defined stages. The Lin–c-kit+Sca1+Flt3+ stage, termed lymphoid-primed multipotent progenitors (LMPPs), have lost megakaryocyte and erythroid potential but are heterogeneous in their fate. Through single cell RNA-sequencing, we identify heterogeneous expression of Dach1 and associated genes in this fraction where it co-expressed with myeloid/stem genes but inversely correlated with lymphoid genes. Through generation of Dach1-GFP reporter mice, we identify a transcriptionally and functionally unique Dach1– subpopulation within LMPPs with lymphoid potential but devoid of myeloid potential. We term these ‘lymphoid-primed progenitors’, or LPPs. These findings define the earliest branch point of lymphoid development in haematopoiesis and a means for their prospective isolation.

2019-08-27 | GSE136341 | GEO

Gfi1 regulates survival and lineage commitment of hematopoietic precursors and prevents myeloproliferative diseases

2011-02-02 | GSE20282 | GEO

A novel lymphoid-primed progenitor marked by Dach1 downregulation identified with single cell multi-omics

2019-08-23 | GSE136225 | GEO

Foetal-specific contributors to infant MLL-AF4-driven Acute Lymphoblastic Leukaemia

Project description:As MLL-rearranged infant leukaemia is known to initiate in utero, we sought to identify developemntal genes expressed in foetal cells that may aid leukaemogenesis. Bulk RNA-Seq was therefore carried out on mouse and human foetal liver blood progenitors (lymphoid-primed multipotent progenitors [LMPPs] and haematopoietic stem cells/ multipotent progenitor cells [HSC/MPPs]) and compared with the same cell types isolated from developmentally later human cord blood and mouse adult bone marrow.

2021-10-07 | GSE167234 | GEO

Common lymphoid progenitor-independent pathways of innate and T lymphocyte development

Project description:All lymphocytes are thought to develop from common lymphoid progenitors (CLPs). However, lymphoid-primed multi-potent progenitors (LMPPs) are more efficient than CLPs in differentiating into T cells and group 2 innate lymphoid cells (ILC2s). Here, we have divided LMPPs into CD127− (LMPP-s) and CD127+ (LMPP+s) subsets and compared them with Ly6D− and Ly6D+ CLPs. Adult LMPP+s differentiated into T cells and ILCs more rapidly and efficiently than other progenitors in transplantation assays. The development of T cells and ILC2s is highly active in the neonatal period. Neonatal CLPs are rare and, unlike prominent neonatal LMPP+s, do not efficiently differentiate into T cells and ILC2s. ILC2s generated in the neonatal period are long-lived and persist in adult tissues. These results suggest that some ILCs and T cells may develop from LMPP+s via CLP-independent pathways.

2016-02-17 | GSE67034 | GEO

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