Down-regulation of the forkhead transcription factor Foxp1 is required for monocyte differentiation and macrophage function

Shi, Chun; Sakuma, Masashi; Mooroka, Toshifumi; Liscoe, Alison; Gao, Hanyu; Croce, Kevin; Sharma, Arjun; Kaplan, David R.; Greaves, David R.; Wang, Yunmei; Simon, Daniel I.

doi:10.1182/blood-2008-01-137018

Cited by 112 publications

(113 citation statements)

References 48 publications

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“…Accordingly, we observed downregulation of the differentiated VSMC marker, SMTN, in AAs, and organelle homeostasis and secretory genes were found associated with DM-CGIs (29). As for inflammation, we observed down-regulation of FOXP1, a forkhead family TF shown to inhibit macrophage activation, and up-regulation of the AGE receptor ligand, S100B (30,31). Relatively few genes involved in chromatin structure regulation were associated with DM-CGIs and their role in atherogenesis is poorly understood.…”

Section: Discussionmentioning

confidence: 69%

Extensive demethylation of normally hypermethylated CpG islands occurs in human atherosclerotic arteries

Castillo-Díaz

Garay-Sevilla²,

Hernández-González³

et al. 2010

Int J Mol Med

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Abstract. Global DNA hypomethylation potentially leading to pro-atherogenic gene expression occurs in atherosclerotic lesions. However, limited information is available on the genomic location of hypomethylated sequences. We present a microarray-based survey of the methylation status of CpG islands (CGIs) in 45 human atherosclerotic arteries and 16 controls. Data from 10,367 CGIs revealed that a subset (151 or 1.4%) of these was hypermethylated in control arteries. The vast majority (142 or 94%) of this CGI subset was found to be unmethylated or partially methylated in atherosclerotic tissue, while only 17 of the normally unmethylated CGIs were hypermethylated in the diseased tissue. The most common functional classes among annotated genes adjacent to or containing differentially methylated CGIs, were transcription (23%) and signalling factors (16%). The former included HOX members, PROX1, NOTCH1 and FOXP1, which are known to regulate key steps of atherogenesis. Expression analysis revealed differential expression of all CGI-associated genes analysed. Sequence analysis identified novel DNA motifs with regulatory potential, associated with differentially methylated CGIs. This study is the first large-scale analysis of DNA methylation in atherosclerosis. Our data suggest that aberrant DNA methylation in atherosclerosis affects the transcription of critical regulatory genes for the induction of a pro-atherogenic cellular phenotype.

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Section: Discussionmentioning

confidence: 69%

Extensive demethylation of normally hypermethylated CpG islands occurs in human atherosclerotic arteries

Castillo-Díaz

Garay-Sevilla²,

Hernández-González³

et al. 2010

Int J Mol Med

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“…33,34 It also inhibits differentiation of monocytes to macrophages. 35 Whereas FOXP1 contribution to HSPC expansion was not foreseen, other forkhead factors, namely FOXOs, are well-known critical regulators of hematopoietic stem cell quiescence and inhibit cell cycle progression. 36,37 They moreover display antileukemic activities.…”

Section: Discussionmentioning

confidence: 99%

PUMILIO/FOXP1 signaling drives expansion of hematopoietic stem/progenitor and leukemia cells

Naudin

Hattabi

Michelet

et al. 2017

Blood

103

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Key Points• The RNA regulators PUMILIO sustain HSPC and acute myeloid leukemia cell growth by upregulating FOXP1 expression through direct binding to 2 FOXP1-39UTR PUMILIO-binding elements.• FOXP1 mediates PUMILIO growth-promoting activities by repressing expression of p21 CIP1 and p27 KIP1 cell cycle inhibitors.RNA-binding proteins (RBPs) have emerged as important regulators of invertebrate adult stem cells, but their activities remain poorly appreciated in mammals. Using a short hairpin RNA strategy, we demonstrate here that the 2 mammalian RBPs, PUMILIO (PUM)1 and PUM2, members of the PUF family of posttranscriptional regulators, are essential for hematopoietic stem/progenitor cell (HSPC) proliferation and survival in vitro and in vivo upon reconstitution assays. Moreover, we found that PUM1/2 sustain myeloid leukemic cell growth. Through a proteomic approach, we identified the FOXP1 transcription factor as a new target of PUM1/2. Contrary to its canonical repressive activity, PUM1/2 rather promote FOXP1 expression by a direct binding to 2 canonical PUM responsive elements present in the FOXP1-39 untranslated region (UTR). Expression of FOXP1 strongly correlates with PUM1 and PUM2 levels in primary HSPCs and myeloid leukemia cells. We demonstrate that FOXP1 by itself supports HSPC and leukemic cell growth, thus mimicking PUM activities. Mechanistically, FOXP1 represses the expression of the p212CIP1 and p27 2KIP1 cell cycle inhibitors. Enforced FOXP1 expression reverses shPUM antiproliferative and proapoptotic activities. Altogether, our results reveal a novel regulatory pathway, underscoring a previously unknown and interconnected key role of PUM1/2 and FOXP1 in regulating normal HSPC and leukemic cell growth. (Blood. 2017;129(18):2493-2506

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“…The 2.9-kb human CD68 promoter and 83-bp first intron expression cassette has been used to direct expression of a range of different transgenes at a high level in macrophages in vivo, including SR-A, 34 interleukin-10, 28 PGC1 b, 35 matrix metallopeptidase-9, 36 FcgIIb, 37 Fox-P1, 38 acyloxyacyl hydrolase, 39 peroxisome proliferatoractivated receptor g, 40 and hPOP3. 41 In previous work, we used chromatin precipitation experiments to show that the ETS transcription factor family members PU.1, Elf-1, and Fli-1 are bound to the CD68 proximal promoter in myeloid THP-1 cells, but these transcription factors are not bound in primary B-lymphocytes because of interactions with IRF-4.…”

Section: Discussionmentioning

confidence: 99%

Human CD68 promoter GFP transgenic mice allow analysis of monocyte to macrophage differentiation in vivo

Iqbal

McNeill

Kapellos

et al. 2014

Blood

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• CD68-GFP reporter mice show GFP transgene expression in both monocytes and tissue resident macrophage populations.• Adoptively transferred CD68-GFP monocytes maintain GFP expression after recruitment in an ongoing inflammatory response.The recruitment of monocytes and their differentiation into macrophages at sites of inflammation are key events in determining the outcome of the inflammatory response and initiating the return to tissue homeostasis. To study monocyte trafficking and macrophage differentiation in vivo, we have generated a novel transgenic reporter mouse expressing a green fluorescent protein (GFP) under the control of the human CD68 promoter. CD68-GFP mice express high levels of GFP in both monocyte and embryoderived tissue resident macrophages in adult animals. The human CD68 promoter drives GFP expression in all CD115 1 monocytes of adult blood, spleen, and bone marrow; we took advantage of this to directly compare the trafficking of bone marrow-derived CD68-GFP monocytes to that of CX 3 CR1 GFP monocytes in vivo using a sterile zymosan peritonitis model. Unlike CX 3 CR1 GFP monocytes, which downregulate GFP expression on differentiation into macrophages in this model, CD68-GFP monocytes retain high-level GFP expression for 72 hours after differentiation into macrophages, allowing continued cell tracking during resolution of inflammation. In summary, this novel CD68-GFP transgenic reporter mouse line represents a powerful resource for analyzing monocyte mobilization and monocyte trafficking as well as studying the fate of recruited monocytes in models of acute and chronic inflammation. (Blood. 2014;124(15):e33-e44)

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Down-regulation of the forkhead transcription factor Foxp1 is required for monocyte differentiation and macrophage function

Cited by 112 publications

References 48 publications

Extensive demethylation of normally hypermethylated CpG islands occurs in human atherosclerotic arteries

Extensive demethylation of normally hypermethylated CpG islands occurs in human atherosclerotic arteries

PUMILIO/FOXP1 signaling drives expansion of hematopoietic stem/progenitor and leukemia cells

Human CD68 promoter GFP transgenic mice allow analysis of monocyte to macrophage differentiation in vivo

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